Author:
Lefebvre Mathilde,Dieux-Coeslier Anne,Baujat Geneviève,Schaefer Elise,Judith Saint-Onge,Bazin Anne,Pinson Lucile,Attie-Bitach Tania,Baumann Clarisse,Fradin Melanie,Pierquin Genevieve,Julia Sophie,Quélin Chloé,Doray Bérénice,Berg Sylvie,Vincent-Delorme Catherine,Lambert Laetitia,Bachmann Nadine,Lacombe Didier,Isidor Bertrand,Laurent Nicole,Joelle Roume,Blanchet Patricia,Odent Sylvie,Kervran Dominique,Leporrier Nathalie,Abel Carine,Segers Karine,Guiliano Fabienne,Ginglinger-Fabre Emmanuelle,Selicorni Angelo,Goldenberg Alice,El Chehadeh Salima,Francannet Christine,Demeer Benedicte,Duffourd Yannis,Thauvin-Robinet Christel,Verloes Alain,Cormier-Daire Valerie,Riviere Jean Baptiste,Faivre Laurence,Thevenon Julien
Abstract
BackgroundSegmentation defects of the vertebrae (SDV) are non-specific features found in various syndromes. The molecular bases of SDV are not fully elucidated due to the wide range of phenotypes and classification issues. The genes involved are in the Notch signalling pathway, which is a key system in somitogenesis. Here we report on mutations identified in a diagnosis cohort of SDV. We focused on spondylocostal dysostosis (SCD) and the phenotype of these patients in order to establish a diagnostic strategy when confronted with SDV.Patients and methodsWe used DNA samples from a cohort of 73 patients and performed targeted sequencing of the five known SCD-causing genes (DLL3, MESP2, LFNG, HES7 and TBX6) in the first 48 patients and whole-exome sequencing (WES) in 28 relevant patients.ResultsTen diagnoses, including four biallelic variants in TBX6, two biallelic variants in LFNG and DLL3, and one in MESP2 and HES7, were made with the gene panel, and two diagnoses, including biallelic variants in FLNB and one variant in MEOX1, were made by WES. The diagnostic yield of the gene panel was 10/73 (13.7%) in the global cohort but 8/10 (80%) in the subgroup meeting the SCD criteria; the diagnostic yield of WES was 2/28 (8%).ConclusionAfter negative array CGH, targeted sequencing of the five known SCD genes should only be performed in patients who meet the diagnostic criteria of SCD. The low proportion of candidate genes identified by WES in our cohort suggests the need to consider more complex genetic architectures in cases of SDV.
Subject
Genetics (clinical),Genetics