Supplementary Material for: Major Contribution of Genomic Copy Number Variation in Syndromic Congenital Heart Disease: The Use of MLPA as the First Genetic Test

Congenital heart disease (CHD) is the most common congenital disorder among live births. When associated with extracardiac abnormalities, it is characterized as a syndromic heart disease (syndromic CHD) and corresponds to 25% of all liveborn infants with a heart defect. The etiology in about 65% of the cases still remains unknown, and in about 35% of the patients, it is associated with genetic factors. In the present study, MLPA and SNP-array techniques were used to investigate a group of 47 patients with syndromic CHD. In total, 16 defects (34%) were identified, of which 12 (25.5%) were classified as pathogenic or probably pathogenic. The most frequent abnormalities were 22q11.2 deletion (22q11.2 deletion syndrome) and 7q11.23 deletion (Williams-Beuren syndrome). We also show that rarer malformations may be associated with syndromic CHD, such as 14q32.33 deletion as well as 17q25.3, 15q11.2 (BP1-BP2), 22q13.31, and 12p13.31 (<i>SLC2A3</i>) duplications. The present study demonstrates that CNVs are important causal factors and should be studied in patients with syndromic CHD. Furthermore, the use of MLPA as a first screening test was appropriate, as this less expensive technology detected 11 of the 12 pathogenic abnormalities (91.6%).

先天性心脏病（Congenital Heart Disease, CHD）是活产婴儿中最常见的先天性病症。当合并心外异常时，该类疾病被归类为综合征性心脏病（syndromic CHD），约占所有存在心脏缺陷的活产婴儿的25%。约65%的病例病因仍未明确，另有约35%的患者发病与遗传因素相关。本研究采用MLPA与SNP-array技术，对47例综合征性CHD患者进行了检测分析。总计检出16处基因缺陷（占比34%），其中12处（占比25.5%）被判定为致病性或疑似致病性变异。最常见的染色体异常为22q11.2缺失（22q11.2缺失综合征）与7q11.23缺失（威廉姆斯-比伦综合征）。本研究还发现，综合征性CHD可与更为罕见的畸形相关，例如14q32.33缺失，以及17q25.3、15q11.2（BP1-BP2区域）、22q13.31与12p13.31区域（<i>SLC2A3</i>基因）的拷贝数重复。本研究证实，拷贝数变异（Copy Number Variations, CNVs）是综合征性CHD的重要致病因素，应对此类患者开展相关检测研究。此外，将MLPA作为首次筛查手段是合理的，这项成本较低的技术成功检出了12处致病性变异中的11处（检出率达91.6%）。