Prevalence of Novel MAGED2 Mutations in Antenatal Bartter Syndrome

Anne Legrand (1) , Cyrielle Treard , Isabelle Roncelin , Sophie Dreux , Aurélia Bertholet-Thomas , Françoise Broux , Daniele Bruno , Stéphane Decramer (2) , Georges Deschenes , Djamal Djeddi , Vincent Guigonis (3) , Nadine Jay , Tackwa Khalifeh (4) , Brigitte Llanas (5, 6) , Denis Morin (7) , Gilles Morin (8) , Francois Nobili (9) , Christine Pietrement , Amélie Ryckewaert , Rémi Salomon (10) , Isabelle Vrillon , Anne Blanchard (11) , Rosa Vargas-Poussou (12)

1 HEGP - Hôpital Européen Georges Pompidou [APHP]
2 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
3 Service de Pédiatrie médicale [CHU Limoges]
4 CHU de Poitiers - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
5 Centre de Référence du Sud Ouest des Maladies Rénales Rares
6 CIC Bordeaux
7 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
8 CHU Amiens-Picardie
9 Service de pédiatrie [CHRU Besançon]
10 Service de néphrologie pédiatrique [CHU Necker]
11 Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP]
12 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers

BACKGROUND AND OBJECTIVES: Mutations in the MAGED2 gene, located on the X chromosome, have been recently detected in males with a transient form of antenatal Bartter syndrome or with idiopathic polyhydramnios. The aim of this study is to analyze the proportion of the population with mutations in this gene in a French cohort of patients with antenatal Bartter syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The French cohort of patients with antenatal Bartter syndrome encompasses 171 families. Mutations in genes responsible for types 1-4 have been detected in 75% of cases. In patients without identified genetic cause (n=42), transient antenatal Bartter syndrome was reported in 12 cases. We analyzed the MAGED2 gene in the entire cohort of negative cases by Sanger sequencing and retrospectively collected clinical data regarding pregnancy as well as the postnatal outcome for positive cases. RESULTS: We detected mutations in MAGED2 in 17 patients, including the 12 with transient antenatal Bartter syndrome, from 16 families. Fifteen different mutations were detected (one whole deletion, three frameshift, three splicing, three nonsense, two inframe deletions, and three missense); 13 of these mutations had not been previously described. Interestingly, two patients are females; in one of these patients our data are consistent with selective inactivation of chromosome X explaining the severity. The phenotypic presentation in our patients was variable and less severe than that of the originally described cases. CONCLUSIONS: MAGED2 mutations explained 9% of cases of antenatal Bartter syndrome in a French cohort, and accounted for 38% of patients without other characterized mutations and for 44% of male probands of negative cases. Our study confirmed previously published data and showed that females can be affected. As a result, this gene must be included in the screening of the most severe clinical form of Bartter syndrome.

Mots clés: Mutation; pediatric nephrology; Polyhydramnios; Pregnancy; Prevalence; Retrospective Studies; RNA Splicing; Sequence Deletion; X Chromosome; Genetic Predisposition to Disease; molecular genetics; Male; Signal Transducing; Phenotype; DNA Mutational Analysis; Antigens; Neoplasm; Prenatal Diagnosis; Pregnancy Outcome; Mutation Rate; Adaptor Proteins; France; Humans; Bartter Syndrome; Female; Frameshift Mutation; genetic renal disease

Domaines: Sciences du Vivant [q-bio]

Anne Legrand, Cyrielle Treard, Isabelle Roncelin, Sophie Dreux, Aurélia Bertholet-Thomas, et al.. Prevalence of Novel MAGED2 Mutations in Antenatal Bartter Syndrome. Clinical Journal of the American Society of Nephrology, 2018, 13 (2), pp.242--250. ⟨10.2215/CJN.05670517⟩. ⟨hal-02355788⟩