Novel compound heterozygous mutations in DYNC2H1 in a patient with severe short‐rib polydactyly syndrome type III phenotype

Abstract

Short-rib polydactyly syndrome type III is an autosomal recessive lethal skeletal ciliopathy, which is phenotypically similar to nonlethal asphyxiating thoracic dystrophy. Mutations in DYNC2H1 have been identified in both of these disorders, indicating that they are variants of a single disorder. However, short-rib polydactyly syndrome type III is the more severe variant. Here, we report novel compound heterozygous mutations in DYNC2H1 (p.E1894fsX10 and p.R3004C) in a patient with typical short-rib polydactyly syndrome type III phenotype. R3004 is located within the microtubule-binding domain of DYNC2H1, and its substitution is predicted to disrupt the interaction with microtubules. Considering the severe phenotype of our patient, our findings suggest that R3004 may be a key residue for the microtubulebinding affinity of dynein.

Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III

“…To date, seven SRPS III families with DYNC2H1 mutations, including the one reported here, have been described worldwide (Table 2) [9,23,24]. All cases showed similar radiographic findings, such as shortened long bones and a narrow thorax, but not all cases exhibited polydactyly or internal organ abnormalities.…”

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

“…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 (Schmidts et al, 2013) and one more case of compound heterozygous mutations in DYNC2H1 was shown to cause the typical SRP III phenotype (Okamoto et al, 2014). …”