Journal
CLINICAL GENETICS
Volume 99, Issue 2, Pages 318-324Publisher
WILEY
DOI: 10.1111/cge.13878
Keywords
Bardet‐ Biedl syndrome; BBS1; founder effect; Mobile element insertion; SVA F
Categories
Funding
- Agence Nationale de la Recherche
- CREGEMES [WGS 2016]
- Fondation pour la Recherche Medicale [ECO20170637509]
- US National Institutes of Health [DK072301, GM121317, HD042601]
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Bardet-Biedl syndrome is a rare ciliopathy with various symptoms, recent studies have identified a rare insertion mutation in the gene of some patients.
Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.
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