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Joubert Syndrome and Related Disorders

Synonym: JSRD

, MD, PhD and , MD.

Author Information
, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland
, MD
Division of Genetics and Developmental Medicine
Department of Pediatrics
Children's Hospital and Regional Medical Center
University of Washington
Seattle, Washington

Initial Posting: ; Last Revision: April 11, 2013.

Summary

Disease characteristics. Classic Joubert syndrome is characterized by three primary findings:

  • A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS)
  • Hypotonia
  • Developmental delays

Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.

Diagnosis/testing. The diagnosis of JSRD is based on the presence of characteristic clinical features and magnetic resonance images (MRI) through the junction of the midbrain and pons (isthmus region) that resemble a molar tooth. To date biallelic mutations in one of the following 19 genes are identified in about 50% of individuals with a JSRD: NPHP1, CEP290, AHI1, TMEM67 (MKS3), RPGRIP1L, CC2D2A, ARL13B, INPP5E, OFD1, TMEM216, KIF7, TCTN1, TCTN2, TMEM237, CEP41, TMEM138, C5orf42, TMEM231, and TCTN3; the other genes in which mutation is causative are unknown. To date, no individuals with JSRD and biallelic mutations in TTC21B have been reported.

Management. Treatment of manifestations: Infants and children with abnormal breathing may require stimulatory medications (e.g., caffeine); supplemental oxygen; mechanical support; or tracheostomy in rare cases. Other interventions may include speech therapy for oromotor dysfunction; occupational and physical therapy; educational support, including special programs for the visually impaired; and feedings by gastrostomy tube. Surgery may be required for polydactyly and symptomatic ptosis and/or strabismus. Nephronophthisis, end-stage renal disease, liver failure and/or fibrosis are treated with standard approaches.

Surveillance: Annual evaluations of growth, vision, and liver and kidney function; periodic neuropsychologic and developmental testing.

Agents/circumstances to avoid: Nephrotoxic medications such as nonsteroidal anti-inflammatory drugs in those with renal impairment; hepatotoxic drugs in those with liver impairment.

Genetic counseling. JSRDs are predominantly inherited in an autosomal recessive manner. JSRD caused by mutation of OFD1 is inherited in an X-linked manner. Digenic inheritance has been reported.

For autosomal recessive inheritance: at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations have been identified in the family. For pregnancies at known increased risk for Joubert syndrome prenatal diagnosis by ultrasound examination with or without fetal MRI has been successful.

Diagnosis

Clinical Diagnosis

Diagnostic criteria for Joubert syndrome and related disorders (JSRD) continue to evolve; most authors concur that the neuroradiologic finding of the the molar tooth sign is obligatory [Valente et al 2008, Parisi 2009, Brancati et al 2010].

The diagnosis of "classic" or “pure” Joubert syndrome is based on the presence of the following three primary criteria:

  • The molar tooth sign. The MRI appearance of hypoplasia of the cerebellar vermis and accompanying brain stem abnormalities in an axial plane through the junction of the midbrain and pons (isthmus region) [Maria et al 1997, Maria et al 1999b, Quisling et al 1999]. The molar tooth sign comprises an abnormally deep interpeduncular fossa; prominent, straight, and thickened superior cerebellar peduncles; and hypoplasia of the vermis, the midline portion of the cerebellum (Figures 1A, 1B) [Maria et al 1999b].
  • Hypotonia in infancy with later development of ataxia
  • Developmental delays/intellectual disability
Figure 1

Figure

Figure 1. Molar tooth sign in Joubert syndrome
A. Axial MRI image through the cerebellum and brain stem of a normal individual showing intact cerebellar vermis (outlined by white arrows)
B. Axial MRI image through the cerebellum and brain (more...)

Additional features often identified in individuals with Joubert syndrome include:

The term “Joubert syndrome and related disorders” (JSRD) refers to those individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and other abnormalities.

In reality, a significant proportion of individuals diagnosed with classic JS in infancy or early childhood will manifest additional findings that represent a JSRD over time.

Molecular Genetic Testing

Genes. The 19 genes in which biallelic mutations are known to cause Joubert syndrome and related disorders are: NPHP1, AHI1, CEP290 (NPHP6), TMEM67 (MKS3), RPGRIP1L, CC2D2A, ARL13B, INPP5E, OFD1, TMEM216, KIF7, TCTN1, TCTN2, TMEM237, CEP41, TMEM138, C5orf42, TMEM231, and TCTN3.

To date, individuals with JSRD and a single (heterozygous) mutation only in TTC21B have been reported. The functional significance of a single mutation in TTC21B is unknown, See TTC21B, Pathogenic allelic variants.

Evidence for additional locus heterogeneity. It is likely that additional loci are involved:

  • Overall, about 50% of individuals with a JSRD have mutations identified in one of the identified genes.
  • The JSRD phenotype in many families is not linked to any of the genes identified to date.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Joubert Syndrome and Related Disorders

Gene 1Proportion of JS Attributed to Mutations in This GeneTest MethodMutations Detected 2
AHI1~7%-10% 3Sequence analysis 4, 5Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
ARL13B<1% 7Sequence analysis 4, 5Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
C5orf42Unknown 8Sequence analysis 4Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
CC2D2A~10% 9Sequence analysis 4Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
CEP41<1% 10Sequence analysis 4Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
CEP290~10% 11Sequence analysis 4Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 11
INPP5EUnknown 8Sequence analysis 4, 5Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
KIF7Unknown 8Sequence analysis 4Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
NPHP1~1%-2% 12, 13Targeted mutation analysisCommon ~290 kb deletion
Duplication/deletion analysis 6, 14Common ~290 kb deletion plus other (multi)exonic or whole-gene deletions
Sequence analysis 4Sequence variants
OFD1Rare (X-linked) 15Sequence analysis 4Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
RPGRIP1L2%-4% 16Sequence analysis 4, 5Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
TCTN1Unknown 8Sequence analysis 4Sequence variants
TCTN2Unknown 8Sequence analysis 4Sequence variants
TCTN3Unknown 8Sequence analysis 4Sequence variants
TMEM67~10% 17Sequence analysis 4, 5Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
TMEM138UnknownSequence analysis 4Sequence variants
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
TMEM216~3% 18Sequence analysis 4, 5Sequence variants
Targeted mutation analysisc.218G>T 19
Duplication/deletion analysis 6(Multi)exonic or whole-gene deletions 5
TMEM231Unknown 8Sequence analysis 4Sequence variants
TMEM237<1% 20Sequence analysis 4Sequence variants
TTC21B 21UnknownSequence analysis 4Sequence variants

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Parisi et al [2006], Valente et al [2006a]

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. No deletions or duplications involving AHI1, TMEM67, RPGRIP1L, CC2D2A, ARL13B, INPP5E, KIF7, OFD1, TMEM67, TMEM138, TMEM216, C5orf42, or CEP41 have been reported to cause Joubert syndrome or related disorders. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Cantagrel et al [2008]

8. The relative contribution of mutations in this gene to JSRD remains unknown, as a limited number of individuals with mutations have been described [Bielas et al 2009, Dafinger et al 2011, Garcia-Gonzalo et al 2011, Sang et al 2011, Srour et al 2012a, Srour et al 2012b, Thomas et al 2012].

9. Gorden et al [2008], Doherty et al [2009]. The prevalence of CC2D2A mutations in one large cohort was 16/209 or 7.7% [Bachmann-Gagescu et al 2012].

10. Only two of 720 individuals with JSRD (many of whom had been excluded for mutations in known JSRD-related genes) had mutations identified in this gene [Lee et al 2012a].

11. Sayer et al [2006], Valente et al [2006b], Valente et al [2008], Travaglini et al [2009]

12. May be higher in individuals with nephronophthisis

13. Parisi et al [2004a], Castori et al [2005], Parisi et al [2006]

14. Homozygous deletions have been associated with rare cases of JSRD. Deletion/duplication analysis alone will detect a heterozygous deletion but not a point mutation in NPHP1; this genotype is expected to be rare.

15. In one survey, 2/250 families (2/84 with only males affected) had mutations identified in OFD1 [Coene et al 2009].

16. Arts et al [2007], Delous et al [2007], Parisi [2009]

17. Baala et al [2007], Brancati et al [2009], Doherty et al [2009]

18. Fourteen of 462 (~3%) families with JSRD had mutations in TMEM216 [Valente et al 2010].

19. Founder mutation [Valente et al 2010]. See Molecular Genetics, TMEM216.

20. Only two families out of 201 individuals with JSRD and 90 individuals with Meckel syndrome (MKS)/JSRD were found to have mutations in this gene [Huang et al 2011].

21. To date, no individuals with JSRD and biallelic mutations in TTC21B have been reported. The functional significance of a single (heterozygous) mutation in TTC21B is unknown. See TTC21B, Pathogenic allelic variants.

Testing Strategy

To confirm / establish the diagnosis in a proband. Although clinical and genetic heterogeneity in the JSRDs is extensive and the clinical manifestations of retinal dystrophy, renal disease, and/or hepatic fibrosis may not be apparent until the second or third decades of life, the observation of some general genotype-phenotype associations (see Table 3) has led to a proposed algorithm for molecular genetic testing [Doherty et al 2009, Parisi 2009] (Figure 2).

Figure 2

Figure

Figure 2. Joubert syndrome and related disorders (JSRD) testing algorithm

Alternatively, clinicans may consider using a Joubert syndrome multi-gene panel that includes varying numbers of JSRD-related genes. Note: These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation(s) in any given individual with the JSRD phenotype also varies.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation(s) in the family.

Note: (1) Autosomal recessive JSRD: Carriers are heterozygotes and are not at risk of developing the disorder. (2) X-linked JSRD: Carriers are heterozygotes for an OFD1 mutation and have no known symptoms.

Prenatal diagnosis/preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Classic Joubert syndrome is characterized by the three primary findings of: a distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS), hypotonia, and developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Table 2 associates phenotypic features with genes; Table 3 associates genes with phenotypic features. Both intra- and interfamilial phenotypic variation are seen in Joubert syndrome.

Many of the clinical features of Joubert syndrome are evident in infancy [Joubert et al 1969, Boltshauser & Isler 1977]. The findings of nystagmus, oculomotor apraxia, and abnormal breathing patterns can be observed in all clinical subtypes. Most children with Joubert syndrome develop truncal ataxia and, in combination with hypotonia, exhibit delayed acquisition of gross motor milestones.

