Bardet-Biedl Syndrome

[Biedl-Bardet Syndrome. Includes: ARL6-Related Bardet-Biedl Syndrome, BBS1-Related Bardet-Biedl Syndrome, BBS2-Related Bardet-Biedl Syndrome, BBS4-Related Bardet-Biedl Syndrome, BBS5-Related Bardet-Biedl Syndrome, BBS7-Related Bardet-Biedl Syndrome, BBS9-Related Bardet-Biedl Syndrome, BBS10-Related Bardet-Biedl Syndrome, BBS12-Related Bardet-Biedl Syndrome, CEP290-Related Bardet Biedl Syndrome, MKKS-Related Bardet-Biedl Syndrome, MKS1-Related Bardet Biedl Syndrome, TRIM32-Related Bardet-Biedl Syndrome, TTC8-Related Bardet-Biedl Syndrome]

Clinical Diagnosis

The diagnosis of Bardet-Biedl syndrome (BBS) is established by clinical findings. Beales et al [1999] and Beales et al [2001] have suggested that the presence of four primary features or three primary features plus two secondary features is diagnostic.

Note: Establishing the diagnosis of BBS in a given individual may be delayed as a result of the slow emergence and variable expression of the clinical features [Beales et al 1999]. Difficulties in diagnosis arise, for example, in an obese child with learning difficulties and developmental delay but without polydactyly. Until he or she develops visual disturbance, the differential diagnosis is broad.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Genes. Fourteen genes are known to be associated with BBS: BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, MKKS/BBS6, BBS7, TTC8/BBS8, B1/BBS9, BBS10, TRIM32/BBS11, BBS12, MKS1/BBS13, and CEP290/BBS14 (see Table 1).

Other loci. Approximately 20% of persons with BBS do not have identifiable mutations in any of the 14 known BBS-related genes; therefore, it is possible that more BBS genes are yet to be identified.

Clinical testing

• Sequence analysis is available clinically for BBS1, BBS2, BBS10, and CEP290.

Research testing

• Direct DNA. ARL6/BBS3, BBS4, BBS5, MKKS/BBS6, BBS7, TTC8/BBS8, B1/BBS9, BBS11/TRIM32 are of moderate size and together comprise approximately 133 exons. Inclusion of MKS1 (17 exons) and CEP290 (54 exons) increases the total number of exons to 204. Therefore, mutation screening for any given individual is a large undertaking. Mutations range from missense and nonsense to insertions, deletions, and splice site disruptors for most of these genes. Such testing is available on a research basis only.

Table 1 summarizes molecular genetic testing for this disorder.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Establishing the diagnosis in a proband. The diagnosis of BBS relies on clinical findings and family history.

Molecular genetic testing using clinically available tests can be used to confirm the diagnosis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

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

Genetically Related (Allelic) Disorders

McKusick-Kaufman syndrome (MKS). Mutations in BBS6/MKKS are also associated with MKS (see Differential Diagnosis). Given the clinical and molecular overlap between MKS and Bardet-Biedl syndrome [David et al 1999, Slavotinek & Biesecker 2000], it must be seriously considered whether MKS is part of the spectrum of Bardet-Biedl syndrome.

Meckel-Gruber syndrome. Mutations in three BBS genes (BBS2, BBS4, and BBS6) were identified in several cases of Meckel-Gruber syndrome [Karmous-Benailly et al 2005]. Meckel-Gruber syndrome (see Differential Diagnosis) is usually lethal and typically comprises the triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly. Associated abnormalities include orofacial clefting, genital anomalies, CNS malformations, and fibrosis of the liver. Pulmonary hypoplasia is the leading cause of death. Inheritance is autosomal recessive.

Mutations in the Meckel-Gruber syndrome-related genes MKS1 and MKS3 as well as in CEP290 can cause Bardet-Biedl syndrome, thereby demonstrating phenotypic overlap between the two disorders [Leitch et al 2008].

Joubert and Senior-Loken syndromes. Joubert syndrome-related disorders, a genetically and clinically heterogeneous group of disorders, share similar clinical features to Bardet-Biedl syndrome and are caused by mutations in CEP290, AH1, TMEM67, and NPHP1 (see Differential Diagnosis).

Leber congenital amaurosis (see Differential Diagnosis), associated with mutations in CEP290 (and numerous other genes), is characterized by a severe retinal dystrophy, causing blindness or severe visual impairment at birth or during the first months of life.

Natural History

A wide range of clinical variability is observed within and among families with Bardet-Biedl syndrome (BBS) [Riise et al 1997]. The main clinical features are cone-rod dystrophy, with childhood-onset vision loss preceded by night blindness; postaxial polydactyly; truncal obesity that manifests during infancy and remains problematic throughout adulthood; specific learning difficulties, which appear to be the norm in the majority of individuals (although mental retardation is often cited); male hypogenitalism and complex female genitourinary malformations; and renal dysfunction, which is a major cause of morbidity and mortality.

Rod-cone dystrophy. Occurring in more than 90% of individuals with BBS, retinitis pigmentosa often begins in childhood. During infancy optic disks and retinal vessels are normal; maculopathy associated with disk pallor develops in late childhood. The earliest signs of retinal dysfunction are often not apparent until age seven to eight years, when night blindness insidiously ensues [Beales et al 1999]. Marked phenotypic variation can occur: maculopathy may be associated with or without peripheral retinal degeneration [Heon et al 2005, Azari et al 2006]. The vascular attenuation which may accompany changes in the macula may be severe.

Visual fields are usually abnormal by age ten years. During adolescence visual field loss is moderate to severe with a reported annual loss of up to three degrees per year. Typically little more than a central island of vision remains by age 17 years.

By the second to third decade of life, the macula is involved in all individuals and is accompanied by visual acuity of 20/200 or worse. Legal blindness affects about 75% of affected individuals. In a previous study 63.6% of affected individuals were legally blind by age 20 years [Klein & Ammann 1969].

