Classic Joubert syndrome is characterized by three primary findings:
- A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS)
- 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.
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 pathogenic variants 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 pathogenic variants in TTC21B have been reported.
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.
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 pathogenic variants 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.
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
Additional features often identified in individuals with Joubert syndrome include:
- Abnormal breathing pattern (alternating tachypnea and/or apnea);
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 mutation is 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) pathogenic variant only in TTC21B have been reported. The functional significance of a single pathogenic variant 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 pathogenic variants identified in one of the identified genes.
- The JSRD phenotype in many families is not linked to any of the genes identified to date.
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 [Parisi 2009, Doherty et al 2010] (Figure 2).
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 pathogenic variant(s) in any given individual with the JSRD phenotype also varies.
Carrier testing for at-risk relatives requires prior identification of the pathogenic variant(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 pathogenic variant and have no known symptoms.
Prenatal diagnosis/preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.
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 mutation of CEP290 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
- Abnormal EEG and/or seizures are present in some affected individuals; the exact incidence is unknown [Saraiva & Baraitser 1992].
JSRD Clinical Subtypes
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].
- Ocular colobomas are most often described as chorioretinal [Saraiva & Baraitser 1992, Parisi 2009] and may be associated with hepatic fibrosis, as in the COACH syndrome variant [Doherty et al 2010]. One survey described colobomas in 19% of families with JSRD [Doherty 2009]. A retinal change described as the “morning glory disc anomaly” has been described in an extended Austrian family from the Tyrolean region with pathogenic variants in TMEM237 [Janecke et al 2004, Huang et al 2011].
- Other. Variably present:
- Ptosis, strabismus, and/or amblyopia
- Third nerve palsy [Hodgkins et al 2004]
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 by mutation of TMEM67 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].
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 2010].
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].
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 [Münke 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 pathogenic variants 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 pathogenic variants 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 pathogenic variants in KIF7 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
- Abnormal collections of cerebrospinal fluid in the fourth ventricle or the posterior fossa that resemble Dandy-Walker malformation (~10% of individuals) [Maria et al 2001]
- Abnormal brain stem and hypothalamic hamartomas, particularly in those with oral-facial-digital syndrome type VI-related findings [Poretti et al 2011]
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].
Table 3 includes preliminary information on genotype-phenotype correlations.
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 pathogenic variant 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 mutation of AHI1 is estimated at 10%. In one study, 13 of 117 (11%) individuals with Joubert syndrome hadpathogenic variants in AHI1 [Parisi et al 2006], whereas another survey of 137 persons identified 7.3% with pathogenic variants in this gene [Valente et al 2006a]. Approximately 80% of those with AHI1 pathogenic variants have retinal dystrophy [Valente et al 2008].
CEP290. In one study, seven of 96 individuals with Joubert syndrome (7%) had identifiablepathogenic variants in CEP290 [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 pathogenic variants [Valente et al 2006b]. It is likely that an estimated 10% or more of JSRD is related to mutation of CEP290, 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, mutation of TMEM67 has 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, Parisi 2009, Doherty et al 2010]. In fact, pathogenic variants in TMEM67 account for 70% of all JSRD and liver involvement when combining several case series [Doherty et al 2010, Iannicelli et al 2010]. For those with JSRD and ocular colobomas, regardless of liver status, 53% had pathogenic variants in this gene [Doherty et al 2010]. More severe loss-of-function variants in TMEM67 have been identified in individuals with lethal forms of Meckel syndrome [Smith et al 2006], in comparison with milder loss-of-function variants causing JSRD with hepatic disease or nephronophthisis and liver fibrosis in the absence of the molar tooth sign and other neurologic symptoms [Otto et al 2009, Doherty et al 2010].
RPGRIP1L. Pathogenic variants 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. Mutation of this gene also causes Meckel syndrome, with more severe truncating pathogenic variants 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 pathogenic variants 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 2010]. 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 pathogenic variants in this gene [Bachmann-Gagescu et al 2012]. Some French Canadians with a mild form of JSRD have pathogenic variants in this gene [Srour et al 2012a].
ARL13B. Mutation of this gene appears 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 pathogenic variants to JSRD remains unknown, as a limited number of individuals with pathogenic variants 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]. Mutation of OFD1 causes X-linked dominant oral-facial-digital syndrome type I, but the few OFD1 pathogenic variants in males with JSRD are predicted to have a less severe effect on the function of the protein than the pathogenic variants 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 pathogenic variants in TMEM216 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 pathogenic variants in TMEM216 [Valente et al 2010].