Nystagmus. Many children with Joubert syndrome demonstrate horizontal nystagmus at birth, which improves with age. Torsional and pendular rotatory nystagmus have also been observed.

Oculomotor apraxia is often identified in childhood rather than in infancy, perhaps because of under-recognition of the finding [Steinlin et al 1997]. Many children with oculomotor apraxia demonstrate head thrusting as a compensatory mechanism for their inability to initiate saccades [Hodgkins et al 2004, Khan et al 2008, Weiss et al 2009]. Visual acuity and functional vision may improve with age as a result of visual maturation, in spite of significantly aberrant eye movements at birth [M Parisi and A Weiss, personal observation].

Respiratory findings. Many children with JSRD exhibit apnea, tachypnea, or both, sometimes alternating, particularly in the neonatal period [Saraiva & Baraitser 1992, Steinlin et al 1997, Maria et al 1999a, Valente et al 2008]. Although some infants have died of apnea, episodic apnea generally improves with age and may completely disappear [Maria et al 1999b]. Children with JSRD are at increased risk for sleep apnea, including central (particularly in infancy and childhood) and obstructive (particularly in later childhood/adolescence related to tongue hypertrophy, hypotonia, and obesity) [Parisi 2009]. A survey of self-reported sleep behaviors in individuals with JSRD using a validated sleep questionnaire suggested sleep-related breathing disorders in six of the 14 individuals surveyed [Kamdar et al 2011]. Some individuals with Leber congenital amaurosis resulting from CEP290 mutations have also been found to have abnormalities in motile respiratory cilia that may predispose to respiratory symptoms including chronic rhinitis, recurrent sinusitis, and bronchitis [Papon et al 2010].

Central nervous system findings

JSRD Clinical Subtypes

See Table 2 and Table 3.

Joubert syndrome with retinal disease (JS-Ret) is characterized by a pigmentary retinopathy that may be indistinguishable from classic retinitis pigmentosa; it can occasionally be severe with neonatal onset of congenital blindness and an attenuated or extinguished electroretinogram (ERG) that resembles Leber congenital amaurosis (LCA) [Tusa & Hove 1999]. However, the retinal disease may not be progressive and is not always present in infancy or early childhood [Steinlin et al 1997]. One survey of 235 families with JSRD identified retinal dystrophy in 30% [Doherty 2009].

Joubert syndrome with renal disease (JS-Ren) has been described traditionally in two forms (nephronophthisis and cystic dysplasia); however, these now appear to be part of a continuum with the specific renal manifestation varying by stage of renal disease. Juvenile nephronophthisis, a form of chronic tubulointerstitial nephropathy often presents in the first or second decade of life with polydipsia, polyuria, urine concentrating defects, growth retardation, and/or anemia. Progression to end-stage renal disease (ESRD) occurs on average by age 13 years [Hildebrandt et al 1998]. Renal changes visible on ultrasound examination occur late in the course and consist of small, scarred kidneys with increased echogenicity and occasional cysts at the corticomedullary junction, findings consistent with cystic dysplasia (i.e., multiple variably-sized cysts in immature kidneys with fetal lobulations) [Saraiva & Baraitser 1992, Steinlin et al 1997, Satran et al 1999].

In addition to the nephronophthisis and cystic dysplasia spectrum a second type of renal disease that resembles autosomal recessive polycystic kidney disease (ARPKD) has been reported.

  • Three individuals with JSRD caused byTMEM67 mutations were reported to have renal disease more typical of ARPKD, with enlarged, diffusely microcystic kidneys and early-onset severe hypertension as well as congenital hepatic fibrosis; in addition, they exhibited chronic anemia characteristic of nephronophthisis [Gunay-Aygun et al 2009].
  • In the Hutterite population, approximately 70% of probands with JSRD caused by TMEM237 mutations have cystic renal disease and abnormal renal function, with hypertension reported in some [Boycott et al 2007, Huang et al 2011].

Renal disease has been reported in 23% [Doherty 2009] and 30% [Saraiva & Baraitser 1992] of persons with JSRD. These prevalence values may increase as a cohort ages, as renal disease can develop during childhood and adolescence [Steinlin et al 1997].

Joubert syndrome with oculorenal disease (JS-OR). Retinal disease and renal impairment often occur together in the same individual, and many of the causative genes for Joubert syndrome are associated with both renal cystic disease and retinal dystrophy [Parisi 2009, Brancati et al 2010] (Table 2). In the past JS-OR was also known as Dekaban Arima syndrome (retinopathy, cystic dysplastic kidneys) which can be evident prenatally or at birth.

Joubert syndrome with hepatic disease (JS-H). Hepatic fibrosis is usually progressive but rarely symptomatic at birth (see Congenital Hepatic Fibrosis Overview). Congenital hepatic fibrosis (CHF) is a developmental disorder of the portobiliary system characterized histologically by defective remodeling of the ductal plate (ductal plate malformation; DPM), abnormal branching of the intrahepatic portal veins, and progressive fibrosis of the portal tracts. Clinical findings include enlarged, abnormally shaped liver, relatively well-preserved hepatocellular function, and portal hypertension (PH) resulting in splenomegaly, hypersplenism, and gastroesophageal varices.

Hepatic fibrosis was observed in 18% of individuals with JSRD in one cohort [Doherty 2009].

When present in JSRD, hepatic fibrosis is often associated with chorioretinal colobomas and sometimes with renal disease. The combination of colobomas, cognitive impairment ("oligophrenia"), ataxia, cerebellar vermis hypoplasia, and hepatic fibrosis has been termed COACH syndrome [Satran et al 1999, Gleeson et al 2004, Doherty et al 2009].

Joubert syndrome with orofacialdigital features (JS-OFD). Polydactyly is described in 8%-19% of probands [Doherty 2009, Brancati et al 2010]. Polydactyly can be unilateral or bilateral and is often postaxial (Figure 3C), although preaxial polydactyly of the toes is also frequently reported (Figure 3D) [Saraiva & Baraitser 1992].

Figure 3

Figure

Figure 3. Clinical features in JSRD

A. Facial features in a girl with JSRD/COACH syndrome at age 27 months showing broad forehead, arched eyebrows, strabismus, eyelid ptosis (on right eye), and open mouth configuration indicating reduced (more...)

Mesaxial polydactyly, in which the extra digit occurs between the central digits and is often accompanied by a Y-shaped metacarpal, has been described in some individuals with Joubert syndrome, many of whom have other features of oral-facial-digital syndrome type VI/Varadi-Papp syndrome [Gleeson et al 2004]. In addition to mesaxial polydactyly, individuals with OFD VI often have cerebellar vermis hypoplasia, oral frenulae, tongue lobulations or hamartomas (Figure 3B), and craniofacial features that include wide-spaced eyes and midline lip groove. Renal and cardiac involvement has been described [Munke et al 1990]. Problems with mastication, swallowing, and respiration may result.

Other Findings in JSRD Not Specific to a Given Subtype

Cone-shaped epiphyses have been described in rare individuals, suggesting an association with Mainzer-Saldino syndrome (cerebellar ataxia with nephronophthisis and retinal dystrophy) [Mainzer et al 1970].

Scoliosis has been described, most likely related to early hypotonia.

Features of Jeune asphyxiating thoracic dystrophy (JATD) have been reported in several children with a JSRD, reflecting the shared ciliary origin of these conditions [Lehman et al 2010], and mutations in TTC21B have been identified in individuals with JSRD or JATD.

Endocrine abnormalities have been described, including pituitary hormone dysfunction ranging from isolated growth hormone deficiency or thyroid hormone deficiency to more extensive panhypopituitarism or micropenis in males [Delous et al 2007, Wolf et al 2007, Parisi 2009].

Obesity may be increased in JSRD, suggesting an association with the ciliary disorder Bardet-Biedl syndrome; the identification of mutations in INPP5E in both JSRD and MORM syndrome (mental retardation, obesity, retinal dystrophy, and micropenis) reinforces this association [Bielas et al 2009, Jacoby et al 2009].

Typical facial features, including long face with bitemporal narrowing, high-arched eyebrows, ptosis, prominent nasal bridge with anteverted nostrils, triangular-shaped mouth, prognathism, and low-set ears are sometimes described [Maria et al 1999a] (Figure 3A); however, these features can be difficult to discern in infancy and are thus far nonspecific. Nonetheless, many observers report a "Joubert syndrome facies" [Braddock et al 2007]. The craniofacial features in those with KIF7 mutations often include macrocephaly, frontal bossing, hypertelorism, high palate, and micrognathia [Dafinger et al 2011, Putoux et al 2011].

Laterality defects including situs inversus are seen in rare individuals [Parisi 2009], congenital heart defects have been reported on occasion, and Hirschsprung disease has also been described [Brancati et al 2010].

Conductive hearing loss may result from middle ear infections [Kroes et al 2010].

Tongue hypertrophy. Many have rhythmic tongue movements that may lead to tongue hypertrophy.

Other CNS malformations

Other findings include: abnormal nuclei and tracts of the pons, cerebellum, and medulla based on neuropathologic evaluation [Doherty 2009]; absence of decussation of the corticospinal and superior cerebellar tracts based on diffusion tensor imaging [Poretti et al 2007]; and abnormal activation patterns during motor tasks based on functional MRI studies [Parisi et al 2004b].

Genotype-Phenotype Correlations

Table 3 includes preliminary information on genotype-phenotype correlations.

