Optical mapping reveals a higher level of large‐scale structural variants in a family with paternally transmitted myotonic dystrophy and independent Parkinson's disease
Hasan, Md Mehedi et al.
Myotonic dystrophy type 1 (DM1) is a clinically challenging multisystem neuromuscular hereditary disorder, with generational increase in severity and earlier age at onset. It is caused by an unstable cytosine‐thymine‐guanine repeat expansion at the DMPK locus, accompanied by associated genetic and epigenetic modifications. While somatic mosaicism and meiotic instability are well established, to the best of our knowledge, no study has performed a genome‐wide interrogation for global inherited instability. Performing whole‐genome optical mapping, with sequence base‐resolved structural variant verification, we examine global inherited genomic instability in an atypical paternally transmitted DM1 family presenting with a range of neurological manifestations, including early‐onset Parkinson's disease (PD). While the juvenile‐onset DM1 proband presented with a 10‐fold repeat expansion with associated hypermethylation, her partially hypermethylated asymptomatic protomutation father transmitted a 1.8‐fold contracted allele in the younger premutation sibling. Adult‐onset symptomatic DM1 and PD phenotypic paternal aunts showed significant genome‐wide copy number alteration, including PD‐associated chr19 aneuploidy loss, with additional losses on chr16, 17, and 22. In the absence of potentially pathogenic de novo or maternally inherited structural variants, the proband presented with large paternally inherited aberrations impacting gene candidates CASC15, CBFA2T3, GPHN, H3F3A, SDK1, and SPAG16, with advanced global hypomethylation. Here we suggest that inherited genomic instability may contribute to phenotypic variability, including multi‐neurological presentations and single‐generation repeat expansion or contraction. By providing a landscape of inherited large structural variants, this single‐family study expands knowledge of this broad and growing class of diseases.
