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

Abstract

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.

Rapid identification of kidney cyst mutations by whole exome sequencing in zebrafish

“…4F) and were also able to exclude cd28 (supplementary material Table S3D). Because mutations in DYNC2H1 cause thoracic dysplasia and ciliary defects in humans (Dagoneau et al, 2009;Merrill et al, 2009;El Hokayem et al, 2012;Schmidts et al, 2013) we first confirmed the nonsense mutation by sequencing single WT and homozygous aa65.6 pd1086 mutant larvae (Fig. 4G).…”

Identification of novel DYNC2H1 mutations associated with short rib-polydactyly syndrome type III using next-generation panel sequencing

“…Dagoneau et al (2009) Okamoto et al (2015) identified compound heterozygosity for mutations c.5682_5683delAA and c.9070C > T in exons 37 and 57, respectively, of the DYNC2H1 gene in a fetus with SRPS3. Mei et al (2015) identified compound heterozygosity for mutations c.1151C > T and c.4351C > T in exons 8 and 28, respectively, of the DYNC2H1 gene in a fetus with SRPS3.…”

Dynein and Intraflagellar Transport

“…Among the five families, children in three were diagnosed with JATD, and in two of the families pregnancies were terminated for SRP type III. These data showed that JATD and SRP type III are variants of a single disorder belonging to the ciliopathy group (Dagoneau et al, 2009). Subsequently, additional DYNC2H1 mutations were identified as a common cause of JATD without major polydactyly, renal, or retinal involvement and one more case of compound heterozygous mutations in DYNC2H1 was shown to cause the typical SRP III phenotype (Okamoto et al, 2014).…”