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DYNC2H1 Mutations Cause Asphyxiating Thoracic Dystrophy and Short Rib-Polydactyly Syndrome, Type III

par Dagoneau, Nathalie;Goulet, Marie;Geneviève, David;Sznajer, Yves ;Martinovic, Jelena;Smithson, Sarah;Huber, Céline;Baujat, Geneviève;Flori, Elisabeth;Tecco, Laura ;Cavalcanti, Denise;Delezoide, Anne-Lise;Serre, Valérie;Le Merrer, Martine;Munnich, Arnold;Cormier-Daire, Valérie
Référence American journal of human genetics, 84, 5, page (706-711)
Publication Publié, 2009-05

Article révisé par les pairs

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Résumé :

Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof. ATD is closely related to the short rib polydactyly syndrome (SRP) type III, which is a more severe condition characterized by early prenatal expression and lethality and variable malformations. We first excluded IFT80 in a series of 26 fetuses and children belonging to 14 families diagnosed with either ATD or SRP type III. Studying a consanguineous family from Morocco, we mapped an ATD gene to chromosome 11q14.3-q23.1 in a 20.4 Mb region and identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1 mutations was also identified in four additional families. Among the five families, 3/5 were diagnosed with ATD and 2/5 included pregnancies terminated for SRP type III. DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the generation and maintenance of cilia. From this study, we conclude that ATD and SRP type III are variants of a single disorder belonging to the ciliopathy group. © 2009 The American Society of Human Genetics.