KIF7. Individuals with pathogenic variants in KIF7 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 pathogenic variants in this gene [Huang et al 2011]. Encephalocele, hydrocephalus, and cystic kidney disease are common in those with pathogenic variants in TMEM237.
C5orf42. Mutation of this gene is the cause of JSRD in the original family described by Joubert et al . There are three founder variants, each linked to a distinct haplotype, and a total of seven different pathogenic variants 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 variants in this gene. Slightly more than 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 pathogenic variants 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. Mutation of this gene appears to account for some individuals with JSRD of French-Canadian descent. Only three individuals in two families have been described with compound heterozygous pathogenic variants 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 variants 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 variants in TTC21B, but only one third of these had a second pathogenic variant identified in a different ciliopathy gene [Davis et al 2011].
TCTN3. Homozygous truncating variants 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 variants 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].
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]
- 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 [Münke et al 1990]. Renal and cardiac involvement has been described.
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  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 pathogenic variants in this gene have been compound heterozygotes.Several French-Canadian individuals are compound heterozygous for pathogenic variants in CC2D2A, and others have pathogenic variants in TMEM231 [Srour et al 2012a, Srour et al 2012b].
Genetically Related (Allelic) Disorders
Pathogenic variants in genes that cause JSRD have also been identified in disorders with clinical findings that overlap with JSRD; thus, in many instances it has become difficult to determine if a previously recognized disorder is truly distinct from JSRD (i.e., is an allelic disorder) or is part of the spectrum of JSRD (see Table 3). Brief descriptions of some of those disorders follow.
Nephronophthisis, an autosomal recessive kidney disease characterized by renal tubular atrophy and progressive interstitial fibrosis with later development of medullary cysts, is caused by pathogenic variants in at least twelve genes [Hildebrandt et al 2009, Hurd & Hildebrandt 2011]. The age of onset of end-stage renal disease can be variable, thereby defining subtypes such as infantile, juvenile, and adolescent. A homozygous, approximately 290-kb deletion of NPHP1 is identified in approximately 25% of individuals with juvenile nephronophthisis [Hoefele et al 2005, Saunier et al 2005, Hildebrandt et al 2009]. Note: The most common form, juvenile nephronophthisis, can also be a renal manifestation in JSRD. Conversely, it is estimated that 10% of individuals with nephronophthisis have extrarenal findings, which can include the molar tooth sign in some cases [Saunier et al 2005].
Cogan syndrome, an autosomal recessive familial form of congenital oculomotor apraxia, is characterized by defective horizontal voluntary eye movements with jerkiness. Oculomotor apraxia is also a common manifestation of JSRD. Detailed neuroimaging via fiber tracking suggests that there may be subtle differences in some of the pathways in Cogan syndrome versus JSRD [Merlini et al 2010].
Some individuals with Cogan syndrome also have cerebellar vermis hypoplasia, with evidence of the molar tooth sign [Whitsel et al 1995, Sargent et al 1997], and occasionally develop nephronophthisis. The approximately 290-kb NPHP1 homozygous deletion or compound heterozygosity for the approximately 290-kb deletion and an NPHP1 single-nucleotide variant have been identified in some individuals with Cogan syndrome [Saunier et al 1997, Betz et al 2000].
Leber congenital amaurosis (LCA), a severe dystrophy of the retina, typically becomes evident in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. Visual acuity is rarely better than 20/400. A characteristic finding is Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing. The appearance of the fundus is extremely variable. While the retina may initially appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The electroretinogram (ERG) is characteristically "nondetectable" or severely subnormal. Mutation of CEP290 accounts for about 20% of LCA, and one homozygous intronic pathogenic variant accounts for at least 20% of isolated congenital blindness in European cohorts [den Hollander et al 2006].
Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by cone-rod retinal dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, hypogonadotropic hypogonadism in males, genital malformations in females, and renal disease, which can include structural malformations, renal hypoplasia, hydronephrosis, cystic kidneys, and glomerulonephritis. Progressive retinal impairment often causes blindness, and renal failure may cause significant morbidity. Some affected individuals have hepatic fibrosis. Although many individuals are ataxic with poor coordination, cerebellar involvement or structural malformations are not typical [Baskin et al 2002]. Pathogenic variants in at least 15 genes, all of which play a role in the primary cilium, have been described. Pathogenic variants in CEP290 have been shown to cause both BBS and JSRD [Leitch et al 2008, Zaghloul & Katsanis 2009]. Heterozygous changes in CEP41 or TTC21B have been identified in probands with BBS [Lee et al 2012a, Davis et al 2011].
Meckel syndrome, an autosomal recessive disorder, is characterized by the triad of cystic renal disease, posterior fossa abnormalities (usually occipital encephalocele), and the hepatic ductal plate malformation leading to hepatic fibrosis and bile duct proliferation. Polydactyly is relatively common. Cerebellar vermis hypoplasia has been described in some individuals. Meckel syndrome is usually lethal in the prenatal or perinatal period [Kyttälä et al 2006, Smith et al 2006]. Pathogenic variants in at least six genes have been identified; variants in five of these genes, CEP290, TMEM67, RPGRIP1L, CC2D2A, and TMEM216, have also been identified in individuals with JSRD [Parisi 2009, Valente et al 2010]. In many cases, pathogenic variants that predict a more severe effect on protein function are associated with the lethal Meckel syndrome phenotype, while milder variants are associated with Joubert syndrome and related disorders. In some families the identical pathogenic variants can be found in a fetus with Meckel syndrome and a child with a JSRD, highlighting that these disorders can represent a spectrum [Valente et al 2010]. Homozygous changes in TMEM138 [Lee et al 2012b] or heterozygous changes in CEP41 or TTC21B have also been identified in probands with MKS [Davis et al 2011, Lee et al 2012a].
MORM (mental retardation, truncal obesity, retinal dystrophy, micropenis) syndrome, an autosomal recessive disorder, appears to be related to Bardet-Biedl syndrome and is caused by mutation of INPP5E [Bielas et al 2009, Jacoby et al 2009]. Individuals with this condition have normal growth parameters and life span with a congenital non-progressive retinal dystrophy and static mild-to-moderate cognitive impairment; in contrast to Bardet-Biedl syndrome, there is no polydactyly, apparent hypogonadism, or obvious renal disease [Hampshire et al 2006].
Oral-facial-digital syndrome describes a heterogeneous group of disorders characterized by facial features, oral abnormalities (often lobulated tongue and oral frenula), and digital anomalies such as polydactyly. Based on other associated clinical features, at least 13 clinical subtypes have been described. These features also overlap considerably with Meckel syndrome, short rib-polydactyly syndrome, and JSRD. Of the few related genes identified thus far, all have all had ciliary roles.
Oral-facial-digital syndrome type I (OFD1) is associated with dysfunction of primary cilia and is characterized by the following abnormalities:
- Oral (lobed tongue, hamartomas or lipomas of the tongue, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia and other dental abnormalities)
- Facial (ocular hypertelorism or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia)
- Digital (brachydactyly, syndactyly of varying degrees, and clinodactyly of the fifth finger; duplicated hallux [great toe]; preaxial or postaxial polydactyly of the hands)
- Brain (intracerebral cysts, corpus callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation)
- Kidney (polycystic kidney disease)
As many as 50% of individuals with OFD1 have some degree of intellectual disability that is usually mild. Almost all affected individuals are female. However, males with OFD1 have been described, mostly as malformed fetuses delivered by women with OFD1.
Of note, the phenotypic spectrum was broadened with recognition that the clinical features described in four individuals (hydrops fetalis, jaundice, brisk deep tendon reflexes, seizures, and trilobate left lung) [Terespolsky et al 1995, Brzustowicz et al 1999] were associated with mutation of OFD1 [Budny et al 2006].
Oral-facial-digital syndrome type IV (OFD IV, Mohr-Majewski syndrome) is characterized by hallucal and postaxial polysyndactyly, tibial dysplasia, with variable short ribs, cystic kidneys and brain anomalies. Truncating variants in TCTN3 were identified in several pedigrees with a severe lethal OFD IV phenotype and bowing of long bones, cystic kidneys, occipital encephalocele and bile duct proliferation of the liver but without short ribs; several of these fetuses also displayed vermis agenesis suggestive of the molar tooth sign [Thomas et al 2012]. Of note, this phenotype clearly overlaps with Meckel syndrome and with JSRD.