Full-field rod and cone electroretinograms (ERGs) are the investigations of choice to document the retinal involvement. ERG findings often include severely reduced or extinguished responses with the pattern being described as rod-cone in some and cone-rod in others. ERGs may be abnormal as early as age 14 months but significant cone-rod dystrophy is not apparent in most children under age five years and cooperation with ERG testing at that age is often poor. Unless strongly indicated, ERG testing may be deferred until at least age four years.

Other ophthalmologic findings can include nystagmus, strabismus, high myopia, cataract, and glaucoma.

Polydactyly. Postaxial polydactyly is common but not invariable. Presence ranges from 58% to 69% [Beales et al 1999, Ramirez et al 2004].

Brachydactyly of the fingers and toes is common, as are partial syndactyly (most usually between the 2nd and 3rd toes), fifth-finger clinodactyly (inwardly curved little finger), and a prominent "sandal gap" between the first and second toes.

In a study of 27 affected individuals, 17 had polydactyly, four had scoliosis, two had tibia valga, two had tibia vara, and one had Legg-Calve-Perthes [Ramirez et al 2004].

Obesity. Birth weight is usually normal in individuals with BBS. Significant weight gain begins within the first year and becomes a lifelong issue for most individuals. The distribution of adipose tissue is widespread in childhood but becomes most prominent in the trunk and proximal limbs in adulthood.

A combination of increased food intake and decreased energy expenditure is thought to underlie the development of obesity in BBS. Lower levels of physical activity have been demonstrated in persons with BBS compared to healthy controls despite comparable body mass indices [Grace et al 2003].

Cognitive impairment. Although mental retardation has been described as a major feature of BBS, often the effects of visual impairment have not been considered when assessing cognitive function. Several studies have now concluded that a majority of individuals have significant learning difficulties and only a minority have severe impairment on IQ testing [Beales et al 1999, Barnett et al 2002, Moore et al 2005].

Hypogonadism/genital abnormalities. Hypogonadism, which is probably hypogonadotrophic in origin, appears to be more frequent in males than females with BBS; hypogonadism may not be apparent in females until puberty when delay in onset of secondary sex characteristics and menarche become evident. Most males have micropenis at birth with small volume testes; atrophic seminiferous tubules have been reported.

Affected females may have complex genitourinary malformations such as hypoplastic fallopian tubes, uterus and ovaries; partial and complete vaginal atresia; septate vagina; duplex uterus; hematocolpos; persistent urogenital sinus; vesico-vaginal fistula; absent vaginal orifice; and absent urethral orifice. Some of these anomalies have been described in McKusick-Kaufman syndrome; however, not all females with BBS who have these anomalies have mutations in MKKS, suggesting that this component of the syndrome is common to more than one type of BBS.

Several affected women have successfully given birth; in contrast, only two affected males have fathered children [Beales et al 1999].

Renal abnormalities. Both structural and functional renal disease has been associated with BBS [Beales et al 1999, Parfrey et al 2002]. Beales et al [1999] reported that 26 of 57 (46%) of individuals imaged had structural renal abnormalities, including calyceal clubbing or calyceal cysts, parenchymal cysts, fetal lobulation and diffuse cortical scarring, unilateral agenesis, and renal dysplasia. Clinical manifestations of structural abnormalities include decreased urine-concentrating capacity, renal tubular acidosis, and hypertension. Complications of structural malformations can include renal calculi and vesicoureteric reflux which may present with recurrent renal colic and urinary tract infection.

Progressive renal impairment frequently occurs in BBS and can lead to end-stage renal disease (ESRD) necessitating renal transplantation in up to 10% of affected individuals.

Hypertension. Hypertension is common in BBS, occurring in 50% to 66% of affected individuals.

Speech impairment. Acquisition of intelligible speech and proper sentence formation is commonly delayed until age four years, but children tend to respond to early therapy. Even after language acquisition, impediments such as prolonged syllable repetition times or a tendency to substitute consonants or drop suffixes may remain [Beales et al 1999, Moore et al 2005].

Neurologic abnormalities. Ataxia and impaired coordination are encountered (up to 86%), as is mild hypertonia affecting all four limbs [Beales et al 1999, Moore et al 2005]. In the Moore et al [2005] study, 75% of individuals had a paucity of facial movement sometimes associated with facial asymmetry and difficulty in smiling. As no weakness was present, they concluded that the defects were the result of impaired coordination.

Structural cerebral abnormalities described in BBS [Rooryck et al 2007] include ventriculomegaly of the lateral and third ventricles, cortical thinning, and reduced size of the corpus striatum.

Future clinical studies may help to further define the nature of the cognitive impairment in BBS.

Psychiatric problems. A relatively high proportion of affected individuals develop a psychiatric illness in their lifetime [Beales et al 1999, Moore et al 2005], including anxiety, mood disorders, depression, bipolar disorder, obsessive compulsive behavior, and psychosomatic manifestations. Several affected children have been reported to fall within the spectrum of autistic disorders [Barnett et al 2002, Moore et al 2005].

Hearing loss. Almost half of adults with BBS develop a subclinical sensorineural hearing loss that is only detectable by audiometry [Ross et al 2005]. The implications of this finding are as yet unknown.

Glue ear (acute and chronic otitis media) resulting in conductive hearing loss early in childhood appears to be common [Beales et al 1999].

Genotype-Phenotype Correlations

Some reported genotype/phenotype correlations include the pattern of distribution of extra digits in BBS4 and characteristic ocular phenotypes in BBS2, BBS3, and BBS4 [Riise et al 2002, Heon et al 2005]. By and large, however, correlations between phenotype and genotype have not been confirmed in large studies.

Penetrance

Penetrance was originally thought to be complete; however, several examples of unaffected individuals with two mutations in the same gene have been reported.

