Azuma Y, Töpf A, Evangelista T, Lorenzoni PJ, Roos A, Viana P, Inagaki H, Kurahashi H, Hanns Lochmüller H
Neurology Genetics, May 2017
Objective: To identify the genetic cause in a patient affected by ptosis and exercise-induced muscle weakness and diagnosed with congenital myasthenic syndromes (CMS) using whole-genome sequencing (WGS).
Methods: Candidate gene screening andWGS analysis were performed in the case. Allele-specific PCR was subsequently performed to confirm the copy number variation (CNV) that was suspected from the WGS results.
Results: In addition to the previously reported frameshift mutation c.1124_1127dup, an intragenic 6,261 bp deletion spanning from the 59 untranslated region to intron 2 of the DOK7 gene was identified byWGS in the patient with CMS. The heterozygous deletion was suspected based on reduced coverage on WGS and confirmed by allele-specific PCR. The breakpoints had microhomology and an inverted repeat, which may have led to the development of the deletion during DNA replication.
Conclusions: We report a CMS case with identification of the breakpoints of the intragenic DOK7 deletion using WGS analysis. This case illustrates that CNVs undetected by Sanger sequencing may be identified byWGS and highlights their relevance in the molecular diagnosis of a treatable neurologic condition such as CMS.