Bardet-Biedl Syndrome 12

A number sign (#) is used with this entry because Bardet-Biedl syndrome-12 (BBS12) is caused by homozygous or compound heterozygous mutation in the BBS12 gene (610683) on chromosome 4q27.

Description

BBS12 is a clinically pleiotropic autosomal recessive ciliopathy. The patients with BBS12 studied by Stoetzel et al. (2007) and Harville et al. (2010) met the diagnostic criteria of Beales et al. (1999), which required 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 (e.g., developmental delay, ataxia, cataracts).

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

Clinical Features

Dulfer et al. (2010) reported 2 female sibs with BBS resulting from compound heterozygous truncating mutations in the BBS12 gene. Each also carried a third heterozygous mutation in the BBS10 gene (610148). The first patient had postaxial polydactyly type A and severe hydrometrocolpos, resulting in prolonged delivery with hypoxia and death at delivery. Examination showed atresia of the distal vagina, a dilated cervix and uterus, and cystic renal dysplasia. The second pregnancy was terminated at 15 weeks' gestation after chorionic villus sampling identified the same 3 mutations in the second fetus, which had no external features of BBS and no abnormalities of the internal genitalia, although cystic renal dysplasia was present. Dulfer et al. (2010) noted the phenotypic variability between these sibs, and suggested that hydrometrocolpos should be considered a feature in females with BBS.

In 6 patients with molecularly confirmed BBS, including 1 patient with BBS12, 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.

Molecular Genetics

Using homozygosity mapping, Harville et al. (2010) identified 17 causative homozygous mutations in 20 families from a worldwide cohort of 45 BBS families. Three of these mutations occurred in the BBS12 gene.

In affected members with BBS from 2 consanguineous Gypsy families, Stoetzel et al. (2007) identified the same homozygous nonsense mutation in the BBS12 gene (R355X; 610683.0001). They identified a further homozygous or compound heterozygous mutations in BBS12 in 10 of 1106 French families, and compound heterozygous mutations in 3 of 139 United States families. A total of 17 different mutations were found; 1 frameshift mutation was found in 4 families (610683.0005).

Dulfer et al. (2010) identified compound heterozygosity for mutations in the BBS12 gene in 2 female sibs with phenotypic variability. Each sib also carried a heterozygous mutation in the BBS10 gene (610148). Dulfer et al. (2010) questioned whether the BBS10 mutation had any influence on the phenotype, since the BBS12 mutations were sufficient to cause the disorder. They reviewed the literature and pointed out that evidence for digenic inheritance was reported in only 36 of all 1,209 families (3.0%), and evidence for triallelic inheritance had been reported in only 10 of the 1,209 families (0.8%).