ORPHA: 110; DO: 0110123;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p35.2 | {Bardet-Biedl syndrome 1, modifier of} | 209900 | Autosomal recessive; Digenic recessive | 3 | CCDC28B | 610162 |
| 3q11.2 | {Bardet-Biedl syndrome 1, modifier of} | 209900 | Autosomal recessive; Digenic recessive | 3 | ARL6 | 608845 |
| 11q13.2 | Bardet-Biedl syndrome 1 | 209900 | Autosomal recessive; Digenic recessive | 3 | BBS1 | 209901 |
A number sign (#) is used with this entry because Bardet-Biedl syndrome-1 (BBS1) is caused by homozygous or compound heterozygous mutation in the BBS1 gene (209901) on chromosome 11q13.
Digenic inheritance has also been reported; see MOLECULAR GENETICS.
Bardet-Biedl syndrome is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism (summary by Beales et al., 1999). Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014).
Genetic Heterogeneity of Bardet-Biedl Syndrome
BBS2 (615981) is caused by mutation in a gene on 16q13 (606151); BBS3 (600151), by mutation in the ARL6 gene on 3q11 (608845); BBS4 (615982), by mutation in a gene on 15q22 (600374); BBS5 (615983), by mutation in a gene on 2q31 (603650); BBS6 (605231), by mutation in the MKKS gene on 20p12 (604896); BBS7 (615984), by mutation in a gene on 4q27 (607590); BBS8 (615985), by mutation in the TTC8 gene on 14q32 (608132); BBS9 (615986), by mutation in a gene on 7p14 (607968); BBS10 (615987), by mutation in a gene on 12q21 (610148); BBS11 (615988), by mutation in the TRIM32 gene on 9q33 (602290); BBS12 (615989), by mutation in a gene on 4q27 (610683); BBS13 (615990), by mutation in the MKS1 gene (609883) on 17q23; BBS14 (615991), by mutation in the CEP290 gene (610142) on 12q21, BBS15 (615992), by mutation in the WDPCP gene (613580) on 2p15; BBS16 (615993), by mutation in the SDCCAG8 gene (613524) on 1q43; BBS17 (615994), by mutation in the LZTFL1 gene (606568) on 3p21; BBS18 (615995), by mutation in the BBIP1 gene (613605) on 10q25; BBS19 (615996), by mutation in the IFT27 gene (615870) on 22q12; BBS20 (619471), by mutation in the IFT172 gene (607386) on 9p21; BBS21 (617406), by mutation in the CFAP418 gene (614477) on 8q22; and BBS22 (617119), by mutation in the IFT74 gene (608040) on 9p21.
The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes.
Although BBS had originally been thought to be a recessive disorder, Katsanis et al. (2001) demonstrated that clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the 6 loci plus an additional mutation in a second locus. While Katsanis et al. (2001) called this 'triallelic inheritance,' Burghes et al. (2001) suggested the term 'recessive inheritance with a modifier of penetrance.' Mykytyn et al. (2002) found no evidence of involvement of the common BBS1 mutation in triallelic inheritance. However, Fan et al. (2004) found heterozygosity in a mutation of the BBS3 gene (608845.0002) as an apparent modifier of the expression of homozygosity of the met390-to-arg mutation in the BBS1 gene (209901.0001).
Allelic disorders include nonsyndromic forms of retinitis pigmentosa: RP51 (613464), caused by TTC8 mutation, and RP55 (613575), caused by ARL6 mutation.
Renal abnormalities appear to have a high frequency in the Bardet-Biedl syndrome (Alton and McDonald, 1973). Klein (1978) observed 57 cases of Bardet-Biedl syndrome in Switzerland. Fifteen affected individuals occurred in one inbred pedigree and 7 in a second. Pagon et al. (1982) reported a 12-year-old boy with the Bardet-Biedl syndrome (retinal dystrophy, polydactyly, mental retardation, and mild obesity) who died of renal failure and was found to have hepatic fibrosis. They reviewed both earlier reported cases and other autosomal recessive entities that combine retinal dystrophy, hepatic fibrosis and nephronophthisis. Harnett et al. (1988) evaluated 20 of 30 patients with Bardet-Biedl syndrome identified from ophthalmologic records in Newfoundland. All had some abnormality in renal structure, function, or both. Most had minor functional abnormalities and a characteristic radiologic appearance, but to date (the mean age was 31 years) only 3 of the 20 had end-stage renal disease, with 2 requiring maintenance hemodialysis. Half the subjects had hypertension. Calyceal clubbing or blunting was evident in 18 of 19 patients studied by intravenous pyelography; 13 had calyceal cysts or diverticula. Of the 19 patients, 17 had lobulated renal outlines of the fetal type.
