Fiche publication


Date publication

février 2016

Journal

European journal of human genetics : EJHG

Auteurs

Membres identifiés du Cancéropôle Est :
Pr THAUVIN-ROBINET Christel


Tous les auteurs :
El Malti R, Liu H, Doray B, Thauvin C, Maltret A, Dauphin C, Gonçalves-Rocha M, Teboul M, Blanchet P, Roume J, Gronier C, Ducreux C, Veyrier M, Marçon F, Acar P, Lusson JR, Levy M, Beyler C, Vigneron J, Cordier-Alex MP, Heitz F, Sanlaville D, Bonnet D, Bouvagnet P

Résumé

The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 ×), NKX2-5 (6 ×), ZIC3 (3 ×), MLPA (2 ×) and ELN (4 ×). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.

Mots clés

Female, GATA4 Transcription Factor, genetics, Genetic Testing, Genetic Variation, Heart Defects, Congenital, diagnosis, High-Throughput Nucleotide Sequencing, Homeobox Protein Nkx-2.5, Homeodomain Proteins, genetics, Humans, Male, Multiplex Polymerase Chain Reaction, Mutation, Pedigree, Transcription Factors, genetics

Référence

Eur J Hum Genet. 2016 02;24(2):228-36