BBS5 – Bardet-Biedl syndrome 5

Bardet-Biedl syndrome 5 is an autosomal recessive ciliopathy characterized by retinal dystrophy, renal anomalies, polydactyly and metabolic disturbances. The causative gene, BBS5, encodes a component of the BBSome complex critical for ciliary trafficking. Patients present with early-onset polydactyly, progressive vision loss, renal dysfunction and endocrine features such as polydipsia and polyuria.

Genetic evidence encompasses five probands from three unrelated families: a Chinese patient with compound heterozygous c.1A>G (p.Met1Val) and a large exon deletion (PMID:35951741), an Iranian family with homozygous splice variant c.208+2T>C (PMID:30850397), and three Saudi siblings homozygous for c.966dup (p.Ala323CysfsTer?) (PMID:24559376). These include initiator methionine, frameshift, and splice site variants confirmed by whole-exome sequencing, Sanger validation and parental segregation.

Segregation analysis in trios and families supports an autosomal recessive inheritance mode without additional affected relatives reported beyond these probands. All pathogenic alleles were inherited in trans, consistent with loss-of-function mechanism.

Functional studies in zebrafish demonstrate that knockdown of bbs5 recapitulates human phenotypes, with morphant embryos showing retinal layering defects, cystic pronephric ducts, impaired dextran clearance and abnormal cardiac looping. Mutant human BBS5 mRNA fails to rescue these defects, and in vitro assays reveal mislocalization of truncated BBS5 protein, confirming deleterious impact on ciliogenesis and renal function (PMID:24559376).

No conflicting reports dispute the role of BBS5 in Bardet-Biedl syndrome 5. A retina-specific splice isoform of BBS5 has been described but lacks evidence of disease causality or unique pathogenic function.

In summary, biallelic loss-of-function and splice site BBS5 variants in multiple families, supported by robust zebrafish modelling, define a Moderate ClinGen gene-disease association. Genetic testing for BBS5 variants is clinically useful for diagnosis, prognosis and management of patients with syndromic ciliopathy features.

References

• Cilia • 2014 • Functional modelling of a novel mutation in BBS5. PMID:24559376
• Nephrology (Carlton, Vic.) • 2022 • Two novel variants in a Bardet-Biedl syndrome type 5 patient with severe renal phenotype. PMID:35951741
• Bioscience reports • 2019 • Novel splicing variant c.208+2T>C in BBS5 segregates with Bardet-Biedl syndrome in an Iranian family by targeted exome sequencing. PMID:30850397

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