DiagnosisClinical DiagnosisThe 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.Primary FeaturesRod-cone dystrophy. Atypical pigmentary retinal dystrophy with early macular involvement is the characteristic fundus abnormality in BBS and is called rod-cone dystrophy (retinitis pigmentosa [RP]) [Héon et al 2005, Azari et al 2006]. Visual acuity (central retinal function mediated by cones), dark adaptation, and peripheral visual fields (peripheral retina function mediated by rods) are affected. Postaxial polydactyly. Polydactyly may involve either all four limbs (21% of cases) or the hands or feet alone. Typically, additional digits are found on the ulnar side of the hand and on the fibular side of the foot.Truncal obesity. Obesity is reported to occur in 72% of cases.The mean body mass index (BMI) in females is estimated to be 31.5 mg/m² while in males it is 36.6 mg/m² [Moore et al 2005]. Learning disabilities. See Secondary Features.Hypogonadism in males or genital abnormalities in females:Males. Small penile shaft and/or reduced volume of testes. Cryptorchidism has been reported in 9% of males [Beales et al 1999]. Females. Hypoplastic fallopian tubes, uterus, and ovaries; partial and complete vaginal atresia; septate vagina; duplex uterus; hydrometrocolpos; persistent urogenital sinus; vesico-vaginal fistula; absent vaginal orifice; and absent urethral orifice [Mehrotra et al 1997, Uguralp et al 2003]Renal anomalies. Renal malformations and abnormal renal function leading to end stage renal disease (ESRD) can be a major cause of morbidity [O’Dea et al 1996]. Renal manifestations include renal dysplasia characterized by malformation of the renal parenchyma and cystic tubular disease (e.g., nephronophthisis) which often presents with anemia, polyuria, and polydipsia in late childhood. Less frequently, glomerular disease, which on occasion presents with focal segmental glomerulosclerosis and histopathologic splitting of the glomerular basement membrane, has been reported [François et al 1987, Barakat et al 1990]. Lower urinary tract malformations such as detrusor instability of the bladder occur, but are less common than upper tract malformations [Beales et al 1999]. Secondary FeaturesSpeech delay/disorder. In BBS establishment of intelligible speech is often delayed until age four years; however, disordered speech (e.g., phonation difficulties such as breathy, high-pitched speech) has been reported infrequently in BBS [Beales et al 1999]. It has been suggested that substitutions of consonants at the beginning of words and the omission of the final consonant are distinctive of BBS [Beales et al 1999]. Videofluoroscopy and palatal articulation studies point to incoordination of the pharyngeal and/or laryngeal muscles as the possible basis of the problem.Developmental delay. Many children with BBS are delayed in reaching major developmental milestones including gross motor skills, fine motor skills, and psychosocial skills (interactive play/ability to recognize social cues). Behavioral abnormalities. Described in about 33% of individuals with BBS, behavioral abnormalities include emotional immaturity, outbursts, disinhibition, depression, lack of social dominance, and obsessive compulsive behavior.Eye abnormalities include strabismus, cataracts, and astigmatism.Brachydactyly/syndactyly. Brachydactyly of both the hands and feet is common as is partial syndactyly (usually between the 2nd and 3rd toes). Formal measurement of digit length and width and comparison with normalized charts may be helpful in assessing brachydactyly.Ataxia/poor coordination/imbalance. Many affected individuals describe a degree of clumsiness and often have a wide-based gait. Tandem walking (in a straight line with one toe abutting the other heel) is usually impossible. Repetitive supination and pronation of the hands at the wrist is slow (dysdiadochokinesia). Despite occasional reports of cerebellar involvement, there is no indication that cerebellar function is abnormal. More likely, a yet-to-be-delineated defect in coordination and processing movements exists. It is not known when these features become evident.Mild hypertonia (especially lower limbs). It is not known when this becomes evident.Diabetes mellitus. Diabetes mellitus tends to become evident in adolescence or adulthood. It is usually non-insulin dependent diabetes mellitus (NIDDM)/type 2 diabetes mellitus, although occasionally insulin is required for acute control of hyperglycemia. Diabetes mellitus may relate to level of obesity. Impaired glucose tolerance has been described in younger