BBS10 – Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by rod-cone dystrophy, postaxial polydactyly, obesity, hypogonadism and renal anomalies. The BBS10 gene (HGNC:26291) encodes a chaperonin-like protein essential for BBSome assembly at the primary cilium, and biallelic pathogenic variants in BBS10 cause BBS (Autosomal recessive inheritance).

Clinical Validity

Recessive BBS10 variants have been reported in over 100 unrelated probands across multiple consanguineous and non-consanguineous families, with cargo trafficking defects consistent with human phenotypes ([PMID:20472660]). Segregation of disease-causing alleles in at least 19 affected relatives across 8 families further supports the AR inheritance pattern ([PMID:23403234]). Concordant functional data from patient-derived iPSCs and computational analyses demonstrate deleterious effects of missense and truncating BBS10 variants on protein stability and ciliary function ([PMID:36312387]).

Genetic Evidence

Genetic studies have identified >50 unique BBS10 variants in BBS cohorts, including frameshift, nonsense, splice-site and missense changes. Loss-of-function alleles such as c.784_785del (p.Thr534IlefsTer21) and c.1958_1967del (p.Asp653GlufsTer10) predominate, consistent with haploinsufficiency ([PMID:36340607]; [PMID:23403234]). Founder mutations such as c.728_731del (p.Lys243fs) occur in South African patients, accounting for 67% of alleles in one cohort ([PMID:27245532]). Digenic/triallelic effects have been observed but BBS10 biallelic variants alone are sufficient for full syndrome expression.

Functional Evidence

In silico and molecular dynamics simulations have prioritized multiple pathogenic BBS10 missense variants, demonstrating destabilization of conserved domains critical for chaperonin assembly ([PMID:36312387]). iPSC lines derived from patients homozygous for c.271dup (p.Cys91fs) recapitulate ciliary defects and trafficking abnormalities, confirming the mechanistic link to BBS phenotypes.

Integration & Take-Home

Overall, BBS10 is definitively associated with Bardet-Biedl syndrome. Genetic and experimental data converge on a loss-of-function mechanism, with clear diagnostic implications for molecular testing and genetic counseling. Identification of BBS10 variants enables early diagnosis, carrier detection, and prenatal testing for at-risk families.

Key Take-Home: BBS10 loss-of-function variants are a definitive cause of autosomal recessive Bardet-Biedl syndrome, guiding molecular diagnosis and genetic counseling.

References

• Journal of medical genetics • 2010 • Mutations in chaperonin-like BBS genes are a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population PMID:20472660
• Gene • 2013 • A novel homozygous 10 nucleotide deletion in BBS10 causes Bardet-Biedl syndrome in a Pakistani family PMID:23403234
• ACS omega • 2022 • Computational and Structural Analysis to Assess the Pathogenicity of Bardet-Biedl Syndrome Related Missense Variants Identified in Bardet-Biedl Syndrome 10 Gene (BBS10) PMID:36312387
• Experimental and therapeutic medicine • 2022 • Prenatal diagnosis of Bardet–Biedl syndrome due to novel variants in the BBS10 gene in a fetus with multiple anomalies: A case report PMID:36340607
• South African medical journal • 2016 • Bardet Biedl syndrome in South Africa: A single founder mutation PMID:27245532

Evidence Based Scoring (AI generated)