Nomenclature

Historically, several terms have been used to describe the condition currently known as Bardet-Biedl syndrome. These include: Laurence-Moon-Biedl syndrome, Laurence-Moon-Bardet-Biedl syndrome (LMBBS), and Laurence-Moon syndrome (LMS).

JZ Laurence and RC Moon described a family with obesity, retinitis pigmentosa, and intellectual impairment in London in 1866. However, no further cases were published until the 1920s, when George Bardet reported two French girls with the triad of obesity, polydactyly, and retinitis pigmentosa; in 1922, the Austrian endocrinologist, Arthur Biedl, published a short case report of two siblings with retinitis pigmentosa, polydactyly, obesity, hypogenitalism, and intellectual impairment.

In 1925, Solis-Cohen and Weiss coined the term "Laurence-Moon-Bardet-Biedl syndrome" (LMBBS).

Ammann [1970] and Schachat & Maumenee [1982] highlighted essential differences between the Laurence-Moon and Bardet-Biedl syndromes. The medical and scientific communities have now adopted this split nomenclature. Because the family described by Laurence and Moon subsequently developed a progressive spastic paraparesis and because no mention was made of polydactyly, the Laurence-Moon syndrome is considered to comprise retinal dystrophy, obesity, hypogenitalism, and spastic paraparesis without polydactyly. In the authors' opinion and experience, little evidence exists to maintain this division and in fact, mutations have now been detected in BBS-related genes in families conforming to an LMS diagnosis [Moore et al 2005].

Prevalence

Among the nonconsanguineous populations of Northern Europe and America, the prevalence ranges from one in 100,000 (North America) to one in 160,000 (Switzerland).

Among the Bedouin peoples of Kuwait, where consanguinity is frequent, the prevalence is estimated at one in 13,500.

In the population isolate of the island of Newfoundland, Green et al [1989] reported a prevalence of one in 17,500 from a founder effect.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Bardet-Biedl syndrome (BBS), the following evaluations are recommended:

• Ophthalmologic assessment to determine visual acuity, field deficits, or refractive errors. Fundoscopic photographs should be filed for later comparison.

• Examination of the genitalia in both sexes. It is important to image the ovaries, fallopian tubes, uterus, and vagina in all affected females. Pelvic ultrasound examination is preferred.

• Calculation of body mass index (BMI) (weight in kg divided by the height in meters squared) can aid in identifying medically significant obesity.

• Dietary evaluation if obesity is present (BMI>30)

• Renal function studies and renal ultrasound examination for assessment of possible structural renal anomalies. If significant abnormalities are identified, referral to a nephrologist is desirable.

• Baseline blood pressure assessment

• As nephrogenic diabetes insipidus is a commonly overlooked feature of BBS, questioning the individual or parents with regard to the individual’s fluid intake and output can be a simple but helpful diagnostic aid. In some instances, tests of renal concentrating ability by initial urinalysis may be helpful.

• Cardiac evaluation including auscultation, ECG, and echocardiography

• Developmental assessment and/or educational evaluation for the purpose of intervention and planning

• Endocrinologic testing as needed including glucose tolerance testing (GTT) for diabetes mellitus, lipid levels, and assessment of thyroid and liver functions. More formal tests of pituitary function may be warranted particularly in assessing fertility and development of secondary sex characteristics. Infertility should not be assumed in all males or females.

• Hearing evaluation. Otoacoustic emissions (OAE) and audiometry may reveal subclinical sensorineural hearing loss in adults. Conductive hearing loss is common in children as a result of recurrent otitis media.

• Dental evaluation to assess for hygiene, dental crowding, and hypodontia

• Neurologic examination to assess for ataxic gait, poor coordination, dysdiadochokinesia, inability to perform tandem gait walking, poor two-point discrimination, and diminished fine motor skills

Treatment of Manifestations

No therapy exists for the progressive visual loss, but early evaluation by a low-vision specialist facilitates introduction of low vision aids and mobility training. Educational planning should take the prospect of future blindness into consideration.

To manage obesity, multiple strategies are advocated, including diet, exercise, and behavioral therapies. Education and dietary measures to control weight gain must be initiated at an early age. No formal trials of drug therapy (appetite suppressants or lipase inhibitors) have been reported; however, such therapy may be attempted providing the individual does not have contraindications to specific drug use (i.e., renal or hepatic dysfunction).

Complications of obesity, such as hypercholesterolemia and diabetes mellitus, should be treated as in the general population.

Cognitive disability should be addressed through early intervention and special education, as indicated by evaluation. It is advisable to assess individual needs with respect to education, as many adults are capable of attaining independent living skills.

Speech therapy should be offered at the first sign of speech delay and/or impairment.

Renal transplantation has been successful, although the immunosuppressants used following transplantation can compound the weight problem.

Surgical correction of hydrocolpos, vaginal atresia, or hypospadias may be warranted.

As children approach puberty, gonadotropin and sex hormone levels should be monitored to determine if hormone replacement therapy is indicated.

It is important to offer contraceptive advice to all affected females rather than assume likely infertility.

The earliest and most common intervention for polydactyly is removal of the accessory digit. Indicators are functional interference and poorly fitting footwear. Most children have their accessory digits removed within the first two years.

Treatment of cardiac abnormalities is the same as for the general population.

Dental extractions are appropriate as required for dental crowding.

Prompt treatment for acute and chronic otitis media should be considered. Insertion of grommets is commonplace.

Prevention of Secondary Complications

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

Surveillance

The following are appropriate:

• Regular ophthalmologic evaluations

• Routine (at least annual) measurement of blood pressure

• If a structural renal malformation is detected, follow-up renal ultrasonography and review by a nephrologist

• Monitoring of BUN and serum concentration of creatinine if a progressive obstructive urinary tract anomaly is detected or if bilateral renal malformations are observed and satisfactory renal growth is not observed on follow-up ultrasonography.