individuals prior to the onset of NIDDM.Orodental abnormalities include dental crowding, hypodontia, small dental roots, and high-arched palate. Cardiovascular anomalies. Echocardiographic studies of 22 individuals with Bardet-Biedl syndrome revealed cardiac abnormalities in 50%. The study of Beales et al [1999] identified congenital heart disease in approximately 7% of affected individuals that was equally divided between aortic stenosis, patent ductus arteriosis, and unspecified cardiomyopathy. Valvular stenoses and atrial/ventricular septal defects are the most commonly reported lesions [Beales et al 1999, Slavotinek & Biesecker 2000].Hepatic involvement. Perilobular fibrosis, periportal fibrosis with small bile ducts, bile duct proliferation with cystic dilatation, biliary cirrhosis, portal hypertension, and congenital cystic dilations of both the intrahepatic and extrahepatic biliary tract have been described.Craniofacial dysmorphism. Craniofacial defects include brachycephaly, macrocephaly, bitemporal narrowing, male frontal balding, large ears, short and narrow palpebral fissures, a long shallow philtrum, nasal bridge hypoplasia, nasal shortening/reduced bulbosity at the nasal tip, relative upward displacement of the nose and upper lip, midfacial hypoplasia, and mild retrognathia [Beales et al 1999, Lorda-Sanchez et al 2001, Moore et al 2005, Tobin et al 2008].Hirschsprung disease (absence of enteric nerves in the distal colon). The incidence of Hirschsprung disease in BBS is unknown [Beales et al 1999, Tobin et al 2008]. (See Hirschsprung Disease Overview.) Anosmia. Partial or complete anosmia has been described following initial observations in mouse models of the condition [Kulaga et al 2004, Nishimura et al 2004, Fath et al 2005, Iannaccone et al 2005]. It remains to be seen whether a relatively simple smell identification test is of diagnostic value.Molecular Genetic TestingGenes. Mutations in 14 genes are known to be associated with BBS: BBS1, BBS2, ARL6 (BBS3), BBS4, BBS5, MKKS (BBS6), BBS7, TTC8 (BBS8), BBS9, BBS10, TRIM32 (BBS11), BBS12, MKS1 (BBS13), and CEP290 (BBS14) (see Table 1).Mutations in WDPCP (BBS15) and SDCCAG8 (BBS16) may be associated with BBS based on the following:WDPCP. Kim et al [2010] identified a homozygous G>T transition at the -1 position of a splice site in WDPCP in a child with BBS. The parents and an unaffected sib were carriers of this mutation; the mutation was not found in 384 control chromosomes or in individuals in the HapMap project or the 1,000 genomes project [Kim et al 2010]. However, neither transcript analysis nor other evidence of pathogenicity was presented. SDCCAG8. Individuals in one large family with BBS, were homozygous for a complex intron 7 insertion that disrupted an exonic splice enhancer site and created a premature stop codon. Detailed analysis of transcripts and proteins demonstrated a near complete absence of normal full-length protein product from SDCCAG8 [Otto et al 2010].Evidence for further locus heterogeneity. 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-related genes are yet to be identified.Clinical testingSequence analysis. Mutations detected range from missense and nonsense to insertions, deletions, and splice site disruptors for most of the known genes. Targeted mutation analysis. The mutation detection frequency is unknown; thus, the benefit of this method over full sequence analysis is unknown.Deletion/duplication analysis. For some genes, deletion/duplication analysis identifies exonic or multiexonic deletions not detectable by genomic sequence analysis.The utility of deletion/duplication analysis for other genes (in which no deletions or duplications have been reported to cause BBS) is unknown.Table 1. Summary of Molecular Genetic Testing Used in Bardet-Biedl Syndrome (BBS) View in own windowGene Symbol% of BBS Attributed to Mutations in This GeneTest Method Mutations Detected Mutation Detection Frequency by Gene and by Test Method ^{1Test AvailabilityBBS1~23.2% 2Sequence analysisSequence variants 3UnknownClinical Targeted mutation analysis Unknown 4Deletion/duplication analysis 5Unknown 6BBS2 ~8.1% 2 Sequence analysisSequence variants 3UnknownClinical Targeted mutation analysisUnknown 4Deletion/duplication analysis 5Unknown 6ARL6~0.4% 2 Sequence analysisSequence variants 3UnknownClinical Targeted mutation analysisUnknown 4Deletion/duplication analysis 5Unknown 6BBS4 2.3% Sequence analysisSequence variants 3UnknownClinical Targeted mutation analysisUnknown 4Deletion/duplication analysis 5 Exonic or multiexonic deletionsBBS5 ~0.4% 2Sequence