Green et al. (1989) examined 32 patients with Bardet-Biedl syndrome for some or all of the cardinal manifestations of the disorder. Of 28 patients examined, all had severe retinal dystrophy, but only 2 had typical retinitis pigmentosa. Polydactyly was present in 18 of 31 patients; syndactyly, brachydactyly, or both were present in all patients. Obesity was present in all but 1 of 25 patients. Only 13 of 32 patients were considered mentally retarded. Scores on verbal subsets of intelligence were usually lower than scores on performance tasks. Of 8 men, 7 had small testes and genitalia, which was not due to hypogonadotropism. All 12 women studied had menstrual irregularities and 3 had low serum estrogen levels (1 of these had hypogonadotropism and 2 had primary gonadal failure). Diabetes mellitus was present in 9 of 20 patients. Renal structural or functional abnormalities were present in all 21 patients studied, and 3 patients had end-stage renal failure.
Gershoni-Baruch et al. (1992) emphasized the occurrence of cystic kidney dysplasia in Bardet-Biedl syndrome. They commented on the fact that the combination of cystic kidney dysplasia and polydactyly occurs also in Meckel syndrome (249000) and in the short rib-polydactyly syndromes (see 613091), and that usually these syndromes are easy to differentiate. They observed 3 sibs with cystic kidney dysplasia and polydactyly who were thought to have Meckel syndrome until extinguished responses on electroretinography were detected in one of them, aged 3.5 years. In 19-year-old female twins and their 22-year-old sister, Chang et al. (1981) described hypogonadotropic hypogonadism with primary amenorrhea and lack of secondary sexual development, associated with retinitis pigmentosa.
Stoler et al. (1995) described 2 unrelated girls with Bardet-Biedl syndrome who also had vaginal atresia. A similar association was suggested in reports of 11 BBS females who had structural genital abnormalities (some of which were missed in childhood), including persistent urogenital sinus; ectopic urethra; hypoplasia of the uterus, ovaries, and fallopian tubes; uterus duplex; and septate vagina. Mehrotra et al. (1997) observed 2 sisters with the Bardet-Biedl syndrome, 1 of whom had congenital hydrometrocolpos. This infant also had tetramelic postaxial polydactyly, making the diagnosis of Kaufman-McKusick syndrome (236700) a possibility in the neonatal period. However, as a teenager she was evaluated for poor vision and found to have mental deficiency, obesity, poor visual acuity, end gaze nystagmus, tapetoretinal degeneration, and extinguished electroretinogram. Her older sister had similar eye complaints; she likewise was born with tetramelic postaxial polydactyly and was also mentally retarded.
David et al. (1999) reported 9 patients who, because of the presence of vaginal atresia and postaxial polydactyly, were diagnosed in infancy with McKusick-Kaufman syndrome; these patients later developed obesity and retinal dystrophy and were diagnosed with Bardet-Biedl syndrome. David et al. (1999) suggested that the phenotypic overlap between McKusick-Kaufman syndrome and Bardet-Biedl syndrome is a diagnostic pitfall, and that all children in whom a diagnosis of McKusick-Kaufman syndrome is made in infancy should be reevaluated for retinitis pigmentosa and other signs of Bardet-Biedl in later childhood.
In Bedouin families in the Negev region of Israel, presumably the same kindreds as those studied by Kwitek-Black et al. (1993), Elbedour et al. (1994) performed echocardiographic evaluations of cardiac involvement in BBS. They stated that they found cardiac involvement in 50% of cases, justifying inclusion of echocardiographic examination in the clinical evaluation and follow-up of these patients. However, their Table 1 gives echocardiographic abnormality in only 7 of 22 cases and these included 1 case of bicuspid aortic valve, 1 case of mild thickening of the interventricular septum, 1 case of 'moderate tricuspid regurgitation,' and 1 case of mild pulmonic valve stenosis. The occurrence of renal abnormality in 11 of the 22 patients on kidney ultrasonography was somewhat more impressive than the cardiac involvement.