Table 3. Genes Associated With JSRD by Phenotypic Features

GenePhenotypic Feature (in addition to the molar tooth sign)Allelic / Related Disorder 3
Retinal dystrophyColoboma 1RenalOculorenal 2Hepatic 1OralPolydactylyOther
NPHP1++++“Mild molar tooth” sometimes described 4Juvenile NPHP type 1; Cogan syndrome
AHI1++ 5(-)6+Polymicrogyria 7
CEP290+++++ ++ 8+Encephalocele; cardiac; situs inversus; other 9LCA; Meckel syndrome; BBS
TMEM6710+++ 11, 12(+)EncephaloceleMeckel syndrome
RPGRIP1L(+)(+)+++(+)(+)EncephaloceleMeckel syndrome; retinal disease 13
CC2D2A 14+++ +Encephalocele, ventriculomegaly, seizures; founder effects in French-Canadian populationMeckel syndrome
ARL13B+Encephalocele 15
INPP5E+++(+)+MORM syndrome 16
OFD1++17+ (postaxial)Encephalocele, Hydrocephalus, macrocephaly, polymicrogyriaOFD1
TMEM216(+)(+)+++(+)++Cardiac; encephalocele; founder effect in Ashkenazi Jewish population 18Meckel syndrome
KIF7(+) 19++ 20 ++Corpus callosum agenesis / hypoplasia; hydrocephalus; cardiac; craniofacial features 21Hydrolethalus syndrome; acrocallosal syndrome
TCTN1 22Pachygyria 22
TCTN2 23Clubfoot 23Meckel syndrome 24
TMEM237+25+++(+)(+)Encephocele; hydrocephalus; posterior fossa anomalies; founder effect in Hutterite
C5orf42(+)Founder effects in French-Canadian population 26
CEP41(+)(+)(+)+ (postaxial)Unilateral coloboma and unilateral kidney disease described in 1 subject only; micropenis +/- growth hormone deficiency in several affected males 27BBS / Meckel syndrome
TMEM138(+)+(+)(+)Encephalocele 27 Meckel syndrome
TMEM231++++Founder effects in French-Canadian population 28
TCTN3++Scoliosis; cardiac 29OFD IV
TTC21BHeterozygous changes only identified in probands with JSRD 30Juvenile NPHP; BBS, Meckel; JATD

(+) = feature is uncommon but has been described

+ = feature is present in some cases

++ = Major feature

NPHP = nephronophthisis

LCA = Leber congenital amaurosis

BBS = Bardet-Biedl syndrome

MORM = mental retardation, truncal obesity, retinal dystrophy, micropenis [Jacoby et al 2009]

OFD1 = oral-facial-digital syndrome type I

JATD = jeune asphyxiating thoracic dystrophy

1. May include COACH syndrome: cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis

2. This refers to retinal disease plus kidney disease; terms used in the past include: Senior-Løken syndrome (retinopathy and juvenile-onset nephronophthisis); Dekaban-Arima syndrome (retinopathy, cystic dysplastic kidneys)

3. See Genetically Related Disorders for details.

4. Some individuals with mutations of NPHP1 and a JSRD have a distinctive appearance of the molar tooth sign: elongated but thin superior cerebellar peduncles and milder vermis hypoplasia [Parisi et al 2004a].

5. The most common clinical association in those with AHI1 mutations is retinal dystrophy, present in ~80% [Valente et al 2008]. Early-onset congenital blindness has also been described [Valente et al 2006a].

6. Renal disease consistent with nephronophthisis has also been described [Parisi et al 2006, Utsch et al 2006].

7. Dixon-Salazar et al [2004], Gleeson et al [2004]

8. Up to 50% of individuals with both retinal and renal involvement harbor mutations in CEP290 [Valente et al 2008].

9. The phenotypic spectrum is very broad, including congenital blindness, ocular colobomas, renal disease, encephaloceles, septal heart disease, and situs abnormalities.

10. Mutations in TMEM67 were present in 53% of those with ocular coloboma regardless of liver status [Doherty et al 2009].

11. Mutations in TMEM67 account for 70% of all JSRD with liver involvement [Doherty et al 2009, Iannicelli et al 2010].

12. Baala et al [2007], Brancati et al [2009], Doherty et al [2009]

13. A coding variant of RPGRIP1L (A229T) is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes [Khanna et al 2009].

14. Hepatic involvement has been described [Gorden et al 2008, Noor et al 2008], as well as increased likelihood of ventriculomegaly and seizures [Bachmann-Gagescu et al 2012].

15. Cantagrel et al [2008]

16. Jacoby et al [2009]

17. Midline oral defects [Coene et al 2009]

18. Edvardson et al [2010]

19. Although elevated liver enzymes were described in one affected individual, this person also had two likely deleterious mutations in TMEM67, which is well known to be associated with hepatic disease [Dafinger et al 2011].

20. Midline oral defects, especially high palate or clefts [Putoux et al 2011]

21. Craniofacial features include macrocephaly, frontal bossing, hypertelorism, high palate, and micrognathia [Putoux et al 2011].

22. A limited number of individuals with causative mutations in these genes have been described; thus the phenotypic spectrum is unknown [Garcia-Gonzalo et al 2011].

23. A limited number of individuals with causative mutations in these genes have been described; thus the phenotypic spectrum is unknown [Sang et al 2011].

24. Shaheen et al [2011]

25. The “morning glory disc anomaly” has also been described in an extended family from Austria with TMEM237 mutations [Janecke et al 2004, Huang et al 2011].

26. There are several mutations that recur within the French-Canadian population found in the lower St. Lawrence region of Quebec province [Srour et al 2012b].

27. An affected fetus had an encephalocele and was diagnosed with Meckel syndrome [Lee et al [2012a].

28. Very rare mutations have been described in two families of French-Canadian extraction [Srour et al 2012a].

29. One out of 58 pedigrees with JSRD (for whom known genes were excluded) was found to have mutations in this gene [Thomas et al 2012].

30. Clinical data for individuals with a mutation in this gene are lacking [Davis et al 2011]. The functional significance of a single (heterozygous) mutation in TTC21B is unknown. See TTC21B Pathogenic allelic variants.

NPHP1. A homozygous, approximately 290-kb deletion of NPHP1 has been identified in a few individuals with JSRD. The proportion of individuals with Joubert syndrome with this mutation is not known; however, it is estimated at 1%-2% [Parisi et al 2004a, Castori et al 2005, Parisi et al 2006].

AHI1. The proportion of Joubert syndrome attributed to mutations in AHI1 is estimated at 10%. In one study, 13 of 117 (11%) individuals with Joubert syndrome had AHI1 mutations [Parisi et al 2006], whereas another survey of 137 persons identified 7.3% with mutations in this gene [Valente et al 2006a]. Approximately 80% of those with AHI1 mutations have retinal dystrophy [Valente et al 2008].

CEP290. In one study, seven of 96 individuals with Joubert syndrome (7%) had identifiable CEP290 mutations [Sayer et al 2006]. In a second series of consanguineous families in which the four other Joubert syndrome loci had been previously excluded, 5/18 had causative CEP290 mutations [Valente et al 2006b]. It is likely that an estimated 10% or more of JSRD is related to CEP290 mutations, and a strong association is seen with both retinal and renal involvement [Valente et al 2008]. The phenotypic spectrum is very broad.

TMEM67. Although originally identified as causative for Meckel syndrome, TMEM67 mutations have been identified in JSRD, particularly the COACH phenotype that includes hepatic disease, and to a lesser extent, ocular colobomas and kidney disease [Baala et al 2007, Brancati et al 2009, Doherty et al 2009, Parisi 2009]. In fact, mutations in TMEM67 account for 70% of all JSRD and liver involvement when combining several case series [Doherty et al 2009, Iannicelli et al 2010]. For those with JSRD and ocular colobomas, regardless of liver status, 53% had mutations in this gene [Doherty et al 2009]. More severe loss-of-function mutations in TMEM67 have been identified in individuals with lethal forms of Meckel syndrome [Smith et al 2006], in comparison with milder loss-of-function mutations causing JSRD with hepatic disease or nephronophthisis and liver fibrosis in the absence of the molar tooth sign and other neurologic symptoms [Doherty et al 2009, Otto et al 2009].

RPGRIP1L. Mutations in this gene are estimated to contribute to 2%-4% of JSRD [Arts et al 2007, Delous et al 2007, Parisi 2009]. Distinguishing clinical features include renal disease (typically, nephronophthisis), and occasionally occipital encephalocele, polydactyly, and hepatic fibrosis. Mutations in this gene also cause Meckel syndrome, with more severe truncating mutations predicting a more severe (and in many cases, lethal) Meckel phenotype [Delous et al 2007, Wolf et al 2007].

CC2D2A. The phenotypic spectrum for individuals with mutations in CC2D2A is highly variable, ranging from classic Joubert syndrome to Joubert syndrome with retinitis pigmentosa or encephalocele to the COACH phenotype with liver involvement and coloboma [Gorden et al 2008, Noor et al 2008]. It caused 9% of all JSRD in one cohort [Gorden et al 2008, Doherty et al 2009]. Null alleles are associated with the Meckel syndrome phenotype and missense and/or hypomorphic alleles with JSRD [Tallila et al 2008, Mougou-Zerelli et al 2009]. An association with ventriculomegaly and seizures has been noted in individuals with JSRD and mutations in this gene [Bachmann-Gagescu et al 2012]. Some French Canadians with a mild form of JSRD have mutations in this gene [Srour et al 2012a].

ARL13B. Mutations in this gene appear to cause a rare form of JSRD, described in only two families, in which the phenotypic spectrum ranged from classic Joubert syndrome to occipital encephalocele and pigmentary retinopathy [Cantagrel et al 2008].

INPP5E. The relative contribution of INPP5E mutations to JSRD remains unknown, as a limited number of individuals with mutations in this gene have been described [Bielas et al 2009]. Phenotypic features include retinal disease in particular, as well as renal cystic disease and hepatic fibrosis in a few affected individuals.

OFD1. This rare X-linked recessive cause of JSRD has been described in a total of three families. In two families, most affected males manifested postaxial polydactyly; retinal disease, occipital encephalocele, and midline oral defects were also seen in some [Coene et al 2009]. Mutations in OFD1 cause X-linked dominant oral-facial-digital syndrome type I, but the few OFD1 mutations in males with JSRD are predicted to have a less severe effect on the function of the protein than the mutations observed in OFD I [Coene et al 2009]. In the third family the phenotypic spectrum has expanded to include renal cystic disease, hydrocephalus, macrocephaly, and polymicrogyria [Field et al 2012].

TMEM216. Individuals with TMEM216 mutations often have nephronophthisis or polydactyly, with some individuals also manifesting features consistent with oral-facial-digital syndrome [Edvardson et al 2010, Valente et al 2010]. There appears to be a founder effect with a carrier rate of 1:92-1:100 in the Ashkenazi Jewish population [Edvardson et al 2010, Valente et al 2010]. Fourteen of 462 (~3%) families with JSRD had mutations in TMEM216 [Valente et al 2010].

