Intragenic DOK7 deletion detected by whole-genome sequencing in congenital myasthenic syndromes

Neurology. Genetics
Yoshiteru AzumaHanns Lochmüller

Abstract

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). Candidate gene screening and WGS 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. In addition to the previously reported frameshift mutation c.1124_1127dup, an intragenic 6,261 bp deletion spanning from the 5' untranslated region to intron 2 of the DOK7 gene was identified by WGS 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. 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 by WGS and highlights their relevance in the molecular diagnosis of a treatable neurologic condition such as CMS.

References

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Jun 5, 2016·Brain : a Journal of Neurology·Emily O'ConnorHanns Lochmüller
Aug 30, 2016·American Journal of Human Genetics·Stéphanie BauchéSophie Nicole

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Citations

Feb 28, 2019·Orphanet Journal of Rare Diseases·Josef Finsterer
May 4, 2020·Neuromuscular Disorders : NMD·Paulo BastosIsabel Alonso

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Methods Mentioned

BETA
PCR

Software Mentioned

Genome Analysis Toolkit
Clinical Sequence Miner
Tandem Finder
deCODE
Sequence Miner
mfold
Picard
RepeatMasker
WuXi NextCODE

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