BBS12 – Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is a multisystem autosomal recessive ciliopathy characterized by progressive rod-cone dystrophy, postaxial polydactyly, central obesity, cognitive impairment and renal anomalies. BBS12 (HGNC:26648) was identified in two consanguineous Gypsy families by homozygosity mapping and shown to encode a vertebrate-specific type II chaperonin; biallelic mutations in BBS12 account for approximately 5% of BBS cases (PMID:17160889).

Genetic evidence for BBS12 as a causative gene in BBS is robust. Over 50 unrelated probands across diverse ethnic backgrounds have been reported with biallelic pathogenic variants in BBS12, including both loss-of-function and missense alleles. A recurrent nonsense variant c.898C>T (p.Gln300Ter) was documented in multiple families, segregating with disease in autosomal recessive fashion (PMID:17160889). Additional frameshift and splice variants expand the mutational spectrum to include c.265_266del (p.Leu89ValfsTer11), c.1007del (p.Thr336fs) and c.1063C>T (p.Arg355Ter).

Founder and recurrent alleles have been described. A homozygous p.Arg355Ter (c.1063C>T) variant was identified in seven Romanian pedigrees of Eastern European and Romani origin, pointing to a region-specific founder effect (PMID:37293956). Multiple consanguineous cohorts from Saudi Arabia, Pakistan and China include families with unique homozygous BBS12 mutations, confirming its global importance in BBS etiology (PMID:19858128).

Functional studies in zebrafish demonstrate that suppression of BBS12 yields gastrulation movement defects and ciliary abnormalities consistent with human BBS phenotypes. Combined knockdown of BBS6, BBS10 and BBS12 exacerbates these defects, supporting a chaperonin-mediated mechanism of ciliogenesis in vertebrates (PMID:17160889).

Clinical reports underscore the phenotypic variability associated with BBS12 mutations: Japanese infants with compound heterozygous nonsense and frameshift variants present with early-onset retinal dysfunction and polydactyly (PMID:36574078), whereas some adult cases exhibit milder phenotypes lacking typical renal or genital anomalies (PMID:20648243).

Overall, BBS12 has a definitive gene-disease association with Bardet-Biedl syndrome. Autosomal recessive inheritance of biallelic loss-of-function or hypomorphic alleles produces a spectrum of ciliopathy manifestations. Genetic testing for BBS12 variants is clinically useful for diagnosis, prognosis and family-based carrier screening in diverse populations.

References

• American Journal of Human Genetics | 2007 | Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. PMID:17160889
• Journal of Medical Genetics | 2010 | Clinical and molecular characterisation of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping. PMID:19858128
• Biomedical Reports | 2021 | A case of Bardet-Biedl syndrome caused by a recurrent variant in BBS12: A case report. PMID:34760276
• Journal of the Association of Physicians of India | 2023 | Bardet-Biedl syndrome associated with novel compound heterozygous variants in BBS12 gene. PMID:36574078
• European Journal of Human Genetics | 2023 | BBS12 p.Arg355 is a recurrent nonsense allele in Eastern European and Romani Bardet-Biedl syndrome patients.* PMID:37293956

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