KIF7. Individuals with KIF7 mutations often have orofaciodigital features, with or without other CNS findings such as agenesis/hypoplasia of the corpus callosum, hydrocephalus, and macrocephaly [Dafinger et al 2011, Putoux et al 2011]. The digital anomalies often consist of postaxial polydactyly of the hands and preaxial (and/or postaxial) polydactyly of the feet. Overlapping genetically related disorders include the severe hydrolethalus syndrome and the acrocallosal syndrome, with several affected individuals with these two diagnoses also exhibiting the MTS, leading to diagnostic ambiguity [Putoux et al 2011] (see Genetically Related Disorders).

TMEM237. This form of JSRD was originally described as Meckel syndrome in the Hutterite population [Boycott et al 2007], in which the carrier rate is estimated at 6% [Huang et al 2011]. Other ethnic groups, including an extended Austrian family with distinctive optic disc anomaly [Janecke et al 2004], exhibit mutations in this gene [Huang et al 2011]. Encephalocele, hydrocephalus, and cystic kidney disease are common in those with mutations in TMEM237.

C5orf42. Mutations in this gene are the cause of JSRD in the original family described by Joubert et al [1969]. There are three founder mutations, each linked to a distinct haplotype, and a total of seven different mutations present in multiple affected individuals from the French-Canadian population; all affected individuals are compound heterozygous for these gene variants [Srour et al 2012a, Srour et al 2012b]. The phenotype most closely resembles pure or classic Joubert syndrome, with one out of 11 individuals with clinical information provided exhibiting preaxial and postaxial polydactyly. None of the affected individuals (ranging in age from 1.5 to 52 years) has evidence of retinal involvement (as determined by ERG, fundoscopy, or history) or renal impairment (as determined by history or ultrasound) [Srour et al 2012a, Srour et al 2012b].

CEP41. Three families with eight individuals affected with JSRD have been described with causative mutations in this gene. Just over half have demonstrated unilateral or bilateral postaxial polydactyly. Only two individuals have evidence of retinal disease, and one of these is described as having unilateral coloboma, unilateral kidney disease, and ambiguous genitalia; this subject died at age seven days, so little is known about the natural history. Within one family, all five affected males had micropenis, and two of these had growth hormone deficiency [Lee et al 2012a].

TMEM138. Eleven individuals from eight Arab consanguineous families have been reported with mutations in this gene; the phenotype includes coloboma in six, retinal dystrophy in three, and cystic kidney or nephronophthisis in three. Polydactyly has also been observed and one fetus diagnosed with Meckel syndrome had an encephalocele [Lee et al 2012b].

TMEM231. Mutations in this gene appear to account for some individuals with JSRD of French-Canadian descent. Only three individuals in two families have been described with compound heterozygous mutations in this gene, resulting in a severe phenotype with lack of ambulation, aggressive behaviors, and lack of independent living skills. Two of these individuals have macroscopic renal cysts and retinal disease, and one has postaxial polysyndactyly [Srour et al 2012a].

TTC21B. No individuals with JSRD and two causative mutations in this gene have yet been described, and there is no clinical information provided for the three subjects with a heterozygous change. In a clinically diverse cohort of 753 individuals with a ciliopathy, 5% were found to have pathogenic mutations in TTC21B, but only one third of these had a second pathogenic mutation identified in a different ciliopathy gene [Davis et al 2011].

TCTN3. Homozygous truncating mutations in this gene have been identified in five pedigrees with a severe prenatal lethal form of OFD type IV (Mohr-Majewski syndrome); however, since the phenotype included postaxial polydactyly, cystic renal disease, bile duct proliferation, and occipital encephalocele in addition to skeletal and oral anomalies, it is debatable whether this represents a type of OFD or Meckel syndrome. In addition, two probands from a Turkish family with JSRD (and MTS) had homozygous missense mutations in a conserved residue in this gene and were reported to have scoliosis with variable polydactyly, oral findings, horseshoe kidney, and ventricular septal defect [Thomas et al 2012].

Nomenclature

The term "classic Joubert syndrome" is reserved for those individuals fulfilling the diagnostic criteria that require the presence of the molar tooth sign on MRI and primary clinical criteria (hypotonia, developmental delay) (see Clinical Diagnosis and Table 2). This may also be termed “pure” Joubert syndrome."

In an earlier, now outdated classification scheme, it was proposed that Joubert syndrome be classified into two groups, those with retinal dystrophy (Joubert syndrome type B) and those without (Joubert syndrome type A) [King et al 1984, Saraiva & Baraitser 1992]. The utility of this system was based on the observation of coincident renal disease and retinal dystrophy in many individuals.

The currently accepted term "Joubert syndrome and related disorders" (JSRD) describes conditions that share the molar tooth sign and the clinical features of classic Joubert syndrome and have other organ system involvement. In an evolving nomenclature designed to reduce reliance on confusing and inconsistently used eponyms, at least six clinical subtypes of JSRD that share the three primary findings have been proposed (Table 2) [Brancati et al 2010].

In the past, some of the following disorders were described as distinct syndromes, but more recent studies indicate that many individuals with these disorders demonstrate the molar tooth sign [Satran et al 1999, Gleeson et al 2004]. Examples of such autosomal recessive disorders include the following:

  • Dekaban-Arima syndrome (retinopathy, cystic dysplastic kidneys) [Dekaban 1969]
  • Senior-Løken syndrome (SLS; retinopathy and juvenile-onset nephronophthisis) [Løken et al 1961, Senior et al 1961]
  • COACH syndrome (cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis) [Verloes & Lambotte 1989, Gentile et al 1996]
  • Varadi-Papp syndrome (oral-facial-digital syndrome VI [OFD VI]) includes cerebellar vermis hypoplasia, oral frenulae, tongue hamartomas, and midline cleft lip, as well as the distinctive feature of central polydactyly with a Y-shaped metacarpal [Munke et al 1990]. Renal and cardiac involvement has been described.

Prevalence

The prevalence of Joubert syndrome and related disorders has not been determined. Many authors use a range between 1:80,000 and 1:100,000, but this may represent an underestimate [Kroes et al 2007, Parisi et al 2007, Brancati et al 2010].

There is a relatively high prevalence of JSRD in the French-Canadian population, with several founder effects noted. The family first described by Joubert et al [1969] has been traced to a founder who immigrated to Quebec from France in the 1600s [Badhwar et al 2000]. However, it appears that there are multiple founder haplotypes involving C5orf42 in the French-Canadian population, as all affected individuals with mutations in this gene have been compound heterozygotes.Several French-Canadian individuals are compound heterozygous for pathogenic mutations in CC2D2A, and others have mutations in TMEM231 [Srour et al 2012a, Srour et al 2012b].

There appears to be a TMEM216 founder mutation (c.218 G>T, resulting in p.Arg73Leu) with a carrier rate of 1:92-1:100 in the Ashkenazi Jewish population [Edvardson et al 2010, Valente et al 2010].

Differential Diagnosis

Disorders in the differential diagnosis include the following (see Genetically Related Disorders for discussion):

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Joubert syndrome and related disorders, the following baseline evaluations to identify the extent of disease in affected infants/children are recommended [Parisi et al 2007 (full text)]. Recommendations were developed by a consensus panel and are outlined on the Joubert Syndrome and Related Disorders Foundation Web site.

  • A high-quality MRI with thin (3-mm thickness) axial cuts through the posterior fossa from the midbrain to the pons as well as standard axial, coronal, and sagittal cuts to evaluate for the presence of the molar tooth sign and other cerebral malformations, neuronal migration disorders, or cephaloceles
  • A baseline neurologic evaluation with particular attention to tone, respiratory pattern (tachypnea and apnea), eye movements, development, and cerebellar function
  • Sleep history with polysomnogram as baseline evaluation and particularly if symptomatic apnea is present
  • Genetic evaluation to document family history, to evaluate growth and head size, and to evaluate for other anomalies including polydactyly, dysmorphic facial features, tongue tumors/lobulations, and micropenis
  • For males with micropenis or any child with signs of growth hormone deficiency, endocrine evaluation for other pituitary abnormalities
  • Assessment of oromotor function by a speech therapist and/or by fluoroscopic swallowing studies
  • Developmental assessment with age-appropriate tools
  • Evaluation by a pediatric ophthalmologist via dilated eye examination for colobomas and retinal changes, as well as strabismus and ptosis, with consideration of specialized testing such as visual-evoked potentials (VEP), electroretinogram (ERG), and ocular motility testing
  • Abdominal ultrasound examination to evaluate for hepatic fibrosis or renal cysts and/or findings consistent with nephronophthisis (e.g., loss of corticomedullary differentiation)
  • Tests of renal function, including blood pressure, blood urea nitrogen (BUN), serum creatinine concentration, complete blood count (CBC), and urinalysis from first-morning void for specific gravity to test concentrating ability (if feasible)
  • Liver function tests including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time (PT)

Treatment of Manifestations

Respiratory

  • Infants and children with abnormal breathing patterns should be considered for apnea monitoring if the abnormality is severe. Supportive therapy may include stimulatory medications such as caffeine or supplementary oxygen, particularly in the newborn period.
  • Anesthetic management during surgical procedures for infants with significant respiratory disturbance may be accomplished in some cases by regional anesthesia without the use of opioids to avoid exacerbation of apneic episodes [Vodopich & Gordon 2004].
  • In rare cases, mechanical support and/or tracheostomy may be considered in a child with severe respiratory dysfunction.
  • Aggressive treatment of middle ear infections is indicated to avoid conductive hearing loss.

Hypotonia and therapeutic interventions

  • Appropriate management and therapy of oromotor dysfunction by a speech therapist
  • Nasogastric feeding tubes or gastrostomy tube placement for feeding in children with severe dysphagia
  • Occupational, physical, and speech therapy through early intervention programs
  • Individualized educational assessment and support for school-aged children to maximize school performance
  • Periodic neuropsychologic and developmental testing at appropriate ages

Other CNS malformations

  • Neurosurgical consultation is indicated for those with evidence of hydrocephalus (rapidly increasing head circumference and/or bulging fontanel).
  • Hydrocephalus rarely requires shunting.
  • Posterior fossa cysts and fluid collections rarely require intervention.
  • Encephalocele may require primary surgical closure.
  • Seizures should be evaluated by EEG and treated with standard antiepileptic drugs (AEDs) under the management of a neurologist.
  • A variety of psychotropic medications have been used to treat the behavioral complications in Joubert syndrome; no single medication has been uniformly effective for all children.

