Identification of a missense mutation of COL3A1 in a Chinese family with atypical Ehlers-Danlos syndrome using targeted next-generation sequencing

Aortopathy represents an important cause of mortality in industrialized countries, with a number of genes identified as predispose factors. It can be difficult to identify the genetic lesions underlying this disorder, particularly when the phenotype is atypical. The present study performed targeted next-generation sequencing of 428 genes associated with cardiovascular diseases in a family with aortopathy, the proband of which presented with abdominal aortic aneurysm rupture only, with tissue fragility noted in surgery. After targeted capture, sequencing and bioinformatics analysis, a missense mutation, p.A1259T, was identified in the collagen type III α1 (COL3A1) gene and co-segregated with the disease in the family. Crystal structure modeling revealed abnormal hydrogen bonds generated by the mutation, which likely affected the spatial structure of the procollagen C-propeptide. Mutations in the procollagen C-propeptide are rare and genotype-phenotype correlation may explain the atypical manifestations of affected individuals. The results of the present study suggested that targeted gene capture combined with next-generation sequencing can serve as a useful technique in the genetic diagnosis of aortopathy, particularly in the content of an atypical phenotype.