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

被引:173
作者
Dagoneau, Nathalie [1 ]
Goulet, Marie [1 ]
Genevieve, David [1 ]
Sznajer, Yves [2 ,3 ]
Martinovic, Jelena [1 ]
Smithson, Sarah [4 ]
Huber, Celine [1 ]
Baujat, Genevieve [1 ]
Flori, Elisabeth [5 ]
Tecco, Laura [6 ]
Cavalcanti, Denise [1 ]
Delezoide, Anne-Lise [7 ]
Serre, Valerie [1 ]
Le Merrer, Martine [1 ]
Munnich, Arnold [1 ]
Cormier-Daire, Valerie [1 ]
机构
[1] Univ Paris 05, Hop Necker Enfants Malad, AP HP, Unite INSERM,U781,Dept Genet, F-75015 Paris, France
[2] Hop Univ Enfants Reine Fabiola, B-1020 Brussels, Belgium
[3] ULB, Ctr Human Genet, B-1020 Brussels, Belgium
[4] St Michaels Hosp, Dept Clin Genet, Bristol BS2 8EG, Avon, England
[5] Hop Hautepierre, Cytogenet Serv, F-67091 Strasbourg, France
[6] CHU Brugmann, Brugmann Univ Hosp, Dept Gynaecol & Obstet, B-1020 Brussels, Belgium
[7] Univ Paris Diderot, Dept Dev Biol, AP HP, Hop Robert Debre, F-75935 Paris, France
关键词
INTRAFLAGELLAR TRANSPORT PROTEIN;
D O I
10.1016/j.ajhg.2009.04.016
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 (DYNC2HI) 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 Ill are variants of a single disorder belonging to the ciliopathy group.
引用
收藏
页码:706 / 711
页数:6
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