Ophthalmologic

  • Surgery as needed for symptomatic ptosis, strabismus, or amblyopia
  • Corrective lenses for refractive errors
  • Possible vision therapies for oculomotor apraxia, although specific studies are lacking in this disorder
  • Therapies for the visually impaired when congenital blindness or progressive retinal dystrophy are present

Renal disease

  • Consultation with a nephrologist is indicated.
  • Nephronophthisis frequently requires dialysis and/or kidney transplantation during the teenage years or later.
  • Hypertension, anemia, and other complications of end-stage renal disease (ESRD) require specific treatment.

Hepatic fibrosis

  • Consultation with a gastroenterologist is indicated.
  • Liver failure and/or fibrosis should be managed by a gastroenterologist with arrangements for surgical intervention such as portal shunting for esophageal varices and portal hypertension, as appropriate.
  • Some individuals have needed orthotopic liver transplantation.

Skeletal

  • Surgical treatment for polydactyly
  • Appropriate medical management by an orthopedic specialist for scoliosis

Other

  • Orofacial clefting is treated by standard surgical interventions.
  • Tongue tumors that impair normal swallowing or cause respiratory obstruction may require surgical resection.
  • Symptoms of obstructive sleep apnea and/or tongue hypertrophy in older individuals may require evaluation with a polysomnogram and/or by an otolaryngologist for consideration of adenoidectomy, tonsillectomy, or surgical tongue reduction. Some children have used BiPAP or C-PAP at night.
  • Consultation with an endocrinologist for menstrual irregularities and for pituitary hormone deficiency (with hormone replacement as indicated) is appropriate.
  • Obesity should be managed with appropriate measures, including diet, exercise, and behavioral therapies
  • Congenital heart defects and situs abnormalities should be treated by conventional therapies
  • Surgical correction of Hirschsprung disease (if present) is indicated.

Prevention of Secondary Complications

Antibiotic prophylaxis for surgical and dental procedures is indicated for individuals with structural cardiac anomalies.

Surveillance

Because no uniformly reliable distinguishing characteristics allow prediction of the complications that may develop in an infant or young child with Joubert syndrome, a number of annual evaluations are recommended (see also Joubert Syndrome and Related Disorders Foundation Web site):

  • Pediatric and neurologic evaluation and monitoring of growth, sexual maturation, breathing (including apnea symptoms), and motor function
  • Neuropsychological and developmental evaluation and testing, as appropriate
  • Ophthalmologic evaluation for visual acuity, tracking ability, and development of retinal dystrophy
  • Abdominal ultrasound examination for evaluation of possible liver and kidney abnormalities
  • Liver function tests
  • Evaluation of renal function: measurement of blood pressure, serum concentrations of BUN and creatinine, CBC, and assessment of first-morning void urinalysis

Agents/Circumstances to Avoid

Individuals with renal impairment should avoid nephrotoxic medications such as NSAIDS (non-steroidal anti-inflammatory drugs).

Individuals with liver impairment should avoid hepatotoxic medications.

Evaluation of Relatives at Risk

Sibs or relatives who have clinical features similar to those of an individual with JSRD warrant genetic consultation. If the disease-causing mutations have been identified in a proband, testing symptomatic relatives for these mutations is appropriate.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Joubert syndrome and related disorders (JSRD) are inherited predominantly in an autosomal recessive manner. OFD1-related JSRD is inherited in an X-linked manner. Digenic inheritance has been reported.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of a proband are obligate carriers. Although no individuals with Joubert syndrome have been reported to have reproduced, the broad spectrum of cognitive impairment now known in this condition may increase the likelihood that reports of individuals who have had offspring will be forthcoming.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Risk to Family Members – X-linked Inheritance

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation are unlikely to be affected; however, no carrier females have been identified.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the disease-causing mutation cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo mutation arose, information that could help determine genetic risk status for the extended family.

Risk to Family Members—Digenic Inheritance

Joubert syndrome is reported to result from a heterozygous CEP41 mutation in combination with either a CC2D2A or a KIF7 mutation [Lee et al 2012a].

Parents of a proband

  • The parents are obligate heterozygotes; one parent carries a CEP41 mutation and the other parent carries either a CC2D2A or a KIF7 mutation.
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib has a 25% chance of having Joubert syndrome, a 50% chance of being a carrier of one of the mutations, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes are asymptomatic.

Offspring of a proband. All offspring are carriers of one of the mutations.

Other family members of a proband. Each sib of an obligate heterozygote has a 50% chance of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the disease-causing mutation(s) have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Prenatal imaging. First-trimester diagnosis of JSRD for pregnancies at 25% risk has been reported using ultrasound examination to identify structural brain abnormalities such as encephalocele [van Zalen-Sprock et al 1996, Wang et al 1999]. More typically, prenatal diagnosis in at-risk fetuses has been accomplished by prenatal ultrasound examination of the posterior fossa and/or kidneys and digits as early as the second trimester [Ni Scanaill et al 1999, Aslan et al 2002, Doherty et al 2005].

Accurate prenatal diagnosis of JSRD in an at-risk fetus has been achieved by serial prenatal ultrasound imaging starting at 11 to 12 weeks’ gestation, with detailed evaluation of cerebellar and other fetal anatomy through 20 weeks' gestation, followed by fetal MRI imaging at 20 to 22 weeks’ gestation [Doherty et al 2005]. In the earliest reported cases to date, MTS was identified in two separate at-risk pregnancies at 17 to 18 weeks’ gestation via fetal MRI [Saleem et al 2011]. Although fetal MRI is useful in diagnosis of posterior fossa anomalies [Levine et al 2003, Adamsbaum et al 2005], its sensitivity in JSRD has not been systematically evaluated.

For a couple who has already had a child with JSRD, the presence of findings that suggest a prenatal diagnosis of Joubert syndrome and related disorders (e.g., encephalocele, renal cystic changes, polydactyly, or posterior fossa anomalies on fetal imaging) is highly significant; however, the absence of these signs does not preclude a diagnosis of Joubert syndrome and related disorders because of the unknown sensitivity of imaging and because of intrafamilial variability.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Joubert Syndrome and Related Disorders Foundation
    414 Hungerford Drive
    Suite 252
    Rockville MD 20850
    Phone: 614-864-1362
    Email: secretary@jsrdf.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • National Library of Medicine Genetics Home Reference

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Joubert Syndrome and Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Joubert Syndrome and Related Disorders (View All in OMIM)

200990ACROCALLOSAL SYNDROME; ACLS
213300JOUBERT SYNDROME 1; JBTS1
243910ARIMA SYNDROME
300170OFD1 GENE; OFD1
300804JOUBERT SYNDROME 10; JBTS10
607100NEPHROCYSTIN 1; NPHP1
608091JOUBERT SYNDROME 2; JBTS2
608629JOUBERT SYNDROME 3; JBTS3
608894ABELSON HELPER INTEGRATION SITE 1; AHI1
608922ADP-RIBOSYLATION FACTOR-LIKE 13B; ARL13B
609583JOUBERT SYNDROME 4; JBTS4
609863TECTONIC FAMILY, MEMBER 1; TCTN1
609884TRANSMEMBRANE PROTEIN 67; TMEM67
610142CENTROSOMAL PROTEIN, 290-KD; CEP290
610188JOUBERT SYNDROME 5; JBTS5
610523CENTROSOMAL PROTEIN, 41-KD; CEP41
610688JOUBERT SYNDROME 6; JBTS6
610937RPGRIP1-LIKE; RPGRIP1L
611254KINESIN FAMILY MEMBER 7; KIF7
611560JOUBERT SYNDROME 7; JBTS7
612013COILED-COIL AND C2 DOMAINS-CONTAINING PROTEIN 2A; CC2D2A
612014TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 21B; TTC21B
612291JOUBERT SYNDROME 8; JBTS8
613037INOSITOL POLYPHOSPHATE-5-PHOSPHATASE, 72-KD; INPP5E
613277TRANSMEMBRANE PROTEIN 216; TMEM216
613820NEPHRONOPHTHISIS 12; NPHP12
613846TECTONIC FAMILY, MEMBER 2; TCTN2
613847TECTONIC FAMILY, MEMBER 3; TCTN3
614173JOUBERT SYNDROME 13; JBTS13
614423TRANSMEMBRANE PROTEIN 237; TMEM237
614424JOUBERT SYNDROME 14; JBTS14
614459TRANSMEMBRANE PROTEIN 138; TMEM138
614464JOUBERT SYNDROME 15; JBTS15
614465JOUBERT SYNDROME 16; JBTS16
614571CHROMOSOME 5 OPEN READING FRAME 42; C5ORF42
614615JOUBERT SYNDROME 17; JBTS17
614815JOUBERT SYNDROME 18; JBTS18
614949TRANSMEMBRANE PROTEIN 231; TMEM231
614970JOUBERT SYNDROME 20; JBTS20

Molecular Genetic Pathogenesis

All of the genes in which mutations are known to cause JSRD localize to the primary cilium and/or basal body and centrosome where they may play a role in the formation, morphology, and/or function of these organelles. The cilia are membrane-found, hair-like projections that are anchored by the basal body.

Motile cilia have a 9+2 microtubule axonemal structure that allows for movement and flow of fluids and are found on specialized cell types such as respiratory epithelia and spermatozoa. Primary cilia have a 9+0 microtubule structure and are usually non-motile. Primary cilia are found on most cell types and appear to play a role in cellular chemo- and mechanosensation and cell signaling, including the WNT, Sonic hedgehog (SHH), and PDGF signaling pathways involved in differentiation, cell division, and planar cell polarity.

Ciliopathies, conditions caused by defects in one or more of the many proteins important in ciliary function, share many features including renal disease, retinal dystrophy, and polydactyly [reviewed in Badano et al 2006]. The association of ciliary defects with specific phenotypes has not been completely elucidated, but in the case of the hindbrain malformation seen in JSRD, it is known that SHH signaling is critical for both dorsal-ventral patterning of the neural tube and cerebellar granule cell proliferation [Doherty 2009].

For a detailed summary of gene and protein information for the genes listed below, see Table A, Gene Symbol.

AHI1

Gene structure. AHI1 comprises 28 exons and several alternative splice variant forms. The most common full-length transcript is 5,528 bp.