analysisSequence variants 3UnknownClinical Targeted mutation analysisUnknown 4Deletion/duplication analysis 5Exonic or multiexonic deletions MKKS ~5.8% 2Sequence analysisSequence variants 3UnknownClinical Targeted mutation analysisUnknown 4Deletion/duplication analysis 5Unknown 6BBS7 ~1.5% 2Sequence analysisSequence variants 3UnknownClinical Targeted mutation analysisUnknown 4Deletion/duplication analysis 5Exonic or multiexonic deletionsTTC8 ~1.2% 2Sequence analysisSequence variants 3UnknownClinical Targeted mutation analysisUnknown 4Deletion/duplication analysis 5Unknown 6BBS9 ~6.0% 7Sequence analysisSequence variants 3UnknownClinical Deletion/duplication analysis 5Exonic or whole-gene deletionsBBS10 ~20% 8 Sequence analysisSequence variants 3UnknownClinical Targeted mutation analysisUnknown 4Deletion/duplication analysis 5Unknown 6TRIM32 9Sequence analysisSequence variants 3UnknownClinical Targeted mutation analysisUnknown 4Deletion/duplication analysis 5Unknown 6BBS12~5% 10Sequence analysisSequence variants 2UnknownClinical Targeted mutation analysisUnknown 4Deletion/duplication analysis 5Unknown 6MKS1~4.5% 11Sequence analysisSequence variants 3UnknownClinical Deletion/duplication analysis 5Unknown 6CEP290~0.6% 10Sequence analysisSequence variants 3UnknownClinical Genes possibly associated with BBSSDCCAG8Unknown 12Sequence analysisSequence variants 3UnknownResearch onlyWDPCPUnknownSequence analysisSequence variants 3UnknownClinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Katsanis [2004]3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Specific mutations in the targeted mutation panels are not always provided.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.6. No deletions or duplications involving TRIM32, BBS1, BBS2, ARL6, MKKS, TTC8, BBS10, BBS12, or MKS1, as causative of Bardet-Biedl syndrome have been reported. The clinical usefulness of these tests is unknown.7. Nishimura et al [2005]8. Stoetzel et al [2006]9. Chiang et al [2006]10. Stoetzel et al [2007]11. Leitch et al [2008]12. Otto et al [2010]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyEstablishing the diagnosis in a probandThe 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) DisordersMcKusick-Kaufman syndrome (MKS). Mutations in MKKS (BBS6) 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-related genes (BBS2, BBS4, and BBS6) were identified in several cases of Meckel-Gruber syndrome [Karmous-Benailly et al 2005]. Meckel-Gruber syndrome 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 TMEM67 (formerly 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, NPHP1, and SDCCAG8 (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 HistoryA 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 intellectual disability 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 [Héon 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 intellectual disability 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; 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 CorrelationsSome 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, Héon et al 2005]. By and large, however, correlations between phenotype and genotype have not been confirmed in large studies.

Differential DiagnosisMcKusick-Kaufman syndrome (MKS) is characterized by the triad of hydrometrocolpos (HMC), postaxial polydactyly (PAP), and congenital heart disease (CHD). HMC in infants is dilatation of the vagina and uterus as a result of the accumulation of cervical secretions from maternal estrogen stimulation. HMC can be caused by failure of the distal third of the vagina to develop (vaginal agenesis), a transverse vaginal membrane, or an imperforate hymen. Many cases of Bardet-Biedl syndrome (BBS) have been misdiagnosed as McKusick-Kaufman syndrome in infancy or early childhood prior to the development of other manifestations of BBS [David et al 1999]. MKS is caused by mutations of MKKS, which can also cause BBS. MKS is inherited in an autosomal recessive manner.Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing impairment, dilated cardiomyopathy, the insulin resistance syndrome, and developmental delay. