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.
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We would like to thank all the subjects for participating in this study. We also thank N. Watanabe, T. Miyama, M. Sato, and K. Takabe for their technical assistance. We are also grateful to Edanz (www.edanzediting.co.jp) for editing the English text of a draft of this manuscript. This work was supported by AMED under grant numbers JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18km045205, and JP18kk020500; JSPS KAKENHI under grant numbers JP17K15630, JP17H01539, JP17K10080, and JP17K15630; the Ministry of Health, Labour, and Welfare; and Takeda Science Foundation.
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Mizuguchi, T., Suzuki, T., Abe, C. et al. A 12-kb structural variation in progressive myoclonic epilepsy was newly identified by long-read whole-genome sequencing. J Hum Genet 64, 359–368 (2019). https://doi.org/10.1038/s10038-019-0569-5
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