Islek et al. (1996) described a boy with postaxial polydactyly and Hirschsprung disease (142623) found at the age of 3 months. Follow-up examination at the age of 7 years showed obesity, mental retardation, retinitis pigmentosa, microphallus, and cryptorchidism. The diagnosis of Bardet-Biedl syndrome was established. According to Islek et al. (1996), 2 other cases of association of Bardet-Biedl syndrome and Hirschsprung disease have been reported.
Beales et al. (1999) reported a study of 109 BBS patients and their families. Average age at diagnosis was 9 years. Postaxial polydactyly was present in 69% of patients at birth, but obesity did not begin to develop until approximately 2 to 3 years of age, and retinal degeneration did not become apparent until a mean age of 8.5 years. As a result of their study, Beales et al. (1999) proposed a set of diagnostic criteria based on primary and secondary features (see DIAGNOSIS). They suggested the use of the term polydactyly-obesity-kidney-eye syndrome in recognition of what they described as the phenotypic overlap between BBS and Laurence-Moon syndrome.
In 2 patients with Bardet-Biedl syndrome, Lorda-Sanchez et al. (2000) identified 2 uncommon manifestations: situs inversus in one and Hirschsprung disease in the other. They were unable to determine which of the 5 forms of BBS known at that time was present in these cases.
Cox et al. (2003) examined the electrophysiologic responses of carriers of BBS. All carriers had decreased corneal positive potential and 60% had a decreased b-wave sensitivity. The authors postulated that the site of the primary defect in the BBS rod pathway appeared to be proximal to the rod outer segments, most likely before the rod-bipolar cell synapse.
Kulaga et al. (2004) showed that individuals with BBS have partial or complete anosmia (107200). To test whether this phenotype is caused by ciliary defects of olfactory sensory neurons, they examined mice with deletions of Bbs1 or Bbs4 (600374) genes. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies.
By detailed neurologic examination of 9 BBS patients, Tan et al. (2007) observed a noticeable decrease in peripheral sensation affecting all modalities in most patients. Tan et al. (2007) concluded that this may be an underrecognized component of the disorder.
In 6 patients with molecularly confirmed BBS, including 1 patient with BBS1, Scheidecker et al. (2015) found a cone-rod pattern of dysfunction. Macular dystrophy was present in all patients, usually with central hypofluorescence surrounded by a continuous hyperfluorescent ring on fundus autofluorescence imaging. Optical coherence tomography confirmed loss of outer retinal structure within the atrophic areas.
Relationship to Laurence-Moon Syndrome
There has been longstanding uncertainty as to the relationship between the Laurence-Moon syndrome (245800) and the Bardet-Biedl syndrome. Solis-Cohen and Weiss (1925) lumped them together as the Laurence-Biedl syndrome. Ammann (1970) concluded that the patients of Laurence and Moon had a distinct disorder with paraplegia and without polydactyly and obesity. As suggested by the study of Ammann (1970), residual heterogeneity may exist even after the Laurence-Moon syndrome is separated; for example, Biemond syndrome II (iris coloboma, hypogenitalism, obesity, polydactyly, and mental retardation; 210350) and Alstrom syndrome (retinitis pigmentosa, obesity, diabetes mellitus, and perceptive deafness; 203800) were considered distinct entities. Schachat and Maumenee (1982) reviewed the nosography of these and related syndromes.
In a 22-year prospective cohort study of 46 patients from 26 Newfoundland families with BBS, Moore et al. (2005) found no apparent correlation of clinical or dysmorphic features with genotype. They reported that of 2 patients clinically diagnosed as having Laurence-Moon syndrome, one was from a consanguineous pedigree with linkage to the BBS5 gene (see 615983), and the other was a compound heterozygote for mutations in the MKKS gene (604896.0007 and 604896.0008). Moore et al. (2005) concluded that the features in this population did not support the notion that BBS and LMS are distinct. The patient with mutations in the MKKS gene (NF-B5) had previously been reported by Katsanis et al. (2000) as having BBS6 (605231), thus illustrating the difficulty in distinguishing these 2 disorders.
