DYNC2H1 was first reported in relation to autosomal recessive DYNC2H1-related Short Rib Thoracic Dysplasia in 2009 (Dagoneau et al., PMID: 19442771). DYNC2H1-related Short Rib Thoracic Dysplasia is a skeletal ciliopathy characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in inheritance pattern and phenotypic variability. Therefore, the following disease entities, asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, have been lumped into one disease entity, DYNC2H1-related Short Rib Thoracic Dysplasia. 18 missense, three frameshift, two nonsense, and two intronic variants that have been reported in 13 probands in four publications (PMIDs: 19442771, 19361615, 22499340, 37100787) are included in this curation. The mechanism of pathogenicity at this time is unknown. This gene-disease relationship is also supported by functional alteration of patient cells, animal models, and rescue in non-human model organisms (PMIDs: 19361615, 16061793, 21552265). In summary, there is definitive evidence supporting the relationship between DYNC2H1 and autosomal recessive DYNC2H1-related Short Rib Thoracic Dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date November 6th, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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