Novel BBS1 deletion and BBS9 nonsense pathogenic variant in Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a rare syndromic ciliopathy characterized with retinal degeneration and a broad range of systemic features. Twenty-six BBS-associated genes have been identified to date and clinical genetic testing resolves around 80% of the cases. Two BBS cases unsolved by clinical genetic testing were recruited to identify causative variants using next-generation sequencing.

Genomic DNA of the probands from both families was extracted from peripheral blood. Whole genome or exome sequencing results were analyzed with comprehensive variant filtering on structural variants, single nucleotide variants (SNVs), insertions/deletions (indels).

Family 1: A novel rare deletion NM_024649.5(BBS1): c.830 + 554_1110 + 1052del; p.(Asp278Metfs*3) was identified in the female proband in trans with a known pathogenic missense variant p.(Met390Arg). This 3k base pair (bp) deletion was predicted to cause a loss in exons 10-11, resulting in a premature stop codon. Family 2: Variant filtering in the male proband identified two rare (gnomAD AF < 0.01%) nonsense SNVs in trans in BBS9, NM_198428.3: c.724 G>T; p.(Gly242*) and c.966 G>A; p.(Trp322*), one of them being a novel pathogenic variant.

All the novel variants identified fell into the pathogenic variant classification following ACMG/AMP criteria. This report highlights the role of whole exome and genome sequencing in unsolved cases.