Pathogenic allelic variants. Homozygous nonsense, missense, deletion, insertion, and splicing mutations have been reported [Dixon-Salazar et al 2004, Ferland et al 2004, Parisi et al 2006, Romano et al 2006, Utsch et al 2006]. (For more information, see Table A, Locus Specific.)

Normal gene product. 1196-amino acid protein, AHI1 (also termed jouberin). The protein includes a coiled-coil domain, an SH3 domain, and six WD40 repeats hypothesized to mediate a variety of functions including signal transduction, RNA processing, and vesicular trafficking.

Abnormal gene product. On some backgrounds, Ahi1-null mice exhibit a perinatal lethal phenotype. In strains that survive, Ahi1-null mice exhibit early retinal degeneration with a failure of proper development of the photoreceptor sensory cilia and outer segments [Westfall et al 2010].

ARL13B

Gene structure. ARL13B is a ten-exon gene that encodes a 428-amino acid protein.

Pathogenic allelic variants. Two families with a phenotype typical of classic Joubert syndrome had missense and/or nonsense mutations in this gene; one of these individuals also had evidence of a retinopathy [Cantagrel et al 2008].

Normal gene product. ARL13B encodes ADP-ribosylation factor-like protein 13B, a member of the ADP-ribosylation factor-like family. Multiple transcript variants result from alternate splicing; two protein isoforms are known. The AR13B protein is a small GTPase in the Ras superfamily that contains both N-terminal and C-terminal guanine nucleotide-binding motifs. It is localized to the cilia and plays a role in cilia formation and maintenance as well as sonic hedgehog signaling.

Abnormal gene product. In C elegans, mutations in the homolog arl13 exhibit defective cilium morphology, localization, and anterograde intraflagellar transport [Cevik et al 2010]. Mice with defects in the murine ortholog have neural tube defects and polydactyly, as well as an embryonic-lethal phenotype [Cantagrel et al 2008, Doherty 2009].

C5orf42

Gene structure. This reference sequence (NM_023073.3) comprises at least 53 exons, including an alternative exon, 40a, found between exons 40 and 41. C5orf42 encodes a predicted 3,197-amino acid protein (NP_075561.3) [Srour et al 2012b].

Pathogenic allelic variants. Six different mutations have been found in multiple affected individuals from seven unrelated families of French-Canadian descent: c.4006C>T (p.Arg1336Trp), c.7400+1G>A, c.7477C>T (p.Arg2493Ter), c.4804C>T (p.Arg1602Ter), c.6407del (p.Pro2136HisfsTer31), and c.4690G>A (p.Ala1564Thr), which occurs in an alternatively spliced exon prevalent in brain and testes. Each of three of these mutations is linked to a distinct haplotype and represents a different founder effect in the French-Canadian population: c.4006C>T (p.Arg1336Trp), c.7400+1G>A, and c.4690G>A (p.Ala1564Thr). All of the affected individuals are compound heterozygous for these gene variants [Srour et al 2012b].

Normal gene product. The encoded protein has features of a transmembrane protein and a putative coiled-coil domain. Proteomic studies have suggested protein interactions with proteins important in neurodevelopment. It appears to be widely expressed in a variety of tissues, including the central nervous system, but little else is known about the gene.

Abnormal gene product. The identified mutations are predicted to result in nonsense mutations, aberrant splicing, exon skipping (c.7400+1G>A) or missense mutations predicted to be damaging by protein prediction algorithms, with the exception of c.4690G>A (p.Ala1564Thr), which is not clearly deleterious and may be linked to another, as-yet unidentified mutation [Srour et al 2012b].

CC2D2A

Gene structure. This 38-exon gene encodes a 1620-amino acid protein that shares domains in common with the RPGRIP1L-encoded protein.

Pathogenic allelic variants. Mutations in this gene cause Meckel syndrome and JSRD, including the COACH syndrome variant; null mutations are associated with the more severe (and often lethal) Meckel syndrome phenotype [Mougou-Zerelli et al 2009].

Normal gene product. The protein has coiled-coil and a C2 calcium-binding domain and appears to play a critical role in cilia formation. Multiple transcript variants arise from alternative splicing. CC2D2A localizes to the basal body and physically interacts with CEP290 [Gorden et al 2008].

Abnormal gene product. Loss of function in the zebrafish homolog results in pronephric cysts (the equivalent of kidney cysts) and other changes consistent with ciliary dysfunction [Gorden et al 2008].

CEP41

Gene structure. The gene consists of 11 exons and spans approximately 50 kb. There are two different isoforms that are alternatively spliced.

Pathogenic allelic variants. All individuals with JSRD and causative mutations in CEP41 had homozygous splice-site mutations. Heterozygous CEP41 mutations have been identified in five additional individuals with Joubert syndrome, three of whom had heterozygous mutations in other ciliopathy genes (KIF7 and CC2D2A). Heterozygous changes in this gene have also been described in individuals with Bardet-Biedl syndrome and Meckel syndrome, supporting a role for CEP41 in digenic inheritance and suggesting that CEP41 may act as a modifier for other ciliopathies. [Lee et al 2012a].

Normal gene product. CEP41 encodes two proteins of 373 and 54 amino acids, respectively; the longer transcript encodes a 41-kd protein with two coiled-coil domains and a rhodanese-like domain. It localizes to the centrioles and cilia in several different cell lines and appears to regulate tubulin glutamylation by facilitating transport of a glutamylation enzyme [Lee et al 2012a].

Abnormal gene product. Zebrafish embryos injected with morphant Cep41 demonstrate peripheral heart edema, tail defects, and other phenotypes associated with ciliary genes in the knockdown animals. However, the broad range of phenotypes in knockout mice included exencephaly, dilated pericardial sac, and lethality to normal. Further experiments demonstrated that CEP41 morphants had specific ultrastructural tubulin defects and were deficient in glutamylation of tubulin, the component of microtubules that forms the structural axoneme of the cilia [Lee et al 2012a].

CEP290

Gene structure. The gene comprises 54 exons and spans 93.2 kb of genomic DNA, with a full-length transcript size of 7972 bp. Alternative splicing results in several different isoforms.

Pathogenic allelic variants. Over 100 distinct mutations have been identified in CEP290, with the vast majority of them truncating (40 nonsense and 48 frameshift out of 112 total). One large heterozygous partial deletion has also been identified, but most truncating mutations are caused by small insertions or deletions. Only three mutations are missense; 20 affect splicing [Coppieters et al 2010].

The most frequent recurrent mutation is a novel one: c.2991+1655 A>G, a substitution within intron 26 that leads to the inclusion of a cryptic exon in the mRNA, with resultant frameshift and premature stop codon at p.Cys998Ter [den Hollander et al 2006]. This homozygous mutation accounts for up to 26% of all Leber congenital amaurosis (LCA) in northern Europe, and its relatively mild phenotype is explained by the “leakiness” of the mutation resulting in some residual wild-type protein being produced.

The spectrum of phenotypes associated with mutations in CEP290 is broad, including LCA, nephronophthisis, Senior-Løken syndrome, JSRD, Meckel syndrome, and Bardet-Biedl syndrome (see Table 3). Although clear genotype-phenotype correlations are difficult to establish, some limited associations have been described and are summarized in the mutation database CEP290base [Coppieters et al 2010].

Normal gene product. CEP290 encodes centrosomal protein of 290 kd (also termed nephrocystin-6), which comprises 2479 amino acid residues. Nephrocystin-6 is a centrosomal protein known to modulate the activity of ATF4, a transcription factor implicated in renal cyst formation. The protein contains 13 putative coiled-coil domains, a region with homology to SMC (structural maintenance of chromosomes) ATPases, six KID motifs, three tropomyosin homology domains, and an ATP/GTP binding site motif A. The protein localizes to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Nephrocystin-6 has also been shown to interact with other JSRD-associated proteins, including CC2D2A and meckelin [Gorden et al 2008, Leitch et al 2008, Tallila et al 2008].

Abnormal gene product. Knockdown experiments in zebrafish result in abnormal cerebellar, renal, and retinal development [Sayer et al 2006]. Evidence suggests that this protein is expressed in the cerebellum during murine embryogenesis [Valente et al 2006b]. Two naturally occurring animal models with mutations in cep290 have been identified, in the rd16 mouse and in Abyssinian cats; both exhibit progressive retinal degeneration but no renal or cerebellar defects [Coppieters et al 2010].

INPP5E

Gene structure. INPP5E comprises nine exons and 3440 bp of mRNA and encodes a 644-amino acid protein.

Pathogenic allelic variants. Missense mutations within the catalytically active phosphatase domain in this gene cause some forms of JSRD [Bielas et al 2009]. In one family with the Bardet-Biedl syndrome-like MORM syndrome, the identified mutation results in premature truncation of the protein and deletion of the terminal 18 amino acids [Jacoby et al 2009].

Normal gene product. The protein encoded by this gene is 72-kd inositol polyphosphate 5-phosphatase ( also known as inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase), an enzyme that is involved in phosphatidylinositol signaling by mobilizing intracellular calcium and acting as a second messenger mediating cell responses to various stimuli. This enzyme localizes to the central core of the primary cilium and appears to affect its metabolism of phosphotidylinositol and stability [Jacoby et al 2009].

Abnormal gene product. The JSRD-associated mutations impair the 5-phosphatase activity of the enzyme and alter the ciliary phosphotidylinositol ratio, destabilizing the cilia. Mice with homozygous deletions of the orthologous gene die soon after birth and exhibit anophthalmos, polydactyly, cystic kidneys, skeletal abnormalities, cleft palate, and cerebral anomalies such as exencephaly [Jacoby et al 2009]. Deletion of the terminal 18 amino acids appears to affect localization of the protein within the cilium [Jacoby et al 2009].

KIF7

Gene structure. KIF7 (the vertebrate homolog of the Drosphila costa [costal-2] gene) comprises 19 exons and encodes a 1343-amino acid protein.

Pathogenic allelic variants. The mutations that cause hydrolethalus syndrome, acrocallosal syndrome, and JSRD are typically nonsense mutations or frameshift mutations leading to nonsense-mediated decay or premature stop codons and are distributed across the gene [Dafinger et al 2011, Putoux et al 2011]. In addition, heterozygous KIF7 mutations were identified in nine persons with other ciliopathies, including Bardet-Biedl syndrome, Meckel syndrome, Pallister-Hall syndrome, OFD VI, and JSRD; four of these individuals had two pathogenic mutations in other genes associated with BBS and one with JSRD had two MKS3 mutations [Dafinger et al 2011, Putoux et al 2011]. Based on rescue studies in morphant zebrafish embryos, it is likely that the KIF7 mutations exacerbate the phenotype of other ciliopathies, especially BBS [Putoux et al 2011].

