講演情報
[OE6-4]次世代シーケンス解析を用いた肥大型心筋症のゲノム研究
○CHA PEI CHIENG1, 園田 桂子2, 大野 聖子2, 高橋 篤1 (1.国立循環器病研究センター研究所 病態ゲノム医学部, 2.国立循環器病研究センター研究所 分子生物学部)
Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by thickened heart muscle that subsequently affects flow of blood from left ventricle to aorta. Clinical manifestation of HCM is highly heterogeneous ranging from asymptomatic to premature sudden death. To clarify the genetic background of HCM, we conducted whole exome sequencing (WES) for 108 HCM subjects. Through comprehensive WES analysis, we identified 3,943 exonic non-synonymous (NS)/splicing variants with minor allele frequency ＜0.001 in general East Asians and Japanese populations. Among the identified variants, 80 reside in genes associated with HCM in Human Phenotype Ontology (HPO) database, and among which 11 variants are ClinVar Pathogenic/Likely Pathogenic. The proportions of rare NS and ClinVar Pathogenic variants detected in HCM genes are 1.6x and 45x significantly higher than those detected in other protein-coding genes, respectively (P＝0.00029 and P＜2.2E-16). 28% of the 80 rare NS variants reside in genes encoding sarcomeric/Z-disc proteins, including MYH7, MYBPC3, TNNI3, TPM1, TTN, and FLNC. On the other hand, most of the remaining variants were found in genes related to cytoskeleton/myopathy, mitochondria, and secondary HCM. Strikingly, half of the investigated subjects carry at least one rare NS variant in HPO’s HCM genes, with 13 subjects carry ClinVar Pathogenic variants for HCM, while 16 other subjects carry either ClinVar Pathogenic variants for other diseases or variants that favor Pathogenic for HCM based on previously reports/related amino acid change.