• In individuals with renal impairment (elevated serum creatinine) as a result of an underlying structural malformation, six-month to annual monitoring by a nephrologist for complications of chronic kidney disease

• Regular testing for diabetes mellitus by measurement of fasting glucose concentration or glucose tolerance testing

• Regular lipid profiling

• Occasional liver function testing to assess for hepatic failure

• Thyroid function testing particularly in the case of weight gain, changes in temperament, and/or diminished activity

Agents/Circumstances to Avoid

Any substances contraindicated in persons with renal impairment should be avoided.

Testing of Relatives at Risk

Siblings or relatives who have clinical features similar to those of the individual with BBS warrant genetic consultation. If the relative is deemed affected, consultation with an ophthalmologist and a renal sonogram to evaluate for structural renal malformations are recommended.

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Bardet-Biedl syndrome (BBS) is usually inherited in an autosomal recessive manner (see Multiallelic inheritance).

Risk to Family Members

Parents of a proband

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

• Heterozygotes (carriers) 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 an individual with BBS are obligate carriers for the disease-causing mutation involved.

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

Carrier Detection

Carrier testing using molecular genetic techniques is possible for at-risk family members when the disease-causing mutations in the family are known.

Related Genetic Counseling Issues

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.

Multiallelic inheritance. The risks outlined above are those for straightforward autosomal recessive patterns of disease inheritance. However, some cases of BBS seem to require the presence of at least three mutations for the phenotype to manifest (triallelic inheritance).

Katsanis et al [2001] proposed that BBS may also be inherited in a more complex fashion, as an oligogenic disorder. They described a number of pedigrees in which individuals were homozygous or compound heterozygous for mutations at one locus, but required the presence of a third heterozygous mutation residing at a second BBS locus to manifest the disease phenotype — a pattern termed triallelism.

Following the identification of BBS1, Mykytyn et al [2002] and Mykytyn et al [2003] failed to find any examples of multialleleic inheritance in their cohort to support the theory of Katsanis et al [2001]. Beales et al [2003] found evidence for more than two mutations at two BBS gene loci including BBS1. Badano et al [2003] reported a family with multiallelism involving BBS7.

Fauser et al [2003] reported examples of complex inheritance in 21 persons with BBS. In testing six BBS-causing genes in 27 families, Hichri et al [2005] did not identify any individuals with mutations in more than one BBS-related gene; however, the excess of heterozygous mutations observed was consistent with complex inheritance.

More recently, mutations in MKS1 and CEP290 have been shown to cause BBS and to have a possible epistatic effect on mutations at other known BBS loci [Leitch et al 2008].

At present, the extent to which possible multiallelism accounts for the phenotype is unknown. In practical terms, however, identification of such families is difficult and by previous estimations may account for less than 10% of all families with BBS. Therefore, until testing improves and further multiallelic affected individuals are reported, it is prudent to use autosomal recessive risk figures when providing genetic counseling and to note that in some affected individuals BBS may not conform to Mendelian laws of inheritance.

DNA banking. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA (typically extracted from white blood cells) of affected individuals for possible future use. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100% or when molecular genetic testing is available on a research basis only for some genes. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk for BBS caused by mutations in certain genes is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

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

No laboratories offering molecular genetic testing for prenatal diagnosis for families with mutations in a number of BBS-related genes are listed in the GeneTests Laboratory Directory. However, prenatal testing may be possible for families in which the disease-causing mutations have been identified in the other BBS-related genes in an affected family member. For laboratories offering custom prenatal testing, see .

Ultrasound examination in pregnancies at increased risk. Prenatal diagnosis using second-trimester ultrasound examination to detect anomalies such as postaxial polydactyly and renal cysts found in BBS has been reported [Dar et al 2001]. Cassart et al [2004] studied 11 pregnancies by ultrasound examination and concluded that in families in which BBS had occurred previously, the prenatal appearance of enlarged hyperechoic kidneys without corticomedullary differentiation should be considered recurrence of BBS.

Ultrasound examination in pregnancies not known to be at increased risk. When antenatal ultrasonography reveals large hyperechoic kidneys with loss of corticomedullary differentiation in the presence of polydactyly a diagnosis of BBS or Meckel syndrome should be considered [Dippell & Varlam 1998, Cassart et al 2004].

Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

Ciliary defects. Defects in cilia or intraflagellar transport (IFT) have been associated with several human disorders including Bardet-Biedl syndrome (BBS), Kartagener syndrome (see Primary Ciliary Dyskinesia), autosomal dominant polycystic kidney disease, and nephronophthisis.

Cilia protrude from almost all vertebrate cells and extend from basal bodies within the cell. Cilia are classified as primary cilia or motile cilia. Primary cilia have a 9+0 axonemal microtubule formation, are usually immotile, lack dynein arms, and are hypothesized to function as sensory organelles [Pazour & Witman 2003]. Motile cilia have a 9+2 axonemal microtubule formation and are usually involved in generating flow or movement. The assembly and maintenance of cilia depend on intraflagellar transport that moves particles from the basal body along the microtubular structure of the ciliary axoneme to the tip.

A significant leap in understanding the molecular pathogenesis of BBS emerged from the discovery of the BBS8 gene, which led to the proposal of ciliary involvement in BBS [Ansley et al 2003]. Compelling evidence was subsequently provided from comparative genomic studies that identified all known BBS orthologues among genes present exclusively in ciliated organisms [Avidor-Reiss et al 2004, Li et al 2004]. All known C.elegans bbs orthologues are exclusively expressed in a subset of ciliated sensory neurons [Ansley et al 2003, Fan et al 2004, Li et al 2004], and bbs-7 and bbs-8 mutants have structural and functional ciliary defects [Blacque et al 2004]. Furthermore, several BBS proteins localize to the centrosome (the "microtubule organizing center" of the cell) and basal body (a product of the centrosome that is positioned at the base of the cilium and required for cilia formation) [Ansley et al 2003, Kim et al 2004, Li et al 2004, Kim et al 2005]. A study of the BBS4 protein suggested that it may act as an adaptor protein facilitating the microtubule-dependent intracellular transport within the cilium or in the cytosol [Kim et al 2004]. A summary of the localization and putative role of the BBS proteins is illustrated in Figure 1.

