A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome.

Clarisse Delvallée, Samuel Nicaise, Manuela Antin, Anne-Sophie Leuvrey, Elsa Nourisson, Carmen C Leitch, Georgios Kellaris, Corinne Stoetzel, Véronique Geoffroy, Sophie Scheidecker, Boris Keren, Christel Depienne, Joakim Klar, Niklas Dahl, Jean-François Deleuze, Emmanuelle Génin, Richard Redon, Florence Demurger, Koenraad Devriendt, Michèle Mathieu-Dramard, Christine Poitou-Bernert, Sylvie Odent, Nicholas Katsanis, Jean-Louis Mandel, Erica E Davis, Hélène Dollfus, Jean Muller

Clinical genetics 2021 Feb

filter terms:

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. © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Citation

PMID: 33169370

View Full Text