title: A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field.
abstract: 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.
authors.affiliation: Laboratoire Cardiogénétique, Hospices Civils de Lyon, Lyon, France.
authors.forename: Rajae
authors.initials: R
authors.lastname: El Malti
authors.affiliation: Laboratoire Cardiogénétique, Hospices Civils de Lyon, Lyon, France.|EA 4173 Université Lyon 1, France and Hôpital Nord Ouest, Lyon, France.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Service de Génétique Médicale, CHU Saint Denis, Saint Denis, France.
authors.forename: Bérénice
authors.initials: B
authors.lastname: Doray
authors.affiliation: Centre de Génétique, Hôpital d'Enfants, CHU Dijon and EA4271, Université de Bourgogne, Dijon, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin
authors.affiliation: Service de Cardiologie, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Maltret
authors.affiliation: Service de Cardiologie, Hôpital Gabriel Montpied, Clermont-Ferrand, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Dauphin
authors.affiliation: Unidade de Genética Médica, Centro de Genética Médica Jacinto de Magalhaes, Porto, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Gonçalves-Rocha
authors.affiliation: Laboratoire de Biologie Clinique, Nancy, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Teboul
authors.affiliation: Unité Fonctionnelle Génétique Prénatale et Foetopathologique, CHRU, Montpellier, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Blanchet
authors.affiliation: Unité de Génétique Médicale, Centre Intercommunal Poissy-St-Germain en Laye, Poissy, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Roume
authors.affiliation: Cardiologie Pédiatrique et Fœtale, Strasbourg, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Gronier
authors.affiliation: Service de Cardiologie Pédiatrique, Hospices Civils de Lyon, Lyon, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Ducreux
authors.affiliation: Service de Cardiologie Pédiatrique, Hospices Civils de Lyon, Lyon, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Veyrier
authors.affiliation: Cardiologie Infantile, Hôpital Brabois, Vandoeuvre les Nancy, France.
authors.forename: François
authors.initials: F
authors.lastname: Marçon
authors.affiliation: Pédiatrie Cardiologie, Hôpital d'Enfants, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Acar
authors.affiliation: Service de Cardiologie, Hôpital Gabriel Montpied, Clermont-Ferrand, France.
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Lusson
authors.affiliation: Service de Cardiologie, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Levy
authors.affiliation: Unité de Cardiologie Pédiatrique, Hôpital Robert Debré, Paris, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Beyler
authors.affiliation: Unité Fonctionnelle de Génétique, Maternité A Pinard, Nancy, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Vigneron
authors.affiliation: Service de Génétique, Hospices Civils de Lyon, Lyon, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Cordier-Alex
authors.affiliation: Clinique Pasteur, Toulouse, France.
authors.forename: François
authors.initials: F
authors.lastname: Heitz
authors.affiliation: Service de Génétique, Hospices Civils de Lyon, Lyon, France.|CRNL, CNRS UMR 5292 and INSERM U1028, Université Lyon 1, Lyon, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Sanlaville
authors.affiliation: Service de Cardiologie, Hôpital Necker-Enfants Malades, Paris, France.|UMR_S 765 INSERM and Université Paris Descartes, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Laboratoire Cardiogénétique, Hospices Civils de Lyon, Lyon, France.|EA 4173 Université Lyon 1, France and Hôpital Nord Ouest, Lyon, France.|Service de Cardiologie Pédiatrique, Hospices Civils de Lyon, Lyon, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Bouvagnet
mesh_terms: D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics; D005820:Genetic Testing; D014644:Genetic Variation; D006330:Heart Defects, Congenital / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors; C491595:ZIC3 protein, human