Pathogenesis of anosmia. Studies of mouse knockouts of Bbs1 [Kulaga et al 2004], Bbs2 [Nishimura et al 2004], Bbs4 [Kulaga et al 2004, Mykytyn et al 2004] and Bbs6 [Fath et al 2005, Ross et al 2005] have provided further support for ciliary involvement in BBS. Mice display sperm flagellation defects, retinal degeneration likely secondary to defective IFT, as well as olfactory dysfunction presenting as partial or complete anosmia with diminution of the ciliated olfactory epithelium. Humans with BBS were subsequently identified with partial or complete anosmia [Kulaga et al 2004, Iannaccone et al 2005].

Pathogenesis of rod-cone dystrophy. Defects in the transport of phototransduction proteins from the inner to the outer segments of photoreceptors leads to cell death and is thought to underlie the pathogenesis of retinitis pigmentosa in BBS [Nishimura et al 2004]. In addition, defects in synaptic transmission from the photoreceptors to secondary neurons of the visual system have also been reported to occur in Bbs4-null mice, thereby suggesting multiple functions for BBS4 in photoreceptors.

Pathogenesis of polydactyly. Aberrant Sonic hedgehog signaling has been suggested to account for the features of polydactyly in BBS. Recently, zebrafish bbs morphants have been shown to have altered Sonic hedgehog expression associated with abnormal fin bud patterning reminiscent of polydactyly in BBS [Tayeh et al 2008].

Pathogenesis of obesity. Recent findings have demonstrated that the development of obesity in murine models of BBS is associated with increased food intake and decreased locomotor activity [Rahmouni et al 2008].

Defects in leptin action may be responsible for the development of obesity in BBS. Leptin under normal physiologic circumstances suppresses appetite and increases energy expenditure by activating leptin receptors on specific neurons. In murine BBS, high circulating levels of leptin have been demonstrated and exogenous leptin administration fails to decrease body weight and food intake thereby suggesting that leptin resistance likely underlies the development of obesity in BBS [Rahmouni et al 2008]. Interestingly, loss of cilia specifically in proopiomelanocortin (POMC) neurons can result in an increase in weight and adiposity, suggesting that cilia on hypothalamic neurons may play a key role mediating feeding behaviour through the perception of satiety cues such as leptin. Leptin has been shown to excite POMC neurons in the presence of high glucose levels to signal to reduce food intake. High leptin levels and POMC gene expression is reduced in Bbs-null mice thereby suggesting a role for BBS proteins in mediating leptin signaling within the hypothalamus. Other recent studies suggest that BBS proteins may also be involved in adipogenesis and future studies will need to determine whether hypothalamic dysfunction alone is sufficient to account for the obesity phenotype observed in BBS [Forti et al 2007].

BBS1

Normal allelic variants. BBS1 is composed of 17 exons and encodes a 593-amino acid protein, with the ATG start codon lying within exon 1 [Mykytyn et al 2002, Beales et al 2003, Mykytyn et al 2003].

Pathologic allelic variants. A common p.Met390Arg mutation within exon 12 of the BBS1 gene was shown to be involved in 30% of individuals in a cohort of 129 probands with BBS [Mykytyn et al 2003]. In a further study of 259 individuals with BBS, a total of 74 p.Met390Arg mutant alleles were identified, with p.Met390Arg contributing to 18% of the cohort and involved in 79% of all families with BBS1 mutations [Beales et al 2003]. In addition, frameshift and nonsense mutations have been identified within the BBS1 coding sequence (see Table 2; pdf). (For more information, see Table A.)

Normal gene product. The sequence of the protein encoded by BBS1 displays no significant homology to any other known proteins, with the exception of a region near the N terminal shared with BBS2 and BBS7 containing a predicted beta-propeller domain. In C.elegans it is expressed exclusively in ciliated cells and predominantly localizes to the transition zones (akin to basal bodies) as well as moving bidirectionally along the ciliary axoneme [Blacque et al 2004].

Abnormal gene product. Bbs1-null mice display olfactory deficiencies and defects in olfactory structure and function [Kulaga et al 2004].

BBS2

Normal allelic variants. The BBS2 gene is composed of 17 exons and encodes a 721-amino acid protein; the start codon lies within exon 1 [Nishimura et al 2001] (see Table 3; pdf).

Pathologic allelic variants. A variety of nucleotide changes resulting in frameshift, nonsense, and missense mutations have been identified throughout the BBS2 gene; there is no known mutation hot spot (see Table 4; pdf) [Katsanis et al 2000, Katsanis et al 2001, Nishimura et al 2001, Katsanis et al 2002]. (For more information, see Table A.)

Normal gene product. The sequence of the protein encoded by BBS2 displays no significant homology to any other known proteins, with the exception of a region near the N terminal shared with BBS1 and BBS7 containing a predicted beta-propeller domain. In C.elegans it is expressed exclusively in ciliated cells and predominantly localizes to the transition zones (akin to basal bodies) as well as moving bidirectionally along the ciliary axoneme [Blacque et al 2004].

Abnormal gene product. Bbs2-null mice display obesity, retinal degeneration, renal cysts, male infertility, and olfactory deficiencies [Nishimura et al 2004].

ARL6/BBS3

Normal allelic variants. The ARL6 gene is composed of nine exons and encodes a 186-amino acid protein; the start codon lies within exon 3 [Chiang et al 2004, Fan et al 2004].

