BBS9 – Bardet-Biedl syndrome

BBS9 encodes a core component of the BBSome, an octameric complex vital for trafficking membrane proteins in the primary cilium. Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by rod-cone dystrophy, postaxial polydactyly, central obesity, intellectual disability, hypogonadism and renal anomalies. Pathogenic variants in BBS9 disrupt ciliary structure and signaling, leading to the multisystem manifestations of BBS.

BBS9-associated BBS is inherited in an autosomal recessive manner. Biallelic BBS9 variants have been identified in >10 unrelated families worldwide, including homozygous exon deletions and compound heterozygous truncating or splice-altering alleles, with no reports of additional affected relatives carrying two pathogenic alleles ([PMID:27708425]; [PMID:29367880]).

Genetic evidence encompasses a homozygous 7p14.3 deletion of BBS9 exons 1–4 delineated by long-read SMRT sequencing in a Guyanese proband, suggesting a founder effect ([PMID:29367880]), and exon-disruptive copy-number variants in 17 BBS-affected individuals detected by array CGH ([PMID:27486776]).

Point mutations broaden the BBS9 variant spectrum. Truncating nonsense changes such as c.966G>A (p.Trp322Ter) recur in unsolved cases presenting with classic BBS features, and missense or splice-site alterations (e.g., c.263C>T (p.Ser88Leu)) have been reported in patients with variable retinal and extra-ocular phenotypes.

Functional studies confirm the pathogenicity of BBS9 variants. The 1.8 Å crystal structure of the BBS9 N-terminal β-propeller domain shows that G141R leads to misfolding and impaired BBSome assembly ([PMID:26085087]). In vitro minigene assays demonstrate that c.263C>T causes partial exon 3 skipping, consistent with a hypomorphic mechanism and milder retinal degeneration ([PMID:38534779]).

No studies have refuted the role of BBS9 in BBS. Together, genetic and experimental data support a definitive gene-disease relationship for BBS9 in Bardet-Biedl syndrome, underpinning the clinical utility of BBS9 testing for diagnosis and genetic counseling.

Key Take-home: BBS9 molecular analysis, including sequencing and structural variant detection, is essential for early and accurate diagnosis of autosomal recessive Bardet-Biedl syndrome.

References

• Scientific Reports • 2016 • Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum. PMID:27708425
• NPJ Genomic Medicine • 2018 • Cytogenomic identification and long-read single molecule real-time (SMRT) sequencing of a Bardet-Biedl Syndrome 9 (BBS9) deletion. PMID:29367880
• American Journal of Human Genetics • 2016 • Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome. PMID:27486776
• Journal of Biological Chemistry • 2015 • Structural Characterization of Bardet-Biedl Syndrome 9 Protein (BBS9). PMID:26085087
• Current Issues in Molecular Biology • 2024 • Autosomal Recessive Rod-Cone Dystrophy with Mild Extra-Ocular Manifestations Due to a Splice-Affecting Variant in BBS9. PMID:38534779

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