日本小児循環器学会雑誌 Pediatric Cardiology and Cardiac Surgery

Chromosomal aneuploidy was the first recognized genetic cause of congenital heart disease (CHD). Methodologies to identify subchromosomal changes in the genome structure led to the discovery of chromosomal micro deletion or copy number variants (CNVs). Chromosomal micro deletion syndrome, including the 22q11.2 deletion syndrome and Williams syndrome, can be identified using fluorescence in situ hybridization (FISH). CNVs are deletions of over 1 kb or amplifications of DNA segments that principally result from inappropriate recombinations. These are detected by cytogenetic analyses, often in combination with FISH and/or array-comparative genomic hybridization. Since 1990’s, CHD-causing gene mutations have been discovered in the TBX5 and NKX2.5 genes by linkage analyses in familial cases and by sequencing analyses of candidate genes. Currently, next-generation sequencing allows reading of the exome and even the whole genome. This approach identifies a large number of variants; however, discriminating pathogenic variants from the non-pathogenic ones is essential to its success. Next-generation sequencing is expected to identify additional CHD-causing genes, which will further clarify the molecular mechanisms involved in cardiac development.