Normal gene product. KIF7 encodes a member of the kinesin family, a putative ciliary motor protein that regulates Hedgehog signaling. The KIF7 protein has a kinesin motor domain, a Gli-binding domain, and a coiled-coil domain. KIF7 has been noted to co-precipitate with Nephrocystin-1 [Dafinger et al 2011] and to form a complex with Gli proteins both at the cilium base and, when bound by ligand, at the cilium tip [Putoux et al 2011].

Abnormal gene product. Discruption of KIF7 expression in cell lines causes defects in cilia formation, abnormal centrosomal duplication, and Golgi fragmentation, suggesting that microtubule stability and growth are impaired [Dafinger et al 2011]. Loss of Kif7 in mice causes polydactyly, skeletal defects, exencephaly and early lethality in mice [Liem et al 2009]. Absent KIF7 expression also causes upregulation of GLI transcription factor targes, consistent with a role in Hedgehog signaling [Putoux et al 2011].

NPHP1

Gene structure. NPHP1 comprises 20 exons and its cDNA is 3,713 bp. The gene resides in a region flanked by two large inverted repeat elements and encodes nephrocystin-1.

Pathogenic allelic variants. In addition to a homozygous, approximately 290-kb deletion encompassing NPHP1 and portions of another gene, BENE [Saunier et al 2000, Parisi et al 2004a], occasional point mutations in NPHP1 have also been identified [Hoefele et al 2005]. (For more information, see Table A.) Some individuals with more severe phenotypes than familial juvenile nephronophthisis type 1 or Senior-Løken syndrome (see Table 3) have the homozygous NPHP1 deletion as well as a heterozygous change in AHI1 or CEP290, suggesting the contribution of modifier genes [Tory et al 2007].

Normal gene product. Nephrocystin-1, a protein of 733 amino acids, has an src homology domain 3 (SH3) domain that may mediate interactions with other proteins. Nephrocystin appears to localize to the primary cilium of the cell, to cell-cell adherens junctions, and to the basal body, where it may function in the control of cell division and in cell-cell and cell-matrix adhesion signaling [Hildebrandt et al 2009]. Nephrocystin interacts with the AHI1 protein as well as with the proteins INVS, NPHP3, and NPHP4, which are encoded by genes mutated in other forms of nephronophthisis.

Abnormal gene product. Absence of the murine homolog of nephrocystin-1 does not lead to nephronophthisis but to infertility and oligospermia in male mice [Jiang et al 2008], suggesting redundancy between nephrocystin-associated proteins within the renal epithelium of mice. However, the association of nephrocystin-1 with many other ciliary proteins and its known localization to the cilium/basal body in renal epithelium suggests a critical role in renal tubular development.

OFD1 (CXORF5)

Gene structure. This gene escapes X-chromosome inactivation, comprises 23 exons, and encodes a 1012-amino acid protein that interacts with lebercilin (encoded by LCA5, NM_181714.3). There are two alternative splice variants: CXORF5-2 differs from CXORF5-1 by an insertion of 663 bp resulting from the use of an alternative 3-prime splice site in intron 9. CXORF5-1 encodes a deduced 1,011-amino acid protein containing a large number of predicted coiled-coil alpha-helical domains. CXORF5-2 encodes a deduced protein of 367 amino acids; the first 353 residues of CXORF5-2 and CXORF5-1 are identical.

Pathogenic allelic variants. Two families with X-linked recessive inheritance have frameshift mutations in exon 21 [c.2841_2847 delAAAAGAC (p.Lys948AsnfsTer8)] and [c.2767 delG (p.Glu923LysfsTer3)] which diminishes the amount of full-length mRNA produced, with resultant effects on protein function [Coene et al 2009]. A third family has an 18-bp deletion in exon 8, resulting in an in-frame deletion of six amino acids [Field et al 2012].

Normal gene product. The coiled-coil regions of oral-facial-digital syndrome 1 protein are predicted to interact with the first two coiled-coil domains of lebercilin. Both proteins localize to the pericentriolar region in human and rat retinal cell lines.

Abnormal gene product. Mutations in CXORF5 have been found to weaken the interaction with lebercilin to varying degrees, with recessive mutations having some residual binding activity, versus dominant ones that abolish binding and cause X-linked oral-facial-digital syndrome type 1 (lethal in males). In addition, the pericentriolar localization of the protein is abolished in females with oral-facial-digital syndrome type 1.

RPGRIP1L

Gene structure. The gene comprises 26 exons and 3948 bp and encodes a 1315-amino acid protein.

Pathogenic allelic variants. A wide variety of missense, nonsense, and splice mutations have been identified. In general, more severe truncating mutations are associated with the lethal Meckel syndrome phenotype, while less severe mutations cause JSRD, including the COACH variant [Delous et al 2007, Wolf et al 2007]. In addition, the coding variant c.685G>A (resulting in amino acid change p.Ala229Thr) is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes [Khanna et al 2009].

Normal gene product. The protein encoded by this gene (protein fantom) has coiled-coil domains, a C2 calcium-binding domain, a RPGR (retinitis pigmentosa GTPase regulator) interacting domain, and a centrosomal protein-related domain. It can localize to the basal body-centrosome complex or to primary cilia and centrosomes in ciliated cells. The protein interacts with nephrocystin-4, the protein defective in some forms of nephronophthisis and Senior-Løken syndrome [Arts et al 2007]. Two transcript variants encoding different protein isoforms have been identified for RPGRIP1L.

Abnormal gene product. Homozygous knockout of the murine ortholog of RPGRIP1L results in defects in ciliary function and assembly, body axis asymmetry, and polyactyly, presumably related to disturbed sonic hedgehog signaling [Vierkotten et al 2007]. In addition, the p.Ala229Thr change appears to alter the interaction of the RPGRIP1L-encoded protein with RPGR protein, resulting in loss of photoreceptor cell loss [Khanna et al 2009].

TCTN1

Gene structure. TCTN1 (tectonic family member 1) is a member of the tectonic family of membrane and secreted proteins. It has at least five splice isoforms, comprises 13 exons, and encodes a 593-amino acid protein [Reiter & Skarnes 2006].

Pathogenic allelic variants. A homozygous mutation in the obligatory splice acceptor consensus sequence of intron 1 (IVS1 -2A>G) of TCTN1 was identified in two affected children in a family from Bangladesh but not in 48 other families with JSRD or in 4 families that mapped to the region [Garcia-Gonzalo et al 2011].

Normal gene product. Tectonic-1 is a signal-sequence-containing protein that localizes to the membrane-spanning transition zone complex, a region between the basal body and ciliary axoneme that regulates ciliogenesis. In mice, Tctn1 is required for ciliogenesis in a tissue-dependent manner and forms a complex with other JSRD- and Meckel-associated proteins, such as Mks1, Tmem216,Tmem67, Cep290 Tctn2, and Cc2d2a [Reiter & Skarnes 2006, Garcia-Gonzalo et al 2011].

Abnormal gene product. TCTN1 regulates Hedgehog signaling, required for both activation and inhibition of ventral patterning of the neural tube. Tctn1 homozygous null mice die during embryogenesis with holoprosencephaly and expansion of dorsal gene expression [Reiter & Skarnes 2006].

TCTN2

Gene structure. TCTN2 (tectonic family member 2) comprises 18 exons and encodes several transcripts, the longest of which is 697 amino acids. The gene encodes an N-terminal signal peptide and a C-terminal transmembrane domain that is conserved in the Drosophila ortholog [Reiter & Skarnes 2006].

Pathogenic allelic variants. Nonsense, frameshift, and splice site mutations in this gene have been implicated in JSRD and MKS [Sang et al 2011, Shaheen et al 2011].

Normal gene product. Tectonic-2. In mice, the Tctn2 protein is known to regulate Hedgehog signaling and ciliogenesis. It interacts with Mks1 and Cc2d2a.

Abnormal gene product. Tctn2 homozygous null mice demonstrate defects in neural tube closure (exencephaly), microphthalmia, cleft palate, polydactyly, structural cardiac defects (VSD), and situs abnormalities, depending on the genetic background [Sang et al 2011]. The concept of a ciliary “interactome” involving NPHP, JBTS, and MKS proteins has been proposed to explain the modular nature of the ciliary structure and the different functions of interacting clusters of proteins involved in a variety of cellular processes [Sang et al 2011].

TCTN3

Gene structure. TCTN3 (tectonic family member 3) has 14 coding exons, at least two alternatively spliced forms, and is a member of the tectonic gene family that includes TCTN1 and TCTN2 [Thomas et al 2012].

Pathogenic allelic variants. Homozygous truncating mutations in this gene have been identified with a severe OFD IV phenotype characterized by long bones bowing, tibial hypoplasia, polydactyly, cystic kidneys, oralfacial anomalies, and encephalocele. Less severe missense mutations have been identified in a form of JSRD characterized by digital and axial skeletal anomalies including scoliosis [Thomas et al 2012].

Normal gene product. TCTN3 encodes a 607-amino acid protein with a transmembrane domain. Although TCTN3 is not critical for cilia biogenesis in the kidney, it encodes a protein that is necessary for GLI3 processing and functioning in the sonic hedgehog pathway and is part of the B9 transition zone complex at the cilium/plasma membrane border [Thomas et al 2012].

Abnormal gene product. Fibroblasts from patients with mutations in TCTN3 fail to respond to sonic sedgehog agonists, suggesting a defect in sonic hedgehog signaling [Thomas et al 2012].

TMEM67 (MKS3)

Gene structure. The gene comprises 28 exons and spans 62.0 kb of genomic DNA with a full-length transcript size of 3,467 bp [Smith et al 2006]. There is at least one splice variant form of 29 exons and length of 3,280 bp encoding a protein with 995 residues [Ensembl Database].

Pathogenic allelic variants. Mutations identified in individuals with Joubert syndrome and related disorders include splice-site mutations resulting in abnormal transcripts and missense mutations, both presumably representing hypomorphic alleles with milder phenotypes than the more severe lethal mutations causing Meckel syndrome [Smith et al 2006, Baala et al 2007]. Mutations in this gene are particularly prevalent in individuals with JSRD and liver involvement (the COACH variant) [Iannicelli et al 2010].

