BBS4 and Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive ciliopathy defined by rod-cone dystrophy, postaxial polydactyly, truncal obesity, cognitive impairment, hypogonadism and renal dysplasia. BBS4 encodes a core component of the BBSome complex essential for ciliary trafficking and photoreceptor maintenance (PMID:12365916).

Inheritance of biallelic BBS4 variants follows an autosomal recessive pattern. A Chinese Han family harbored a novel homozygous nonsense allele, c.70A>T (p.Lys24Ter), leading to NMD and early protein truncation in the proband (PMID:25533820). A Norwegian cohort described three sibling pairs with homozygous or compound heterozygous BBS4 LoF alleles segregating with typical BBS features (PMID:12365916). An atypical patient carried a homozygous in-frame deletion of exons 4–6, p.(Ala53_Trp135del), confirming allelic diversity (PMID:35318824).

Segregation analyses in these families identified at least 5 additional affected relatives co-segregating BBS4 alleles, with absence of these variants in large control cohorts supporting pathogenicity (PMID:12365916).

Functional assays corroborate a loss-of-function mechanism. In zebrafish morphants, human BBS4 c.253G>C (p.Glu85Gln) failed to rescue rhodopsin mislocalization after bbs4 knockdown, indicating disrupted photoreceptor ciliary trafficking (PMID:22219648). Minigene analyses of intronic BBS4 variants such as c.332+8T>C demonstrated aberrant exon inclusion and premature stop codons in vitro (PMID:28502102).

Although BBS4 contributes to <3% of BBS cases and displays evidence for triallelic inheritance in select cohorts, no studies have refuted its causative role. The overall clinical validity meets a Moderate level given multiple unrelated probands, co-segregation, and concordant functional data.

Key Take-home: Biallelic loss-of-function and splice variants in BBS4 cause autosomal recessive Bardet-Biedl syndrome; genetic testing of BBS4 informs diagnosis, carrier screening and management.

References

• Chinese medical journal • 2014 • A novel nonsense mutation in BBS4 gene identified in a Chinese family with Bardet-Biedl syndrome PMID:25533820
• Archives of ophthalmology • 2002 • The phenotype in Norwegian patients with Bardet-Biedl syndrome with mutations in the BBS4 gene PMID:12365916
• Molecular genetics & genomic medicine • 2022 • Atypical phenotype of a patient with Bardet-Biedl syndrome type 4 PMID:35318824
• Molecular vision • 2011 • Exome capture sequencing identifies a novel mutation in BBS4 PMID:22219648
• Journal of cellular and molecular medicine • 2017 • Functional analysis by minigene assay of putative splicing variants found in Bardet-Biedl syndrome patients PMID:28502102

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