Bardet-Biedl Syndrome 1
Beales et al. (1997) observed only subtle phenotypic differences among Bardet-Biedl families mapping to the BBS1, BBS2 (615981), or BBS4 (615982) loci, the most striking of which was the finding of taller affected offspring compared with their parents in the BBS1 category. Affected subjects in the BBS2 and BBS4 groups were significantly shorter than their parents. In more than one-fourth of the pedigrees, linkage to no known locus could be established, suggesting the existence of a fifth BBS locus.
Reviews
Khan et al. (2016) reviewed the clinical spectrum and genetics of BBS, including genotype-phenotype correlations and contribution of each responsible gene to the total BBS mutational load.
Katsanis et al. (2001) screened 163 BBS families for mutations in both BBS2 and BBS6 and reported the presence of 3 mutant alleles in affected individuals in 4 pedigrees. In addition, Katsanis et al. (2001) detected unaffected individuals in 2 pedigrees who carried 2 BBS2 mutations but not a BBS6 mutation. One of these was found to be homozygous by descent for a BBS1 allele, and the other was found to be homozygous by descent for a BBS4 allele.
The identification of the gene most commonly mutated in individuals with BBS (BBS1; 209901) allowed Mykytyn et al. (2002) to examine the hypothesis that 3 mutated alleles are required for penetrance of the BBS phenotype (triallelic inheritance), as had been suggested by Katsanis et al. (2001). They did not find the common M390R mutation (209901.0001) in any of 12 unrelated individuals who had previously been shown to have 2 mutations in BBS2, BBS4, or BBS6 (MKKS). Moreover, complete sequencing of BBS1 in these individuals revealed no coding sequence variations. In addition, they sequenced BBS2, BBS4, and MKKS in 10 unrelated North American individuals who were homozygous with respect to the BBS1 M390R mutation. All sequence alterations identified in affected individuals were also found in controls. Although it is possible that these individuals could harbor an additional mutated allele in an unidentified gene underlying BBS, the fact that the remaining genes account for a very small proportion of Bardet-Biedl syndrome makes this unlikely. Finally, in 6 multiplex families in which affected individuals harbored BBS1 mutations, Mykytyn et al. (2002) did not detect any unaffected individuals with 2 BBS1 mutations. Thus, in the families studied by them, the disorder segregated as an autosomal recessive disease, with no evidence that BBS1 acts in triallelic inheritance.
Mykytyn et al. (2003) demonstrated that the common BBS1 M390R mutation accounts for approximately 80% of all BBS1 mutations and is found on a similar genetic background across populations.
Abu-Safieh et al. (2012) presented evidence that most cases of BBS are inherited in a classic autosomal recessive pattern, and that the triallelic model is very rare, if it exists at all. The authors conducted a comprehensive sequence analysis of all 14 BBS genes as well as the modifier gene CCDC28B (610162) in a cohort of 29 Arab BBS families. Two pathogenic mutations in trans were identified in affected members of each family, and in no instance was a third allele identified that convincingly acted as a modifier of penetrance supporting the triallelic model of BBS. The massive sequencing effort uncovered a number of novel sequence variants in BBS genes other than the 2 pathogenic mutations per family, but the majority of these variants were noncoding and none of the possible splicing variants were predicted to be pathogenic.
Muller et al. (2010) screened the BBS1 through BBS12 genes and identified pathogenic mutations in 134 (77%) of 174 BBS families: 117 families had 2 pathogenic mutations in a single gene, and 17 families had a single heterozygous mutation, 8 of which were the BBS1 recurrent mutation M390R (209901.0001). BBS1 and BBS10 were the most frequently mutated genes, each found in 32.6% of families, followed by BBS12, found in 10.4% of families. No mutations were found in BBS11, which has only been identified in 1 consanguineous family. There was a high level of private mutations, and Muller et al. (2010) discussed various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.
In a 53-year-old woman with 'juvenile retinitis pigmentosa-like' retinal features consistent with those seen in other BBS1 patients, but who had no syndromic features, Wang et al. (2013) identified homozygosity for the recurrent M390R mutation in the BBS1 gene. The authors stated that the mutation segregated with disease in the family, and noted that such patients should be followed for the potential development of syndromic features.
Modifier Genes
The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes.
