Optical Genomic Mapping and Next-Generation Sequencing Identified Retrotransposon Insertion and Missense Variant Disrupting Gene in Dyskeratosis Congenita.

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by defects in telomere biology and clinical manifestations such as nail dystrophy, skin pigmentation abnormalities, and mucosal leukoplakia. Here, using whole exome sequencing (WES), whole genome sequencing (WGS), optical mapping sequencing (OGM), third-generation sequencing, and mRNA sequencing, we diagnosed a participant with gene complex compound heterozygous variants. In addition, protein structure simulation, immunohistochemistry, and western blot were conducted to investigate the structure and expression level of the PARN protein. WES revealed a maternal variant, c.204G>T (p.Gln68His) (NM_002582.3). An insertion variant in the gene from the father was identified by OGM and mRNA sequencing. Third-generation sequencing results determined the insertion position of the SINE-VNTR-Alu (SVA) transposon and its size (2537 bp), which was found to lead to a premature stop codon (p.Gly469delinsGlu∗). The PARN protein level of the parents was reduced due to complex heterozygous variants. Overall, OGM diagnosed the structural variants of the participant with DC, supplementing the disease variant spectrum of DC. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.