Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.
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Schmidts Miriam, Arts Heleen H, Bongers Ernie M H F, Yap Zhimin, Oud Machteld M, Antony Dinu, Duijkers Lonneke, Emes Richard D, Stalker Jim, Yntema Jan-Bart L, Plagnol Vincent, Hoischen Alexander, Gilissen Christian, Forsythe Elisabeth, Lausch Ekkehart, Veltman Joris A, Roeleveld Nel, Superti-Furga Andrea, Kutkowska-Kazmierczak Anna, Kamsteeg Erik-Jan, Elçioğlu Nursel, van Maarle Merel C, Graul-Neumann Luitgard M, Devriendt Koenraad, Smithson Sarah F, Wellesley Diana, Verbeek Nienke E, Hennekam Raoul C M, Kayserili Hulya, Scambler Peter J, Beales Philip L, UK10K, Knoers Nine Vam, Roepman Ronald, Mitchison Hannah M
Аннотация
AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing.
RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.