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

• Published in: American journal of human genetics Vol. 84; no. 5; pp. 706 - 711
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 15-05-2009; Cell Press; Elsevier
• Subjects: Biological and medical sciences; Bone diseases; Bones; Carrier Proteins - genetics; Carrier Proteins - metabolism; Chromosomes, Human, Pair 11 - genetics; Cytoplasmic Dyneins; Diseases of the osteoarticular system; Dyneins - chemistry; Dyneins - genetics; Fetuses; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Humans; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical genetics; Medical sciences; Models, Molecular; Molecular and cellular biology; Mutation; Pedigree; Respiratory Insufficiency - genetics; Short Rib-Polydactyly Syndrome - genetics; Studies; Morocco; Human; Diseases of the osteoarticular system; Dysostosis; Thorax; Congenital disease; Syndrome; Malformation; Disease of the hand; Cause; Polydactyly; Genetics; Upper limb; Dystrophy; Mutation; Rib (bone)
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2009.04.016

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.