Putoux et al. (2011) identified 8 different heterozygous missense mutations in the KIF7 gene (611254) in 8 patients with ciliopathies, including Bardet-Biedl syndrome, Meckel syndrome (MKS; 249000), Joubert syndrome (JBTS; 213300), Pallister-Hall syndrome (PHS; 146510), and OFD6 (277170). Four of these patients had additional pathogenic mutations in other BBS genes. Rescue studies of somites in morphant zebrafish embryos demonstrated that the heterozygous KIF7 missense mutations were hypomorphs, and Putoux et al. (2011) concluded that these alleles may contribute to or exacerbate the phenotype of other ciliopathies, particularly BBS.
Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene (A229T; 610937.0013) may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations, including BBS.
Kousi et al. (2020) performed a systematic secondary-variant burden analysis of 2 independent cohorts of patients with Bardet-Biedl syndrome with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. Kousi et al. (2020) observed a significant enrichment of trans-acting rare nonsynonymous secondary variants in patients with BBS compared with either population controls or a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, they found a significant overrepresentation of secondary alleles in chaperonin-encoding genes, a finding corroborated by the observation of epistatic interactions involving this complex in vivo. Kousi et al. (2020) clustered the 17 BBS genes into 3 previously defined modules: the BBSome complex (e.g., BBS1); the transition zone complex (e.g., MKS1, 609883); and the chaperonin complex (e.g., BBS10, 610148). For the remaining 3 genes (WDPCP, 613580; TRIM32, 602290; and ARL6, 608845) Kousi et al. (2020) had no information about the macromolecular complexes to which their transcribed proteins belonged. The authors restricted themselves to alleles at a minor allele frequency of less than 0.001%, which was the bin with the most robust evidence for burden enrichment, and collapsed all alleles per module and plotted all of the observed interactions. This distribution of interactions was nonrandom across the combined set of 277 individuals with BSS; most recessive events were contributed by chaperonin-encoding components (Bonferroni-corrected p = 4 x 10(-3)), suggesting that this module potentially has the most physiologically potent interaction capability.
Oligogenic Inheritance and Copy Number Variation
Lindstrand et al. (2016) found exon-disruptive copy number variants (CNVs) in 17 (18.5%) of 92 probands with various forms of BBS who underwent array CGH of 20 candidate genes and 74 ciliopathy loci. The lesions ranged in size from 700 bp to over 100 kb and contributed recessive alleles. Eleven of the 17 probands carried pathogenic mutations in one or more BBS genes in addition to their driver locus, consistent with significant oligogenic inheritance. The data suggested that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals, and that it remains important to continue the studies of exomes and genomes of affected individuals beyond the discovery of a primary disease driver, as these additional molecular changes may worsen or mitigate the phenotype.
Associations Pending Confirmation
For discussion of a possible association between Bardet-Biedl syndrome and variation in the CEP19 gene, see 615586.
Based on a review of 109 BBS patients, Beales et al. (1999) proposed modified diagnostic criteria, requiring the presence of either 4 primary features, including rod-cone dystrophy, polydactyly, obesity, learning disabilities, hypogonadism (in males), and/or renal anomalies; or 3 primary plus 2 secondary features, including speech disorder or delay; strabismus, cataracts, or astigmatism; brachydactyly/syndactyly; developmental delay; polyuria/polydipsia (nephrogenic diabetes insipidus); ataxia, poor coordination, or imbalance; mild spasticity, especially of lower limbs; diabetes mellitus; dental crowding, hypodontia, small dental roots, or high-arched palate; left ventricular hypertrophy or congenital heart disease; and/or hepatic fibrosis.
Janssen et al. (2011) used a DNA pooling and massively parallel resequencing strategy to screen 132 individuals with BBS from 105 families. This method allowed identification of both disease-causing mutations in 29 (28%) of 105 families. Thirty-five different disease-causing mutations were identified, 18 of which were novel.
BBS Gene Heterozygosity
On the basis of a study of 75 relatives in 5 generations of the extended family of 2 adult Bardet-Biedl sibs, Croft and Swift (1990) suggested that heterozygotes have an increased frequency of obesity, hypertension, diabetes mellitus, and renal disease. They pointed out that homozygotes have hepatic disease.
