Bardet-Biedl Syndrome 2

A number sign (#) is used with this entry because Bardet-Biedl syndrome-2 (BBS2) is caused by homozygous or compound heterozygous mutations in the BBS2 gene (606151) on chromosome 16q13.

Description

BBS2 is an autosomal recessive ciliopathy characterized by retinal degeneration, polydactyly, renal disease, hypogonadism, obesity, dysmorphic features, and variable degrees of cognitive impairment (Innes et al., 2010). Mutation in the BBS2 gene is the third most frequent cause of BBS, accounting for approximately 8% of cases (Zaghloul and Katsanis, 2009).

For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900).

Clinical Features

Kwitek-Black et al. (1993) studied a large inbred Bedouin family from the Negev region of Israel (pedigree 1) in which Bardet-Biedl syndrome was linked to chromosome 16q21. Nine affected persons evaluated had polydactyly and mental retardation; 8 of these had retinitis pigmentosa, which in the ninth could not be evaluated because of the patient's age. Most of the patients were markedly obese, and hypogenitalism was present in affected males. Two patients had unilateral renal hypoplasia.

Elbedour et al. (1994) studied 3 Bedouin families with Bardet-Biedl syndrome from the Negev region of Israel, 2 of which had been studied by Kwitek-Black et al. (1993). In the 16q21-linked family (family 1) they identified dilated cardiomyopathy, bicuspid aortic valve, and secundum atrial septal defect in 3 different patients by echocardiography, and by ultrasonography they identified kidney defects in most patients examined.

Among 18 BBS families of various ethnic origins, Beales et al. (1997) observed that 17% (3) were linked to chromosome 16q21 (BBS2). Affected subjects in this category and those linked to the BBS4 locus (615982) were significantly shorter than their parents.

Sheffield et al. (1994) reported that the clinical features of Bedouin families with BBS2 and BBS3 (600151) were very similar. For example, all affected individuals in both kindreds showed postaxial polydactyly. The authors hypothesized that the identical phenotype resulting from different mutations at 2 separate loci might have its explanation in involvement of a ligand-receptor complex, protein subunits, or proteins involved in a common biochemical pathway.

Genotype/Phenotype Correlations

Carmi et al. (1995) compared the clinical manifestations of BBS in 3 unrelated, extended Arab-Bedouin kindreds in which linkage had been demonstrated to chromosomes 3 (BBS3; 600151), 15 (BBS4; 615982), and 16 (BBS2). Observed differences included the limb distribution of the postaxial polydactyly and the extent and age-association of obesity. It appeared that the chromosome 3 locus is associated with polydactyly of all 4 limbs, while polydactyly of the chromosome 15 type is mostly confined to the hands. The chromosome 15 type is associated with early-onset morbid obesity, while the chromosome 16 type appears to present the 'leanest' end of BBS.

Mapping

Kwitek-Black et al. (1993) used linkage and the candidate gene approach to exclude all known autosomal pigmented retinopathy loci in 2 large inbred Bedouin families. Thereafter, a genomewide search for linkage was conducted using short tandem repeat polymorphisms (STRPs). By this approach, they identified linkage of the BBS locus to markers that mapped to 16q21. Maximum likelihood calculations for 2-point linkage between D16S408 and the disease phenotype resulted in Z = 4.2 at theta = 0.0. A multilocus lod score of 5.3 was observed. By demonstrating homozygosity in all affected individuals for the same allele of marker D16S408, further support for linkage was found, and the utility of homozygosity mapping using inbred families was demonstrated. In a second family with BBS from a different Bedouin tribe and unrelated to the first family, linkage to the same chromosome 16 markers was excluded over a stretch of at least 20 cM centered on marker D16S408. The symbol BBS2 was used for the locus on chromosome 16 and BBS1 for the non-chromosome 16 locus (McAlpine, 1994).

Molecular Genetics

Nishimura et al. (2001) used physical mapping and sequence analysis to identify the BBS2 gene at 16q21. They detected homozygous mutations in the BBS2 gene (606151.0001-606151.0002) in 2 unrelated BBS families, including a large Bedouin family previously reported by Kwitek-Black et al. (1993) (family 1). Direct sequencing of the BBS2 gene in 18 additional BBS probands identified 1 homozygous truncating mutation in 1 patient.

Katsanis et al. (2001) screened a cohort of 163 BBS families for mutations in BBS2 and BBS6 and identified 6 BBS pedigrees in which 2 independent BBS2 mutations segregated with the disorder. In 8 other pedigrees they identified mutation in BBS2 on only 1 allele. In affected individuals in 4 pedigrees they detected 3 mutant alleles; in 3 of these families affected individuals carried 2 mutant alleles of BBS2 and 1 of BBS6; in the other family affected individuals were homozygous for mutation in BBS6 and carried an additional mutated BBS2 allele. In one of these families an individual with 2 mutant BBS2 alleles and wildtype for BBS6 was unaffected. Another unaffected individual was identified with 2 mutant BBS2 alleles but who was homozygous by descent for the BBS4 locus. Katsanis et al. (2001) proposed that BBS may not be a single-gene recessive disorder but a complex trait requiring 3 mutant alleles to manifest the phenotype, and referred to this mode of inheritance as 'triallelic.'

Laurier et al. (2006) identified an extended consanguineous Bardet Biedl syndrome family in which a homozygous mutation in BBS2 (G139V; 606151.0017) was detected in one sibship. In 3 other sibships, homozygous mutation in BBS10 (610148) was detected, and in 1 other sibship compound heterozygous mutation in BBS10 was found. There was no evidence for triallelism in this family.