9q33.3q34.11 microdeletion: delineation of a new contiguous gene syndrome including the STXBP1, LMX1B and ENG genes using reverse phenotyping. S. Nambot1, A. Mosca Boidron2, A. Masurel1, M. Lefebvre1, N. Marle2, J. Thevenon1,2, J. De Montléon3, S. Perez Martin3, M. Chouchane3, E. Sapin4, J. Metaizeau4, V. Dulieu5, F. Huet2, C. Thauvin Robinet1, L. Chatel6, V. Abadie7, G. Plessis8, J. Andrieux9, P. Jouk10, G. Billy Lopez10, C. Coutton11, F. Morice Picard12, M. Delrue12, C. Rooryck Thambo13, L. Faivre1,2 1) Centre de Génétique et Centre de Référence Maladies Rares, Anomalies du Développement et Syndromes Malformatifs de lInter région Est, Hôpital dEnfants, CHU Dijon, France; 2) Laboratoire de Cytogénétique, Plateau Technique de Biologie, CHU Dijon, France; 3) Service de Pédiatrie 1, Hôpital dEnfants, CHU Dijon, France; 4) Service de Chirurgie pédiatrique, Hôpital dEnfants, CHU Dijon, France; 5) 5Service de Soins de suite et Réeducation pédiatrique, Pôle Réeducation Réadaptation, CHU Dijon, France; 6) Service de Psychiatrie de lenfant, CHU Dijon, France; 7) Service de Pédiatrie générale, Hôpital Necker, Paris, France; 8) Centre de Compétence des Anomalies du Développement, CHU Caen, France; 9) Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre CHRU Lille, France; 10) Service de Génétique Clinique, Département de Génétique et Procréation, Hôpital Couple Enfant, CHU Grenoble, France; 11) Laboratoire de Génétique Chromosomique, Département de Génétique et Procréation, Hôpital Couple Enfant, CHU Grenoble, France; 12) Centre de Référence des Anomalies du Développement et Syndromes malformatifs , CHU Bordeaux, France; 13) Laboratoire de Génétique Moléculaire, Plateau technique de Biologie Moléculaire, CHU Bordeaux, France.

   Four patients, 3 females and 1 male aged 5 to 18 years, carrying a de novo overlapping 1.5, 3.1, 3.5 and 4.1 Mb deletion of chromosome 9q33.3q34.11 permitted to define a new contiguous gene syndrome. Patients display common clinical features including facial dysmorphism, epilepsy, intellectual deficiency of various degree and multiple congenital abnormalities. The analysis of the genes comprised in the deletions prompted us to use reverse phenotyping. The STXBP1 gene, in which de novo heterozygous mutations or deletions have been reported in patients with Ohtahara syndrome, was the best candidate to explain the cognitive and epileptic phenotype. The LMX1B gene, in which heterozygous mutations or deletions have been reported with Nail-patella syndrome, explained the presence of nail dysplasia and bone malformations, in particular patellar abnormalities. The ENG gene, in which autosomal dominant mutations or deletions have been reported in patients with Hereditary hemorrhagic telangiectasia type 1, was likely responsible for epistaxis and cutaneous-mucous telangiectases described in the oldest patients. The NR5A1 gene, deleted in one patient only, was likely responsible of his genital malformations. A high genotype-phenotype correlation was found in these 4 patients, except for the remarkable facial dysmorphism, including prominent metopic ridge, large forehead, high arched eyebrows, strabismus, bulbous nose and small mouth. This systematic analysis of genes comprised in the deletion permitted to identify genes whose happloinsufficiency is expected to lead to disease manifestations and complications that will lead to a personalized follow-up, in particular for renal, eye, ears, vascular and neurologic manifestations.

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