A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome.
Fiche publication
Date publication
novembre 2020
Journal
Clinical genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MANDEL Jean-Louis
Tous les auteurs :
Delvallée C, Nicaise S, Antin M, Leuvrey AS, Nourisson E, Carmen LC, Kellaris G, Stoetzel C, Geoffroy V, Scheidecker S, Keren B, Depienne C, Klar J, Dahl N, Deleuze JF, Génin E, Redon R, Demurger F, Devriendt K, Mathieu-Dramard M, Poitou-Bernert C, Odent S, Katsanis N, Mandel JL, Erica DE, Dollfus H, Muller J
Lien Pubmed
Résumé
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 8 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.
Mots clés
BBS1, Bardet-Biedl syndrome, Founder effect, Mobile element insertion, SVA F
Référence
Clin Genet. 2020 Nov 9;: