BBS5 – Bardet-Biedl syndrome

BBS5 encodes a subunit of the BBSome complex essential for protein trafficking in primary cilia. Pathogenic biallelic variants in BBS5 underlie autosomal recessive Bardet-Biedl syndrome, characterized by retinal dystrophy, post-axial polydactyly, obesity, hypogonadism, renal anomalies, and cognitive impairment. The gene–disease relationship is supported by multiple unrelated families and consistent functional data.

Clinical Validity

The BBS5–Bardet-Biedl syndrome association is classified as Strong. Eight unrelated probands across five studies harbor biallelic BBS5 variants with congruent autosomal recessive inheritance, and one family shows complete co-segregation of a homozygous splice variant ([PMID:30850397]) and consistent carrier status in parents.

Genetic Evidence

Inheritance is autosomal recessive. Case reports include a Saudi sibship (3 probands) with a frameshift variant c.966dup (p.Ala323CysfsTer57) ([PMID:24559376]), a Filipino sib‐pair with compound heterozygous indels c.143-1G>A and c.925_931del (p.Gln309IlefsTer14) ([PMID:32811249]), an Iranian family with a homozygous splice donor c.208+2T>C ([PMID:30850397]), and a European patient with a large first-exon deletion identified by WGS ([PMID:37240074]). Variants span frameshifts, splice-site, and large structural changes, consistent with loss‐of‐function.

Functional Evidence

In zebrafish morphants, knockdown of bbs5 recapitulates human retinal layering defects, cardiac looping anomalies, and pronephric cysts, and mutant human mRNA fails to rescue these phenotypes. Mutant BBS5 protein mislocalizes away from the basal body in cultured cells, demonstrating a deleterious mechanism consistent with ciliopathy pathology ([PMID:24559376]).

Integration and Conclusion

Biallelic loss‐of‐function and splice variants in BBS5 disrupt BBSome assembly and ciliary trafficking, leading to the multisystem features of Bardet-Biedl syndrome. Functional studies reinforce genetic findings, establishing a robust gene–disease link. Additional evidence from population screens and deep intronic variant analyses further supports clinical testing utility.

Key Take-home: BBS5 is readily included in genetic testing panels for Bardet-Biedl syndrome to inform diagnosis, management, and genetic counseling.

References

• Dermatology online journal • 2008 • Bardet-Biedl syndrome: a case report. [PMID:18319026]
• Cilia • 2014 • Functional modelling of a novel mutation in BBS5. [PMID:24559376]
• 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]
• Ophthalmic genetics • 2020 • Novel compound heterozygous pathogenic BBS5 variants in Filipino siblings with Bardet-Biedl syndrome (BBS). [PMID:32811249]
• International journal of molecular sciences • 2023 • WGS Revealed Novel BBS5 Pathogenic Variants, Missed by WES, Causing Ciliary Structure and Function Defects. [PMID:37240074]

Evidence Based Scoring (AI generated)