Bardet-Biedl Syndrome 8

A number sign (#) is used with this entry because Bardet-Biedl syndrome-8 (BBS8) is caused by homozygous mutations in the TTC8 gene (608132) on chromosome 14q31.

Description

BBS8 is an autosomal recessive disorder characterized by retinitis pigmentosa, obesity, postaxial polydactyly, hypogonadism, and developmental delay (Ansley et al., 2003).

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

Clinical Features

Ansley et al. (2003) identified 3 families, 1 of Pakistani and 2 of Saudi Arabian lineage, with BBS8. Affected members had retinitis pigmentosa, obesity, postaxial polydactyly of at least 2 limbs, brachycephaly, hypogonadism, speech impediment, and developmental delay. In the Saudi families, onset of retinitis pigmentosa was in early childhood. Additionally, situs inversus, hemophilia, deafness, and asthma were each found in a single patient.

Stoetzel et al. (2006) identified patients with BBS8 from 2 families. The first family was consanguineous and of North African descent. The proband had retinitis pigmentosa, polydactyly of hands and feet, cognitive impairment, and micropenis. One of his affected sisters had a presentation suggestive of McKusick-Kaufman syndrome (236700) as she was operated on at birth for hydrometrocolpos. The other affected sister had, in addition to polydactyly and retinitis pigmentosa, kidney dysplasia. The other proband was born of consanguineous Lebanese parents.

Pathogenesis

Ansley et al. (2003) demonstrated that BBS is probably caused by a defect of the basal body of ciliated cells. The TTC8 gene (608132), mutations in which are responsible for BBS8, encodes a protein with a prokaryotic domain, pilF, involved in pilus formation and twitching mobility. In 1 family a homozygous null BBS8 mutation (608132.0002) led to BBS with randomization of left-right body axis symmetry, a defect of the nodal cilium. Ansley et al. (2003) showed that TTC8 localizes to centrosomes and basal bodies and colocalizes with gamma-tubulin (see 191135), BBS4 (600374), and PCM1 (600299). Furthermore, Ansley et al. (2003) found that all available C. elegans BBS homologs are expressed exclusively in ciliated neurons and contain regulatory elements for RFX, a transcription factor that modulates the expression of genes associated with ciliogenesis and intraflagellar transport.

Molecular Genetics

Ansley et al. (2003) screened the TTC8 gene in a cohort of 120 unrelated BBS patients. They identified homozygous alterations (608132.0001 and 608132.0002) in patients from 3 families. These mutations were not identified in 192 ethnically matched control chromosomes.

Stoetzel et al. (2006) identified homozygous mutations in the TTC8 gene (608132.0003 and 608132.0004) in 2 of 128 BBS families. One additional family had a heterozygous mutation. Stoetzel et al. (2006) concluded that TTC8 mutations account for only about 2% of BBS families.

Using homozygosity mapping, Harville et al. (2010) identified 17 causative homozygous mutations in 20 families from a worldwide cohort of 45 BBS families. Two of these mutations occurred in the TTC8 gene.