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A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet‐Biedl syndrome
Author(s) -
Delvallée Clarisse,
Nicaise Samuel,
Antin Manuela,
Leuvrey AnneSophie,
Nourisson Elsa,
Leitch Carmen C.,
Kellaris Georgios,
Stoetzel Corinne,
Geoffroy Véronique,
Scheidecker Sophie,
Keren Boris,
Depienne Christel,
Klar Joakim,
Dahl Niklas,
Deleuze JeanFrançois,
Génin Emmanuelle,
Redon Richard,
Demurger Florence,
Devriendt Koenraad,
MathieuDramard Michèle,
PoitouBernert Christine,
Odent Sylvie,
Katsanis Nicholas,
Mandel JeanLouis,
Davis Erica E.,
Dollfus Hélène,
Muller Jean
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13878
Subject(s) - bardet–biedl syndrome , genetics , polydactyly , biology , ciliopathy , indel , population , copy number variation , exon , gene , genome , single nucleotide polymorphism , medicine , genotype , phenotype , environmental health
Abstract 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.