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus starting between birth and age 15 months. Affected individuals have no light perception by age 20 years. Children usually have normal birth weight but become obese during their first year, resulting in childhood truncal obesity. Progressive sensorineural hearing loss presents in the first decade in as many as 70% of individuals. Hearing loss may progress to the moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance/type 2 diabetes mellitus often presents in childhood and is typically accompanied by the skin changes of acanthosis nigricans. Over 60% of individuals with Alström syndrome develop cardiac failure as a result of dilated cardiomyopathy at some stage of their lives. About 50% of individuals have delays in early developmental milestones. Males may have hypogonadotrophic hypogonadism. Renal disease may present as polyuria and polydipsia resulting from a concentrating defect secondary to interstitial fibrosis. End-stage renal disease (ESRD) can occur as early as the late teens. In contrast to BBS, Alström syndrome is characterized by relative preservation of cognitive function and the absence of polydactyly. Alström syndrome is caused by mutations in ALMS1 and is inherited in an autosomal recessive manner.Joubert syndrome is a rare condition that is genetically heterogeneous. Nine genes in which mutations cause Joubert syndrome have so far been identified, including JBTS1 [Saar et al 1999], CORS2 [Keeler et al 2003, Valente et al 2003], ARL13B [Cantagrel et al 2008], CC2D2A [Noor et al 2008], RPGRIP1L [Delous et al 2007], TMEM67 [Baala et al 2007], NPHP1 [Parisi et al 2004, Castori et al 2005], AHI1 [Dixon-Salazar et al 2004, Ferland et al 2004, Parisi et al 2006, Utsch et al 2006] and CEP290 [Sayer et al 2006, Valente et al 2006]. Clinical manifestations include irregular breathing in infancy (episodic hyperpnea), developmental delay, intellectual disability, hypotonia, oculomotor apraxia, and inability to coordinate voluntary muscle movements (ataxia). Distinctive cerebellar and brain stem malformations associated with Joubert syndrome include vermis hyoplasia or agenesis (e.g., abnormalities at the pontomesencephalic junction). The characteristic molar tooth sign on cranial magnetic resonance imaging (MRI) is demonstrated by elongated but thin superior cerebellar peduncles and mild vermis hypoplasia with the resulting images reminiscent of section through a molar tooth. Dandy-Walker malformations may be evident in approximately 10% of cases as a result of abnormal cerebrospinal fluid collections in the posterior fossa. Additional clinical features include retinal dystrophy, cystic kidney disease (cystic dysplasia and nephronopthisis), ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas and endocrine abnormalities. Senior-Loken syndrome (SLS) is another rare disorder that shares phenotypic overlap with Joubert syndrome and Bardet-Biedl syndrome. Genes identified to date include CEP290 [Sayer et al 2006], NPHP3 [Omran et al 2002], NPHP4 [Schuermann et al 2002], IQCB1 [Otto et al 2002], and SDCCAG8 [Otto et al 2010].The main clinical features are retinitis pigmentosa and renal disease. Retinitis pigmentosa may present either as congenital retinal blindness caused by retinal hypoplasia or as progressive retinal degeneration later in childhood. The spectrum of cystic kidney diseases includes cystic renal dysplasia, nephronopthisis, medullary cystic kidneys, and polycystic kidneys. Presentation may occur in infancy or late childhood. Typically nephronopthisis presents in late childhood with end-stage renal disease (ESRD) often preceeded by a long history of polydipsia and polyuria. Like Joubert syndrome and other related disorders, other features of SLS include cerebellar vermis hypoplasia and ataxia, developmental delay and intellectual disability, occiptal encephalocele, and oculomotor apraxia. 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. The diagnosis of LCA is established by clinical findings. Genes implicated in LCA include GUCY2D [Perrault et al1996], RPE65 [Marlhens et al 1997], SPATA7 [Wang et al 2009], AIPL1 [Sohocki et al 2001], LCA5 [den Hollander et al 2007], RPGRIP1 [Gerber et al 2001, Dryja et al 2001, Hameed et al 2003, Lu & Ferreira 2005], CRX [Freund et al 1998, Swaroop et al 1999, Nakamura et al 2002], CRB1 [den Hollander et al 2001], IMPDH1 [Bowne et al 2006], RD3 [Friedman et al 2006], and RDH12 [Janecke et al 2004, Perrault et al 2004, Thompson et al 2005].The ophthalmologic manifestations of LCA may present as a manifestation of Joubert syndrome or SLS syndrome and the fact that mutations in many of the same genes are responsible for these three overlapping phenotypes leaves much to be sorted out in the nosology of these disorders. Biemond syndrome type II (BS2) is characterized by intellectual disability, ocular coloboma, obesity, polydactyly, hypogonadism, hydrocephalus, and facial dysostosis. No responsible genes have been mapped or identified.