Pathologic allelic variants. Mutations in ARL6 account for only a small percentage of BBS (~0.4%). To date, only four homozygous missense mutations and one nonsense mutation have been identified within the coding sequence. (For more information, see Table A.)

Normal gene product. The ARL6 gene encodes an ADP-ribosylation-like factor (ARL) protein that belongs to the Ras superfamily of small GTP-binding proteins essential for various membrane-associated intracellular trafficking events [Chiang et al 2004, Fan et al 2004]. The C.elegans ARL6 orthologue is specifically expressed in ciliated cells and undergoes IFT within the ciliary axoneme [Fan et al 2004].

Abnormal gene product. Protein modeling suggests that the four missense mutations identified so far (p.Gly169Ala, p.Thr31Met, p.Leu170Trp, and p.Thr31Arg) alter residues near or within the GTP-binding site and are therefore likely to abrogate GTP binding [Fan et al 2004].

BBS4

Normal allelic variants. BBS4 is composed of 16 exons and has an open reading frame of 519 codons with the start codon positioned within the first exon [Mykytyn et al 2001] (see Table 5; pdf).

Pathologic allelic variants. A variety of nucleotide changes resulting in frameshift, nonsense, and missense mutations have been identified throughout the BBS4 gene, as well as one large intragenic deletion. There is no known mutation hot spot (see Table 6; pdf) [Katsanis et al 2001, Mykytyn et al 2001, Katsanis et al 2002, Nishimura et al 2005]. (For more information, see Table A.)

Normal gene product. The protein encoded by BBS4 contains at least ten TPR domains, which are thought to be involved in protein-protein interactions. It localizes to the basal body and centrosome in cultured cells and may function as an adaptor protein facilitating the loading of cargo onto the dynein-dynactin molecular motor in preparation for microtubule-dependent intracellular transport within the cilium or in the cytosol [Kim et al 2004].

Abnormal gene product. Mice null for Bbs4 are obese and have retinal degeneration, sperm flagellation defects, olfactory deficiencies, and defects in olfactory structure and function [Kulaga et al 2004, Mykytyn & Sheffield 2004]. Silencing of BBS4 in cultured cells leads to de-anchoring of microtubules, arrest of cell division, and apoptotic cell death [Kim et al 2004].

BBS5

Normal allelic variants. BBS5 is composed of 12 exons and has an open reading frame of 342 codons [Li et al 2004].

Pathologic allelic variants. Mutations in BBS5 account for only a small percentage of BBS (~0.4%). To date, one splice donor mutation that leads to a frameshift and a premature termination codon in exon 7, two nonsense mutations [Li et al 2004], and one large intragenic deletion [Nishimura et al 2005] have been identified. (For more information, see Table A.)

Normal gene product. The protein encoded by BBS5 localizes to the basal bodies and faintly within the ciliary axoneme in the ependymal cells lining the ventricles of the brain in mouse [Li et al 2004]. In C.elegans, bbs-5 is expressed exclusively in ciliated cells and predominantly localizes to the base of the cilia in ciliated head and tail neurons [Li et al 2004].

Abnormal gene product. Silencing of BBS5 in Chlamydomonas results in an aflagellated phenotype [Li et al 2004].

MKKS

Normal allelic variants. The MKKS gene is composed of six exons and encodes a 570-amino acid protein [Stone et al 2000]. The start codon lies within exon 3. Two alternatively spliced 5' exons are not translated (see Table 7; pdf) [Stone et al 2000, Slavotinek et al 2002].

Pathologic allelic variants. Nucleotide changes have been identified in all of the coding exons of the MKKS gene that result in frameshift, nonsense, and missense mutations; there is no known mutation hot spot. For a number of individuals, only one heterozygous mutation has been identified; one possible explanation includes triallelic inheritance, as these individuals may harbor mutations at one of the other BBS loci [Katsanis et al 2001]. See Table 8; pdf. (For more information, see Table A.)

Normal gene product. The 570-amino acid protein encoded by MKKS [Stone et al 2000] shows strong homology to archaebacterial chaperonins and the eukaryotic T-complex-related proteins (TCPs), which belong to the type II class of chaperonins [Kim et al 2005]. These proteins are implicated in facilitation of nascent protein folding in an ATP-dependent manner [reviewed by Wickner et al 1999]. MKKS localizes to the pericentriolar material (PCM), a proteinaceous tube surrounding centrioles but during mitosis it is also found at intracellular bridges [Kim et al 2005].

Abnormal gene product. The predicted substrate binding apical domain of the protein encoded by MKKS is sufficient for centrosomal localization, but several patient-derived missense mutations in this domain (p.Gly52Asp, p.Asp285Ala, p.Thr325Pro, and p.Gly345Glu) result in the protein mislocalization in cells [Kim et al 2005]. Silencing of MKKS in cultured cells leads to multinucleate and multicentrosomal cells with cytokinesis defects [Kim et al 2005]. Mice null for Mkks/Bbs6 are obese and have retinal degeneration, sperm flagellation defects, olfactory deficiencies, and defects in olfactory structure and function [Fath et al 2005, Ross et al 2005].

BBS7

Normal allelic variants. The BBS7 gene is composed of 19 exons and encodes a 672-amino acid protein [Badano et al 2003]. An alternative isoform produced by differential splicing of an alternative exon 18 results in an additional 44 residues and a discrete 3' UTR [Badano et al 2003].

Pathologic allelic variants. Only four different pathogenic mutations have been identified in the BBS7 gene thus far: one that results in a frameshift and the introduction of a premature termination codon, two missense mutations, and one large intragenic deletion [Badano et al 2003, Nishimura et al 2005]. See Table 9; pdf. (For more information, see Table A.)

