A de novo nonsense variant in the DMD gene associated with X‐linked dystrophin‐deficient muscular dystrophy in a cat

Abstract Background X‐linked dystrophin‐deficient muscular dystrophy (MD) is a form of MD caused by variants in the DMD gene. It is a fatal disease characterized by progressive weakness and degeneration of skeletal muscles. Hypothesis/Objectives Identify deleterious genetic variants in DMD by whole‐genome sequencing (WGS) using a next‐generation sequencer. Animals One MD‐affected cat, its parents, and 354 cats from a breeding colony. Methods We compared the WGS data of the affected cat with data available in the National Center for Biotechnology Information database and searched for candidate high‐impact variants by in silico analyses. Next, we confirmed the candidate variants by Sanger sequencing using samples from the parents and cats from the breeding colony. We used 2 genome assemblies, the standard felCat9 (from an Abyssinian cat) and the novel AnAms1.0 (from an American Shorthair cat), to evaluate genome assembly differences. Results We found 2 novel high‐impact variants: a 1‐bp deletion in felCat9 and an identical nonsense variant in felCat9 and AnAms1.0. Whole genome and Sanger sequencing validation showed that the deletion in felCat9 was a false positive because of misassembly. Among the 357 cats, the nonsense variant was only found in the affected cat, which indicated it was a de novo variant. Conclusion and Clinical Importance We identified a de novo variant in the affected cat and next‐generation sequencing‐based genotyping of the whole DMD gene was determined to be necessary for affected cats because the parents of the affected cat did not have the risk variant.