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 assessmentAs 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 echocardiographyDevelopmental assessment and/or educational evaluation for the purpose of intervention and planningEndocrinologic 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 hypodontiaNeurologic examination to assess for ataxic gait, poor coordination, dysdiadochokinesia, inability to perform tandem gait walking, poor two-point discrimination, and diminished fine motor skillsTreatment of ManifestationsNo 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 ComplicationsAntibiotic prophylaxis for surgical and dental procedures is indicated for individuals with structural cardiac anomalies.SurveillanceThe following are appropriate:Regular ophthalmologic evaluationsRoutine (at least annual) measurement of blood pressureIf a structural renal malformation is detected, follow-up renal ultrasonography and review by a nephrologistMonitoring 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 testingRegular lipid profilingOccasional liver function testing to assess for hepatic failureThyroid function testing particularly in the case of weight gain, changes in temperament, and/or diminished activityAgents/Circumstances to AvoidAny substances contraindicated in persons with renal impairment should be avoided.Evaluation of Relatives at RiskSiblings 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 InvestigationSearch 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Bardet-Biedl Syndrome: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDWDPCP2p15WD repeat-containing and planar cell polarity effector protein fritz homologWDPCP @ LOVDWDPCPSDCCAG81q43Serologically defined colon cancer antigen 8SDCCAG8 @ LOVDSDCCAG8BBS1BBS111q13​.2Bardet-Biedl syndrome 1 proteinRetina International Mutations of the Bardet-Biedl Syndrome Type 1 Gene (BBS2L2)
BBS1 homepage - Mendelian genesBBS1BBS2BBS216q12​.2Bardet-Biedl syndrome 2 proteinRetina International Mutations of the Bardet-Biedl Syndrome Type 2 Gene (BBS2)BBS2BBS3ARL63q11​.2ADP-ribosylation factor-like protein 6ARL6 @ LOVDARL6BBS4BBS415q24​.1Bardet-Biedl syndrome 4 proteinRetina International Mutations of the Bardet-Biedl Syndrome Type 4 Gene (BBS4)BBS4BBS5BBS52q31​.1Bardet-Biedl syndrome 5 proteinBBS5 @ LOVDBBS5BBS6MKKS20p12​.2McKusick-Kaufman/Bardet-Biedl syndromes putative chaperoninRetina International Mutations of the McKusick-Kaufman Gene (MKKS)MKKSBBS7BBS74q27Bardet-Biedl syndrome 7 proteinRetina International Mutations of the Bardet-Biedl Syndrome Type 7 Gene (BBS2L1)BBS7BBS8TTC814q31​.3Tetratricopeptide repeat protein 8TTC8 homepage - Mendelian genesTTC8BBS9BBS97p14​.3Protein PTHB1BBS9 @ LOVDBBS9BBS10BBS1012q21​.2Bardet-Biedl syndrome 10 proteinBBS10 @ LOVDBBS10BBS11TRIM329q33​.1E3 ubiquitin-protein ligase TRIM32 TRIM32BBS12BBS124q27Bardet-Biedl syndrome 12 proteinBBS12 @ LOVDBBS12BBS13MKS117q22Meckel syndrome type 1 proteinFinnish Disease Database
MKS1 @ LOVDMKS1BBS14CEP29012q21​.32Centrosomal protein of 290 kDaFinnish Disease DatabaseCEP290Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Bardet-Biedl Syndrome (View All in OMIM) View in own window 209900BARDET-BIEDL SYNDROME; BBS 209901BBS1 GENE; BBS1 600374BBS4 GENE; BBS4 602290TRIPARTITE MOTIF-CONTAINING PROTEIN 32; TRIM32 603650BBS5 GENE; BBS5 604896MKKS GENE; MKKS 606151BBS2 GENE; BBS2 607590BBS7 GENE; BBS7 607968PARATHYROID HORMONE-RESPONSIVE B1 GENE 608132TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 8; TTC8 608845ADP-RIBOSYLATION FACTOR-LIKE 6; ARL6 609883MKS1 GENE; MKS1 610142CENTROSOMAL PROTEIN, 290-KD; CEP290 610148BBS10 GENE; BBS10 610683BBS12 GENE; BBS12 613524SEROLOGICALLY DEFINED COLON CANCER ANTIGEN 8; SDCCAG8 613580CHROMOSOME 2 OPEN READING FRAME 86; C2ORF86Molecular Genetic PathogenesisCiliary 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 BBS8, 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.FigureFigure 1. Schematic diagram of the primary cilium illustrating the concept of intraflagellar transport (IFT) and the component parts therein. The protein cargo is manufactured in the Golgi apparatus and carried by vesicles to the cell membrane where receptor (more...)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].BBS1Normal 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 BBS1 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].BBS2Normal allelic variants. BBS2 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 BBS2; 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. ARL6 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. ARL6 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].BBS4Normal 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 BBS4, as well as two deletions of multiple exons. 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].BBS5Normal 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 multiexon 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].MKKSNormal allelic variants. MKKS comprises 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 MKKS 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].BBS7Normal allelic variants. BBS7 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 BBS7 thus far: one that results in a frameshift and the introduction of a premature termination codon, two missense mutations, and one multiexon 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. TTC8 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].BBS9 (B1)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 BBS9 mutations, including nonsense, splice site, missense, frameshift, and one single- and one multiexon deletion have been identified [Nishimura et al 2005]. (For more information, see Table A.)Normal gene product. PTHB1 is widely expressed. It has no similarity to other BBS proteins and its specific function is unknown.Abnormal gene product. PTHB1 is downregulated in the retina of Bbs4-null mice [Nishimura et al 2005].BBS10Normal 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].TRIM32 (BBS11)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].BBS12Normal allelic variants. BBS12 encodes a vertebrate-specific predicted chaperonin-like protein [Stoetzel et al 2007]. The gene 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, p.Phe372* [also known as F372fs*373], 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.MKS1 (BBS13)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 p.Arg123Gln, identified in two unrelated families, one of Lebanese origin; in the affected individual, a homozygous frameshift mutation in BBS10, p.Ser73fs*91, was also identified. Similarly, the p.Arg123Gln variant was also described in a Saudi family bearing an affected heterozygous mutation in BBS10 (p.Gln242fs*258). Another heterozygous variant, p.Val339Met, was detected in a third Middle Eastern family who also had a homozygous BBS1 variant, p.Arg146*. In a fifth family of Northern European descent, another mutation, p.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 p.Cys492Trp substitution and a base pair deletion that removes phenylalanine (p.Phe371del) [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 p.Asp123Gln, p.Asp286Gly, and p.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].CEP290 (NPHP6) (BBS14)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, p.Glu1903*, 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 TMEM67 (MKS3) (p.Gly218Ala and p.Ser320Cys) [Leitch et al 2008]. The clinical manifestations in this person included retinitis pigmentosa, nystagmus, renal disease, developmental delay, obesity, and intellectual disability. 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 GTPase Rab8 to the ciliary membrane [Kim et al 2008]. Abnormal gene product. The CEP290 p.Glu1903* 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].WDPCP (BBS15)Normal allelic variants. WDPCP contains 12 exons and a transcript of 3326 bp (NM_015910.5). Pathologic allelic variants. A homozygous c.76-1G>T is the only putative mutation reported to date [Kim et al 2010]. The transcript has not been analyzed to determine the affect of this putative mutation and its pathogenicity has not been proven.Normal gene product. WDPCP encodes WD repeat-containing and planar cell polarity effector protein fritz homolog.Abnormal gene product. A splice defect has been identified, but it is not known it’s affect on the transcript or if an abnormal gene product is produced. SDCCAG8 (BBS16)Normal allelic variants. This gene has 18 exons and a transcript of 2632 bp (NM_006642.3). Pathologic allelic variants. Affected individuals in one large family with BBS, were homozygous for a complex intron 7 insertion that was shown to disrupt an exonic splice enhancer site and create a premature stop codon [Otto et al 2010].Normal gene product. SDCCAG8 encodes a centrosome associated protein that may be involved in organizing the centrosome during interphase and mitosis. Abnormal gene product. This mutation led to a near complete absence of normal full-length protein product from SDCCAG8. The residual full-length transcript and product was proposed as an explanation for the late onset of renal failure and retinal degeneration in affected persons of this kindred [Otto et al 2010].