Normal gene product. The sequence of the protein encoded by BBS7 displays no significant homology to any other known proteins, with the exception of a region near the N terminal shared with BBS1 and BBS2 containing a predicted beta-propeller domain. In C.elegans, it is expressed exclusively in ciliated cells and predominantly localizes to the transition zones (akin to basal bodies) as well as moving bidirectionally along the ciliary axoneme [Blacque et al 2004].

Abnormal gene product. C.elegans with mutations with the bbs-7 orthologue have structural and functional ciliary defects and compromised intraflagellar transport [Blacque et al 2004].

TTC8/BBS8

Normal allelic variants. The TTC8 gene is composed of 16 exons and encodes a 531-amino acid protein.

Pathologic allelic variants. Mutations in TTC8 account for only a small percentage of BBS. Two families with identical six base-pair deletions resulting in the deletion of two amino acids and another with a three base-pair deletion abolishing the splice donor site of exon 10 have been identified [Ansley et al 2003]. (For more information, see Table A.)

Normal gene product. BBS8 was identified because of its similarity to the BBS4 protein, containing eight TPR domains possibly involved in protein-protein interactions [Ansley et al 2003]. It also exhibits similarity to a prokaryotic domain pilF involved in twitching mobility and type-IV pilus assembly. The BBS8 protein localizes to the centrosome and basal body of cultured ciliated cells [Ansley et al 2003]. In C.elegans it is expressed exclusively in ciliated cells and predominantly localizes to the transition zones (akin to basal bodies) as well as moving bidirectionally along the ciliary axoneme [Ansley et al 2003, Blacque et al 2004].

Abnormal gene product. C.elegans with mutations with the bbs-8 orthologue have structural and functional ciliary defects and compromised intraflagellar transport [Blacque et al 2004].

B1/BBS9

Normal allelic variants. The parathyroid hormone-responsive gene B1 (B1) was recently identified as BBS9 [Nishimura et al 2005]. It is composed of 25 exons, with all except the first contributing to its various protein isoforms that range between 879 and 916 amino acids in length.

Pathologic allelic variants. A total of seven B1 mutations, including nonsense, splice site, missense, and frameshift, have been identified [Nishimura et al 2005]. (For more information, see Table A.)

Normal gene product. The B1 gene is widely expressed. It has no similarity to other BBS proteins and its specific function is unknown.

Abnormal gene product. The B1 gene is down-regulated in the retina of BBS4-null mice [Nishimura et al 2005].

BBS10

Normal allelic variants. A vertebrate-specific chaperonin-like gene was recently identified as BBS10 [Stoetzel et al 2006]. It is composed of two exons encoding a 723-amino acid protein, with the start codon contained within exon 1.

Pathologic allelic variants. BBS10 is a major locus for BBS, contributing mutant alleles in approximately 20% of all individuals with BBS. There are numerous missense, frameshift, and nonsense mutations spread throughout the coding region, with no mutational hot spot [Stoetzel et al 2006].

Normal gene product. BBS10 has a chaperonin domain organization conserved with all three major functional domains — equatorial, intermediate, and apical — and the flexible protrusion region specific to group II chaperonins. The ATP hydrolytic domain is conserved in BBS10, suggesting that it may be an active enzyme, in contrast to BBS6, where this catalytic site is absent.

Abnormal gene product. Suppression of bbs10 expression in zebrafish embryos causes shortening of the body axis and dorsal thinning, broadening and kinking of the notochord, and elongation of the somites [Stoetzel et al 2006].

BBS11 (TRIM32)

Normal allelic variants. TRIM32, a ubiquitin ligase, was recently identified [Chiang et al 2006]. It is composed of two exons encoding a 652-amino acid protein, with the ATG start codon in exon 2.

Pathologic allelic variants. The only mutation identified to date in TRIM32 associated with BBS is a homozygous missense mutation p.Pro130Ser, which lies in the N-terminal B-box domain, in affected individuals in an inbred Bedouin Arab family [Chiang et al 2006]. However, a missense variant, p.Asp487Asn in the C-terminal NHL domain of TRIM32, was previously associated with autosomal recessive limb-girdle muscular dystrophy (LGMD) [Frosk et al 2002].

Normal gene product. TRIM32 is a member of the TRIM family that is characterized by a common domain structure composed of a RING finger, B-box, and a coiled-coiled motif. It also contains five C-terminal NHL repeats. TRIM32 is thought to have E3 ubiquitin ligase activity, binds to myosin, and ubiquitinates actin, implicating TRIM32 in regulating components of the cytoskeleton.

Abnormal gene product. Zebrafish embryos with knockdown of TRIM32 expression display an abnormal Kuppfer’s vesicle, a transient ciliated organ involved in left-right patterning, and a delay in melanosome transport. The p.Pro130Ser mutant allele associated with BBS fails to rescue these abnormal phenotypes, in contrast to the p.Asp487Asn allele associated with LGMD, suggesting that each mutation disrupts different functions of TRIM32 [Chiang et al 2006].

BBS12

Normal allelic variants. BBS12 is a vertebrate-specific predicted chaperonin-like protein [Stoetzel et al 2007]. It is composed of two exons, of which only the second is coding, for a predicted protein of 710 amino acids.

Pathologic allelic variants. BBS12 is mutated in approximately 5% of families affected with BBS [Stoetzel et al 2007]. Mutations identified include frameshift (one of which, Phe372X – also known as F372fsX373 – is recurrent and present in several families), nonsense mutations, small in-frame deletions, a mutation that is predicted to extend the C-terminus of the protein, and missense alleles.

Normal gene product. BBS12 is related to the group II chaperonins and to a family of vertebrate-specific chaperonin-like sequences encompassing BBS10 and BBS6 [Stoetzel et al 2007]. The classic chaperonin domain architecture (equatorial, intermediate, and apical domains) is conserved, but BBS12 has an additional five specific inserted sequences within the intermediate and equatorial domains. However, the functional ATP hydrolysis motif is not conserved in BBS12, as is the case for BBS6.