Croft et al. (1995) studied obesity and hypertension among nonhomozygous relatives of BBS patients, hypothesizing that BBS heterozygotes might be predisposed to these conditions. Among 34 parents of BBS homozygotes (obligate heterozygotes), a proportion of severely overweight fathers (26.7%) were significantly higher than that in comparably aged U.S. white males (8.9%). They concluded that the BBS gene may predispose male heterozygotes to obesity. If heterozygotes represent 1% of the general population, they estimated that approximately 2.9% of all severely overweight white males carry a single BBS gene. The BBS parents of both sexes were also significantly taller than U.S. white men and women of comparable age.
Beales et al. (1999) found renal cell adenocarcinomas in 3 parents of individuals with BBS, and congenital renal malformations in a number of others. They suggested that these findings may be a consequence of heterozygosity for disease-causing mutations in BBS genes.
Linkage to 11q13 (BBS1)
Leppert et al. (1994) performed linkage analysis in 31 multiplex BBS families and reported linkage with 2 markers on 11q, PYGM (608455) and an anonymous marker, D11S913. The homozygosity testing demonstrated genetic heterogeneity within the set of families. The confidence interval for BBS1, based on a 1 lod difference, extended approximately 1 cM proximal to PYGM and 2 cM distal to PYGM. PYGM is located in band 11q13. Leppert et al. (1994) stated that they had seen families unlinked to either chromosome 16 (BBS2) or chromosome 11.
Beales et al. (1997) studied 18 families with 2 or more members affected with Bardet-Biedl syndrome, noting the presence of both major and minor manifestations. They performed linkage studies in the hope of finding phenotypic differences between the 4 linkage categories identified to that time. Eight of the families (44%) were found to be linked to 11q13 (BBS1), and 3 (17%) were linked to 16q21 (BBS2). Only 1 family was linked to 15q22 (BBS4; 600374), and none were linked to 3p12 (BBS3; 608845). They concluded that BBS1 is the major locus among white Bardet-Biedl patients and that BBS3 is extremely rare. Only subtle phenotypic differences were observed, the most striking of which was the finding of taller affected offspring compared with their parents in the BBS1 category. Affected subjects in the BBS2 and BBS4 groups were significantly shorter than their parents. In more than one-fourth of the pedigrees, linkage to no known locus could be established, suggesting the existence of a fifth BBS locus.
Katsanis et al. (1999) collected a large number of BBS pedigrees of primarily North American and European origin and performed genetic analysis using microsatellites from all known BBS genomic regions. Heterogeneity analysis established a 40.5% contribution of the 11q13 locus to BBS, and haplotype construction on 11q-linked pedigrees revealed several informative recombinants, defining the BBS1 critical interval between D11S4205 and D11S913, a genetic distance of 2.9 cM, equivalent to approximately 2.6 Mb. Loss of identity by descent in 2 consanguineous pedigrees was also observed in the region, potentially refining the region to 1.8 Mb between D11S1883 and D11S4944.
Young et al. (1999) used linkage disequilibrium (LD) mapping in an isolated founder population in Newfoundland to reduce significantly the BBS1 critical region. Extensive haplotype analysis in several unrelated BBS families of English descent revealed that the affected members were homozygous for overlapping portions of a rare, disease-associated ancestral haplotype. The LD data suggested that the BBS1 gene lies in a 1-Mb, sequence-ready region on 11q13.
Mapping Studies
In a study of 19 BBS families of mixed but predominantly European ethnic origin, Bruford et al. (1997) obtained results showing that an estimated 36 to 56% of the families were linked to 11q13. A further 32 to 35% of the families were linked to 15q22.3-q23. Three consanguineous families showed homozygosity for 3 adjacent chromosome 15 markers, consistent with identity by descent for this region. In one of these families haplotype analysis reported a localization for BBS4 between D15S131 and D15S114, a distance of about 2 cM. Weak evidence of linkage to 16q21 was observed in 24 to 27% of families. A fourth group of families, estimated at 8%, were unlinked to all 3 of the above loci. Bruford et al. (1997) found no evidence of linkage to markers on chromosome 3, corresponding to the BBS3 locus, or on chromosome 2 or 17, arguing against the involvement of a BBS locus in a patient with Bardet-Biedl syndrome and a t(2;17) translocation reported by Dallapiccola (1971).
