6533b7d9fe1ef96bd126b8f6

RESEARCH PRODUCT

Diagnostic strategy in segmentation defect of the vertebrae: a retrospective study of 73 patients

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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,HES7andTBX6) in the first 48 patients and whole-exome sequencing (WES) in 28 relevant patients.ResultsTen diagnoses, including four biallelic variants inTBX6, two biallelic variants inLFNGandDLL3, and one inMESP2andHES7, were made with the gene panel, and two diagnoses, including biallelic variants inFLNBand one variant inMEOX1,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.