Hydrolethalus syndrome (HLS), a lethal autosomal recessive disorder, is associated with midline brain anomalies (usually hydrocephaly or anencephaly with a keyhole foramen magnum), migrognathia, postaxial polydactyly of the hands, and preaxial polydactyly of the feet. Pathogenic variants in HYLS1 were identified in affected persons in the Finnish population [Mee et al 2005]. More recently, pathogenic variants in KIF7 were identified in a consanguineous Algerian pedigree in which four affected fetuses had features consistent with HLS, but also a midbrain-hindbrain malformation similar to the MTS [Putoux et al 2011].
Acrocallosal syndrome (ACLS), an autosomal recessive disorder, is characterized by macrocephaly, intellectual disability, agenesis of the corpus callosum and occasional posterior fossa abnormalities, ocular hypertelorism, polyaxial polydactyly of the hands, and preaxial polydactyly of the feet. It has been postulated that ACLS is allelic to hydrolethalus syndrome; recent identification of several families with both disorders and pathogenic variants in KIF7 confirms the proposed association [Putoux et al 2011]; of note, several of the probands had evidence of the MTS on cranial imaging, suggesting that ACLS and JSRD may represent overlapping ciliopathies.
Jeune asphyxiating thoracic dystrophy (JATD), an autosomal recessive skeletal dysplasia characterized by a long, narrow thorax, short stature, short limbs, polydactyly, and renal cystic disease, with skeletal findings that may include cone-shaped epiphyses in hands and feet, irregular metaphyses, shortened ilium, and trident-shaped acetabulum. It is often lethal in infancy secondary to respiratory insufficiency. At least five genes and/or loci have been identified, with several ciliary genes implicated (including 2 intraflagellar transport proteins [IFTs]). Heterozygous pathogenic variants in TTC21B have been identified in three families with JATD, with one proband demonstrating compound heterozygosity for a null allele and a hypomorphic allele [Davis et al 2011].
Disorders in the differential diagnosis include the following (see Genetically Related Disorders for discussion):
- Cogan syndrome
- Meckel syndrome
- MORM (mental retardation, truncal obesity, retinal dystrophy, micropenis) syndrome
- Oral-facial-digital syndrome type I, type IV, and type VI
- Hydrolethalus syndrome
- Acrocallosal syndrome
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
- 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.
- 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
- 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.
- 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.
- Surgical treatment for polydactyly
- Appropriate medical management by an orthopedic specialist for scoliosis
- 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.
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 pathogenic variants have been identified in a proband, testing symptomatic relatives for these variants 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 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 mutated 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—Digenic Inheritance
Joubert syndrome is reported to result from a heterozygous pathogenic variant in CEP41 in combination with mutation of either CC2D2A or KIF7 [Lee et al 2012a].
Parents of a proband
- The parents are obligate heterozygotes; one parent carries a CEP41 pathogenic variant and the other parent carries either a CC2D2A or a KIF7 pathogenic variant.
- 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 pathogenic variants, 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 pathogenic variants.
Other family members of a proband. Each sib of an obligate heterozygote has a 50% chance of being a carrier.
Carrier testing for at-risk family members is possible once the pathogenic variant(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.
- 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 and Preimplantation Genetic Diagnosis
Molecular genetic testing. Once the pathogenic variant(s) have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.
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 [Ní 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.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
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 FoundationPhone: 614-864-1362Email: firstname.lastname@example.org
- My46 Trait Profile
- National Institute of Neurological Disorders and Stroke (NINDS)PO Box 5801Bethesda MD 20824Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
- National Library of Medicine Genetics Home Reference
- Ciliopathy AllianceUnited KingdomPhone: 44 20 7387 0543
- Joubert Syndrome Link to Information & Family Exchange (JS-LIFE Registry)
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Molecular Genetic Pathogenesis
All of the genes in which mutation is 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.
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 variants 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].
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 pathogenic missense and/or nonsense variants 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, pathogenic variants 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].
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 pathogenic variants 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 pathogenic variants 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 pathogenic variants are predicted to result in nonsense, aberrant splicing, exon skipping (c.7400+1G>A), or pathogenic missense variants, all but one of which are predicted to be damaging by protein prediction algorithms; the exception is c.4690G>A (p.Ala1564Thr), which is not clearly deleterious and may be linked to another, as-yet unidentified pathogenic variant [Srour et al 2012b].
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. Mutation of this gene causes Meckel syndrome and JSRD, including the COACH syndrome variant; null variants 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].
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 allelic variants in CEP41 had homozygous splice-site variants. Heterozygous CEP41 pathogenic variants have been identified in five additional individuals with Joubert syndrome, three of whom had heterozygous pathogenic variants 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].
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. More than 100 distinct pathogenic variants 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 variants are caused by small insertions or deletions. Only three pathogenic variants are missense; 20 affect splicing [Coppieters et al 2010].
The most frequent recurrent pathogenic variant 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 pathogenic variant 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 pathogenic variant resulting in some residual wild-type protein being produced.
The spectrum of phenotypes associated with mutation of 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 pathogenic variant 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 pathogenic variants 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].
Gene structure. INPP5E comprises nine exons and 3440 bp of mRNA and encodes a 644-amino acid protein.
Pathogenic allelic variants. Pathogenic missense variants 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 pathogenic variant 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 pathogenic variants 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].
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 pathogenic variants that cause hydrolethalus syndrome, acrocallosal syndrome, and JSRD are typically nonsense variants or frameshift variants 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 pathogenic variants 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 variants in other genes associated with BBS and one with JSRD had two MKS3 pathogenic variants [Dafinger et al 2011, Putoux et al 2011]. Based on rescue studies in morphant zebrafish embryos, it is likely that the KIF7 pathogenic variants 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].
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 single-nucleotide variants 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.
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 variants 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. Mutation of CXORF5 has been found to weaken the interaction with lebercilin to varying degrees, with recessive pathogenic variants 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.
Gene structure. The gene comprises 26 exons and 3948 bp and encodes a 1315-amino acid protein.
Pathogenic allelic variants. A wide variety of pathogenic missense, nonsense, and splice variants have been identified. In general, more severe truncating variants are associated with the lethal Meckel syndrome phenotype, while less severe variants 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 mutation of 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].
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 pathogenic variant 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].
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].
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].
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 variants 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 variants 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 individuals with pathogenic variants in TCTN3 fail to respond to sonic sedgehog agonists, suggesting a defect in sonic hedgehog signaling [Thomas et al 2012].
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. Pathogenic variants identified in individuals with Joubert syndrome and related disorders include splice-site variants resulting in abnormal transcripts and missense variants, both presumably representing hypomorphic alleles with milder phenotypes than the more severe lethal pathogenic variants causing Meckel syndrome [Smith et al 2006, Baala et al 2007]. Mutation of this gene is 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 single-nucleotide variant 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].
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. Pathogenic variants in TMEM138 were identified when pathogenic variants 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 variants in conserved residues and one splice-site variant 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 mutated 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].
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 variants include missense, nonsense, and splice variants. One common pathogenic variant (c.218G>T), resulting in the protein change p.Arg73Leu, appears to be a founder variant in the Ashkenazi Jewish population with carrier frequency of 1:92 to 1:100 [Edvardson et al 2010, Valente et al 2010]. TMEM216 pathogenic variants, 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].
Gene structure. There are multiple TMEM231 transcript variants, with at least six exons each [Srour et al 2012a].
Pathogenic allelic variants. The two pathogenic variants identified thus far disrupt the translation start site of one isoform or predict a nonsense change or missense change predicted to be damaging. These pathogenic variants 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].
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. Pathogenic variants in individuals with JSRD include nonsense, frameshift, large insertions, and splice-site variants. The Hutterite variant 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].
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 pathogenic variants 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 variants in TTC21B in 5%, representing a significant contribution; of these, one third had an additional mutated 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 mutated allele but had no other causative pathogenic variants identified. The p.Pro209Leu hypomorphic allele was identified in several probands with NPHP with or without extrarenal manifestations. The pathogenicity of these variants was confirmed by a variety of functional analyses [Davis et al 2011].
Normal gene product. The gene product is THM1, “tetratricopeptide repeat-containing 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].
Published Guidelines/Consensus Statements
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- 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
National Institutes of Health
Department of Pediatrics
Children's Hospital and Regional Medical Center
University of Washington
Initial Posting: July 9, 2003; Last Revision: April 11, 2013.
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Parisi M, Glass I. Joubert Syndrome and Related Disorders. 2003 Jul 9 [Updated 2013 Apr 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.