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J Hum Genet. 2019 Feb 13. doi: 10.1038/s10038-019-0569-5. [Epub ahead of print]

A 12-kb structural variation in progressive myoclonic epilepsy was newly identified by long-read whole-genome sequencing.

Author information

1
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
2
Division of Pediatric Neurology, Aichi Prefectural Colony Central Hospital, Kasugai, Aichi, 480-0392, Japan.
3
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
4
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, 856-8562, Japan.
5
Division of Biomedical Information Analysis, Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
6
Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
7
Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8573, Japan.
8
Graduate School of Information Sciences, Tohoku University, Sendai, 980-8579, Japan.
9
Clinical Genetics Department, Yokohama City University Hospital, Yokohama, 236-0004, Japan.
10
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan. naomat@yokohama-cu.ac.jp.

Abstract

We report a family with progressive myoclonic epilepsy who underwent whole-exome sequencing but was negative for pathogenic variants. Similar clinical courses of a devastating neurodegenerative phenotype of two affected siblings were highly suggestive of a genetic etiology, which indicates that the survey of genetic variation by whole-exome sequencing was not comprehensive. To investigate the presence of a variant that remained unrecognized by standard genetic testing, PacBio long-read sequencing was performed. Structural variant (SV) detection using low-coverage (6×) whole-genome sequencing called 17,165 SVs (7,216 deletions and 9,949 insertions). Our SV selection narrowed down potential candidates to only five SVs (two deletions and three insertions) on the genes tagged with autosomal recessive phenotypes. Among them, a 12.4-kb deletion involving the CLN6 gene was the top candidate because its homozygous abnormalities cause neuronal ceroid lipofuscinosis. This deletion included the initiation codon and was found in a GC-rich region containing multiple repetitive elements. These results indicate the presence of a causal variant in a difficult-to-sequence region and suggest that such variants that remain enigmatic after the application of current whole-exome sequencing technology could be uncovered by unbiased application of long-read whole-genome sequencing.

PMID:
30760880
DOI:
10.1038/s10038-019-0569-5

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