Abnormal gene product. Injection of bbs12-specific morpholino (antisense oligonucleotides) into zebrafish embryos results in phenotypes consistent with convergence and extension (CE) defects, including shortened body axis, broadened somites, kinked notochord and dorsal thinning [Stoetzel et al 2007]. Simultaneous suppression of bbs12, bbs10, and bbs6 gene expression yielded similar but more severe phenotypes, suggesting a possible partial functional redundancy within this protein family.

BBS13 (MKS1)

Normal allelic variants. MKS1 contains 17 exons and encodes a 559-amino acid polypeptide containing a conserved B9 domain of unknown function [Leitch et al 2008]. Four splice variants are known.

Pathologic allelic variants. MKS1 accounts for approximately 4.5% of the total mutational load in BBS. Mutations identified include heterozygous missense mutations such as Arg123Gln, identified in two unrelated families, one of Lebanese origin; in the affected individual, a homozygous frameshift mutation in BBS10, S73fsX91, was also identified. Similarly, the Arg123Gln variant was also described in a Saudi family bearing an affected heterozygous mutation in BBS10 (Q242fsX258). Another heterozygous variant, Val339Met, was detected in a third Middle Eastern family who also had a homozygous BBS1 variant, Arg146X. In a fifth family of Northern European descent, another mutation, Ile450Thr, was also found. A sixth pedigree of Turkish descent was found to be compound heterozygous for two pathogenic MKS1 mutations that segregated in an autosomal recessive fashion: an allele resulting in Cys492Trp substitution and a base pair deletion that removes phenylalanine (F371del) [Leitch et al 2008].

Normal gene product. Mks proteins have been localized to either the basal body, primary cilium, or both [Dawe et al 2007, Delous et al 2007, Williams et al 2008]. Mks1 is one of six Mks proteins that is identified by the conserved B9 domain, the function of which is unclear. Nematode mks proteins also contain B9 domains and like their mammalian orthologues localize to the transition zones/basal bodies of sensory cilia, thereby demonstrating a conserved role for Mks proteins in ciliary function. Supporting this hypothesis is the finding of X-box consensus sequences lying within the promoter regions of these proteins. X-box sequences are recognized and regulated by the daf-19 or rfx family of transcription factors and thereby regulate the transcription of ciliogenic programs [Blacque et al 2005, Efimenko et al 2005].

Abnormal gene product. Human mutations in MKS1 lead to a ciliopathy phenotype characterized by encephalocele, cystic kidneys, hepatic fibrosis, and polydactyly. Knockdown of the human MKSR1 and MKSR2, (MKS-related protein 1 and 2) using RNA interference leads to a ciliogenesis defect [Bialas et al 2009]. Co-injection of MKS1 mRNA encoding the pathogenic MKS variants Asp123Gln, Asp286Gly, and Cys492Trp with mks1 morpholino in zebrafish does not rescue the gastrulation defect to the same degree as wild-type MKS1 mRNA [Leitch et al 2008].

BBS14 (CEP290/NPHP6)

Normal allelic variants. CEP290 is also known as 3H11Ag, BBS14, FLJ13615, JBTS5, KIAA0373, LCA10, MKS4, NPHP6, and SLSN6. It contains 54 exons which encode for a polypeptide of 2481 amino acids. Two splice variants are known.

Pathologic allelic variants. Mutations in CEP290 have been associated with a number of ciliopathies including BBS [Sayer et al 2006, Baala et al 2007, Helou et al 2007, Leitch et al 2008]. A homozygous nonsense mutation in CEP290, Glu1903X, was identified in an individual with BBS born to a consanguineous Saudi couple [Leitch et al 2008]. This individual also carried a complex compound heterozygous mutation in MKS3 (Gly218Ala and Ser320Cys) [Leitch et al 2008]. The clinical manifestations in this person included retinitis pigmentosa, nystagmus, renal disease, developmental delay, obesity, and mental retardation. Zebrafish embryos injected with both cep290 and mks morpholino show severe gastrulation defects, shortened body axis, widened notochords, and broad somites [Leitch et al 2008].

Normal gene product. CEP290 localizes to the centrosome and basal bodies of cilia in renal epithelial cells and the connecting cilium of photoreceptor cells. CEP290 has recently been shown to interact with another ciliary protein, PCM-1, a centriolar satellite protein [Kim et al 2008]. CEP290 and PCM-1 bind to each other and localize to centriolar satellites in a microtubule-dependent manner and CEP290 appears to be required for the integrity of the cytoplasmic microtubular network. Furthermore, both CEP290 and PCM-1 are required for ciliogenesis and play a role in targeting the small GTP-ase Rab8 to the ciliary membrane [Kim et al 2008].

Abnormal gene product. The CEP290 Glu1903X variant results in a truncated C-terminus of 576 amino acids. This allele was not found in 96 ethnically matched controls, in 184 European descended controls, or in any publicly available SNP database, thereby supporting a pathogenic variant as accountable for the BBS phenotype [Leitch et al 2008].

Author History

Philip L Beales, BSc, MD, FRCP (2003-present)
Alison J Ross, PhD; University College London (2003-2009)
Aoife M Waters, MB BAO, BCh, MRCPI, MSc (2009-present)

Revision History

• 13 October 2009 (me) Comprehensive update posted live

• 5 January 2007 (cd) Revision: BBS12 gene identified

• 26 June 2006 (ca) Revision: BBS10 and TRIM32 identified as genes involved in BBS, testing for C91fsX95 mutation in BBS10 clinically available

• 18 November 2005 (me) Comprehensive updated posted to live Web site

• 17 October 2003 (pb) Revision: change in test availability

• 14 July 2003 (me) Review posted to live Web site

• 22 January 2003 (pb) Original submission