WGS Revealed Novel BBS5 Pathogenic Variants, Missed by WES, Causing Ciliary Structure and Function Defects

Area of Science:

• Genetics
• Molecular Biology
• Medical Research

Background:

• Bardet-Biedl syndrome (BBS) is a complex genetic ciliopathy with diverse clinical manifestations.
• Genetic heterogeneity of BBS involves at least 24 identified genes, with BBS5 being a less common contributor.
• The BBSome complex, including BBS5, is crucial for ciliary protein trafficking.

Observation:

• A European patient presented with a severe BBS phenotype.
• Standard next-generation sequencing (NGS) tests (exome sequencing) failed to identify biallelic pathogenic variants.
• Whole-genome sequencing (WGS) successfully detected a large deletion in the first exons of the BBS5 gene.

Findings:

• The study confirmed biallelic pathogenic variants in BBS5 using WGS, including a previously undetected large deletion.
• Functional analysis in patient cells demonstrated impaired ciliary function and altered Sonic Hedgehog pathway activity.
• The pathogenicity of the identified variants was confirmed through cellular and pathway assessments.

Implications:

• This case underscores the critical role of WGS in diagnosing genetic disorders when exome sequencing is insufficient.
• Accurate detection of structural variants remains a challenge in genetic diagnostics.
• Functional studies are essential for validating variant pathogenicity and understanding disease mechanisms in BBS.