Normal gene product. Meckelin, a 995-amino acid protein with a calculated molecular weight of 108 kd, is predicted to contain a signal peptide, at least two cysteine-rich repeats, and a 490-amino acid extracellular region, followed by seven transmembrane domains and a small 30-residue cytoplasmic tail [Smith et al 2006]. The protein has been localized to the primary cilium and plasma membrane of renal and biliary epithelial cells and other ciliated cells and has been shown to interact with the MKS1 protein involved in Meckel syndrome. Meckelin is involved in centrosome migration to the apical cell surface during early ciliogenesis, and is essential for ciliary development and function [Dawe et al 2007].

Abnormal gene product. The spontaneous rat mutant, wpk/wpk, with a point mutation in TMEM67, exhibits polycystic kidneys and hydrocephalus with agenesis of the corpus callosum [Smith et al 2006]. A comparable phenotype is observed in the spontaneous murine deletion mutants, which typically die by age three weeks of polycystic nephropathy; some also develop hydrocephalus [Cook et al 2009].

TMEM138

Gene structure. The gene contains five exons, the first of which is non-coding. The 23-kb intergenic region between TMEM138 and TMEM216 appears to coordinate the expression of these two ciliary genes, both of which can cause JSRD [Lee et al 2012b].

Pathogenic allelic variants. Mutations in TMEM138 were identified when mutations in TMEM216 were absent in about half of the families linked to 11q12.2; a search for other causative genes identified TMEM138, adjacent to TMEM216 in a head-to-tail configuration. Four missense mutations in conserved residues and one splice-site mutation have been identified in affected individuals with JSRD [Lee et al 2012b].

Normal gene product. The normal gene product (NP_057548.1) comprises 162 amino acids and has an N-terminal signal sequence followed by 3 transmembrane domains. TMEM138 and TMEM216 are required for ciliogenesis, and each localizes to a distinct vesicle pool that carries proteins necessary for ciliary assembly from the Golgi to the primary cilia; one of the proteins that colocalizes with TMEM138 is CEP290 [Lee et al 2012b].

Abnormal gene product. Fibroblasts from individuals with the mutant protein display shortened cilia. Zebrafish with morpholino knockdown of TMEM138 have the ciliary phenotypes of pericardial effusion, kinked tail, and gastrulation defects [Lee et al 2012b].

TMEM216

Gene structure. TMEM216 comprises six exons. The longest splice isoform (NM_001173990) encodes a 148-amino acid protein. There are multiple splice variants. The 23-kb intergenic region between TMEM216 and TMEM138 appears to coordinate the expression of these two ciliary genes, both of which can cause JSRD [Lee et al 2012b].

Pathogenic allelic variants. Pathogenic mutations include missense, nonsense, and splice mutations. One common mutation (c.218G>T), resulting in the protein change p.Arg73Leu, appears to be a founder mutation in the Ashkenazi Jewish population with carrier frequency of 1:92 to 1:100 [Edvardson et al 2010, Valente et al 2010]. Mutations, many of which are predicted to produce a truncated protein, also cause the lethal Meckel syndrome phenotype [Valente et al 2010].

Normal gene product. The longest isoform is transmembrane protein 216, a tetraspan transmembrane protein containing four hydrophobic transmembrane domains. These proteins appear to regulate signaling and trafficking properties of other partner proteins, including Wnt receptors. TMEM216 localizes to the base of primary cilia and forms a complex with Meckelin, another transmembrane protein defective in JSRD encoded by TMEM67 [Valente et al 2010]. In addition, TMEM216 and TMEM138 are required for ciliogenesis, as each localizes to a distinct vesicle pool that carries proteins necessary for ciliary assembly from the Golgi to the primary cilia [Lee et al 2012b].

Abnormal gene product. Disruption of tmem216 in zebrafish causes defects in gastrulation as well as other changes typical of altered ciliary function [Valente et al 2010].

TMEM231

Gene structure. There are multiple TMEM231 transcript variants, with at least six exons each [Srour et al 2012a].

Pathogenic allelic variants. The two pathogenic mutations identified thus far disrupt the translation start site of one isoform or predict a nonsense change or missense change predicted to be damaging. These mutations are very rare, even in the French-Canadian population [Srour et al 2012a].

Normal gene product. There are at least three isoforms encoded by TMEM231 with one or two transmembrane domains [Srour et al 2012a]. TMEM231 is a transmembrane protein localized to the base of the ciliary axoneme where it is part of the B9 complex that forms a barrier between the cilium and plasma membrane; almost all of the proteins that form this complex cause JSRD and/or MKS when altered [Chih et al 2011].

Abnormal gene product. Knockdown of TMEM231 disrupts the ciliary barrier and the localization of B9 complex components to the transition zone, with reduction in formation of cilia. The Tmem231 knockout mice die during embryonic development with many features characteristic of ciliopathies, including vascular defects, polydactyly, and eye abnormalities [Chih et al 2011].

TMEM237 (ALS2CR4)

Gene structure. TMEM237 is a 14-exon gene encoding two alternatively spliced transcripts, the largest of which encodes a 408-amino acid protein [Huang et al 2011].

Pathogenic allelic variants. Mutations in individuals with JSRD include nonsense, frameshift, large insertions, and splice-site mutations. The Hutterite mutation is c.52C>T, resulting in p.Arg18Ter; it is estimated to have a carrier frequency of 6% in this population [Huang et al 2011].

Normal gene product. Transmembrane protein 237 contains four transmembrane domains and has both N- and C-termini directed to the cytoplasm. In mouse kidney cells, it localizes to the transition zone at the proximal region of primary cilia, and in mouse photoreceptor cells, it localizes to the connecting cilium and outer segments [Huang et al 2011].

Abnormal gene product. Loss of TMEM237 in mammalian cells causes defects in ciliogenesis and Wnt signaling. In zebrafish, disruption of tmem237 expression results in defects in gastrulation. TMEM237 appears to functionally interact with NPHP4, RPGRIP1L, TMEM216, and other proteins implicated in the ciliary transition zone [Huang et al 2011].

TTC21B

Gene structure. The gene has 29 coding exons, encodes a presumed 1,316-amino acid protein of approximately 150 kd, and is predicted to contain 11 tetratricopeptide repeat (TPR) domains [Davis et al 2011].

Pathogenic allelic variants. Homozygous or compound heterozygous mutations in this gene have been identified in individuals with NPHP and JATD. Sequencing of a clinically diverse cohort of 753 individuals or families with ciliopathies (NPHP, BBS, MKS, JATD, JSRD) revealed pathogenic mutations in TTC21B in 5%, representing a significant contribution; of these, one third had an additional mutant allele in one of 13 established ciliopathy genes in trans, suggesting the possibility of digenic inheritance. Within this cohort, three individuals with JSRD were heterozygous for a TTC21B mutant allele but had no other causative mutations identified. The p.Pro209Leu hypomorphic allele was identified in several probands with NPHP with or without extrarenal manifestations. The pathogenicity of these mutations was confirmed by a variety of functional analyses [Davis et al 2011].

Normal gene product. The gene product is THM1, “tetratricopeptide repeat-contatining hedgehog modulator-1,” also known as IFT139, an axonemal protein required for retrograde intraflagellar transport [Davis et al 2011] (reference sequence NP_079029.3).

Abnormal gene product. Knockout of the orthologous murine gene Ttc21b is responsible for the 'alien' (aln) locus in mouse which shows ciliary defects and impaired retrograde intraflagellar transport [Tran et al 2008]. Functional deficits in zebrafish morphants were consistent with ciliary defects [Davis et al 2011].

References

Published Guidelines/Consensus Statements

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Suggested Reading

  1. Fluss J, Blaser S, Chitayat D, Akoury H, Glanc P, Skidmore M, Raybaud C. Molar tooth sign in fetal brain magnetic resonance imaging leading to the prenatal diagnosis of Joubert syndrome and related disorders. J Child Neurol. 2006;21:320–4. [PubMed: 16900929]
  2. Helou J, Otto EA, Attanasio M, Allen SJ, Parisi M, Glass I, Utsch B, Hashmi S, Fazzi E. Mutation analysis of NPHP6/CEP290 in patients with Joubert-syndrome and Senior-Løken syndrome. J Med Genet. 2007;44:657–63. [PMC free article: PMC2597962] [PubMed: 17617513]
  3. Sturm V, Leiba H, Menke MN, Valente EM, Poretti A, Landau K, Boltshauser E. Ophthalmological findings in Joubert syndrome. Eye (Lond.) 2010;24:222–5. [PubMed: 19461662]

Chapter Notes

Revision History

  • 11 April 2013 (cd/mp) Revision: mutations in TMEM231 and TCTN3 identified to cause JSRD; clarification of the uncertainty of a role for mutation in TTC21B; sequence analysis and deletion/duplication analysis available clinically for mutations in C5orf42 and CEP41; edits to Figure 2
  • 13 September 2012 (cd) Revision: sequence analysis available clinically for TCTN1, TCTN2, TTC21B, and TMEM13; deletion/duplication analysis available for TMEM138
  • 14 June 2012 (cd/mp) Revision: targeted mutation analysis for the TMEM216 founder mutation c.218G>T available clinically
  • 24 May 2012 (cd/mp) Revision: Joubert syndrome 11, 15, 16, and 17 result from mutations in TTC21B, CEP41, TMEM138, and C5orf52 respectively
  • 29 March 2012 (me) Comprehensive update posted live
  • 8 March 2007 (cd) Revision: mutations in TMEM67 (MKS3) identified in 3/22 individuals with JS who did not have NPHP1 deletions; MKS3 is sixth JS locus.
  • 4 August 2006 (cd) Revision: clinical testing and prenatal diagnosis available for CEP290 mutations
  • 25 July 2006 (cd) Revision: AHI1 sequence analysis clinically available; prenatal diagnosis for AHI1 and NPHP1 clinically available
  • 30 June 2006 (ca) Revision: mutations in CEP290 (NPHP6) identified in individuals with JTS
  • 24 February 2006 (me) Comprehensive update posted to live Web site
  • 9 July 2003 (me) Review posted to live Web site
  • 27 January 2003 (mp) Original submission
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