BBS1 – Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is a multisystem autosomal recessive ciliopathy marked by rod-cone dystrophy, postaxial polydactyly, obesity, renal malformations, hypogonadism, and intellectual disability. The BBS1 gene encodes a core component of the BBSome complex required for primary cilia assembly and function. Pathogenic variants in BBS1 disrupt ciliary homeostasis, leading to the pleiotropic manifestations of BBS1-related Bardet-Biedl syndrome.

Genetic analyses across independent cohorts confirm autosomal recessive inheritance of BBS1-related BBS. In a study of 129 unrelated probands, biallelic BBS1 variants were identified in multiple families, with the recurrent missense variant c.1169T>G (p.Met390Arg) accounting for ~80% of BBS1 alleles and segregating with disease in affected siblings and parents (PMID:12524598). Compound heterozygous and homozygous occurrences of c.1169T>G have been reported in diverse populations, supporting a founder effect and strong allele pathogenicity.

The spectrum of BBS1 variants includes missense changes (e.g., c.1169T>G (p.Met390Arg)), splice-site mutations (e.g., c.723+2T>G), small insertions/deletions, and retrotransposon insertions in exon 13. The predominance of missense and loss-of-function alleles highlights the critical role of BBS1 protein integrity in ciliary biogenesis.

Phenotypically, BBS1 mutation carriers uniformly present with obesity (HP:0001513), postaxial polydactyly (HP:0010442), rod-cone dystrophy/retinal dystrophy (HP:0000556), hypogonadism (HP:0000135), intellectual disability (HP:0001249), and renal anomalies (HP:0000077). Variable expressivity is observed, with some individuals displaying mild retinal involvement or late-onset obesity.

Functional studies of the Bbs1 M390R knock-in mouse model recapitulate key human phenotypes, including obesity, ventriculomegaly, retinopathy, and ciliary axoneme abnormalities, confirming haploinsufficiency and ciliary dysfunction as disease mechanisms (PMID:18032602). Patient-derived cell assays and U1 snRNA rescue experiments further validate splicing defects and support targeted therapeutic approaches.

Integration of genetic and experimental data establishes a Strong clinical validity for the BBS1–Bardet-Biedl syndrome association. Routine testing for the common c.1169T>G (p.Met390Arg) variant and comprehensive BBS1 sequencing are essential for early diagnosis, family counseling, and management. Key take-home: BBS1 genotyping informs prognostic assessment and supports timely multidisciplinary interventions in affected individuals.

References

• American Journal of Human Genetics • 2003 • Evaluation of complex inheritance involving the most common Bardet-Biedl syndrome locus (BBS1) PMID:12524598
• Proceedings of the National Academy of Sciences of the United States of America • 2007 • A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity PMID:18032602

Evidence Based Scoring (AI generated)