The prevalence of BBS in Newfoundland is approximately 10-fold greater than in Switzerland (1 in 160,000) and similar to the prevalence among the Bedouin of Kuwait (1 in 13,500). Woods et al. (1999) performed a population-based genetic survey of 17 BBS families in the island portion of the province of Newfoundland. The families contained a total of 36 well-documented affected individuals; 12 families had 2 or more affected persons. Linkage at each of the 4 then-known loci was tested with 2-point linkage and haplotype analysis. Three of the kindreds showed linkage to 11q (BBS1), 1 to 16q (BBS2), and 1 to 3p (BBS3). The BBS3 family was the first to be identified in a population of northern European descent. Six families remained undetermined because of poor pedigree structure or inconclusive haplotype analyses. Six families were excluded from all 4 then-known BBS loci, including BBS4.
Farag and Teebi (1988) concluded that the frequency of both the Bardet-Biedl and the Laurence-Moon syndromes is increased in the Arab population of Kuwait. Farag and Teebi (1989) pointed to a high frequency of the Bardet-Biedl syndrome among the Bedouin; the estimated minimum prevalence was 1 in 13,500.
Ross et al. (2005) showed that mice with mutations in genes involved in Bardet-Biedl syndrome share phenotypes with planar cell polarity (PCP) mutants including open eyelids, neural tube defects, and disrupted cochlear stereociliary bundles. Furthermore, they identified genetic interactions between BBS genes and a PCP gene in both mouse (LTAP, also called VANGL2; 600533) and zebrafish (vangl2). In zebrafish, the augmented phenotype resulted from enhanced defective convergent extension movements. Ross et al. (2005) also showed that VANGL2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins. These data suggested that cilia are intrinsically involved in planar cell polarity processes.
Davis et al. (2007) generated a knockin mouse model of the BBS1 M390R mutation (209901.0001). Mice homozygous for M390R recapitulated aspects of the human phenotype, including retinal degeneration, male infertility, and obesity. Morphologic evaluation of Bbs1 mutant brain revealed ventriculomegaly of the lateral and third ventricles, thinning of the cerebral cortex, and reduced volume of the corpus striatum and hippocampus. Ultrastructural examination of the ependymal cell cilia that lined the enlarged third ventricle of Bbs1 mutant brains showed that, whereas the 9+2 arrangement of axonemal microtubules was intact, elongated cilia and cilia with abnormally swollen distal ends were present. Davis et al. (2007) concluded that the M390R mutation does not affect axonemal structure, but it may play a role in regulation of cilia assembly and/or function.
By immunostaining for axonemal proteins, Tan et al. (2007) demonstrated that mouse dorsal root ganglion neurons contain cilia. Bbs1-null and Bbs4-null mice demonstrated behavioral deficits in thermosensation and mechanosensation associated with alterations in the trafficking of the thermosensory channel Trpv1 (602076) and the mechanosensory channel Stoml3 (608327) within sensory neurons. The findings were replicated in C. elegans lacking Bbs7 or Bbs8. Detailed examination of 9 patients with BBS showed a noticeable decrease in peripheral sensation in most of them.
Using mice lacking Bbs2, Bbs4, or Bbs6 and mice with the M390R mutation in Bbs1, Shah et al. (2008) showed that expression of BBS proteins was not required for ciliogenesis, but their loss caused structural defects in a fraction of cilia covering airway epithelia. The most common abnormality was bulges filled with vesicles near the tips of cilia, and this same misshapen appearance was present in airway cilia from all mutant mouse strains. Cilia of Bbs4-null and Bbs1 mutant mice beat at a lower frequency than wildtype cilia. Neither airway hyperresponsiveness nor inflammation increased in Bbs2- or Bbs4-null mice immunized with ovalbumin compared with wildtype mice. Instead, mutant animals were partially protected from airway hyperresponsiveness.
Abu-Safieh, L., Al-Anazi, S., Al-Abdi, L., Hashem, M., Alkuraya, H., Alamr, M., Sirelkhatim, M. O., Al-Hassnan, Z., Alkuraya, B., Mohamed, J. Y., Al-Salem, A., Alrashed, M., and 11 others. In search of triallelism in Bardet-Biedl syndrome. Europ. J. Hum. Genet. 20: 420-427, 2012. [PubMed: 22353939] [Full Text: https://doi.org/10.1038/ejhg.2011.205]
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