Chromodomain helicase DNA‐binding protein 7 (CHD7) pathogenic variants are identified in more than 90% of infants and children with CHARGE (Coloboma of the iris, retina, and/or optic disk; congenital Heart defects, choanal Atresia, Retardation of growth and development, Genital hypoplasia, and characteristic outer and inner Ear anomalies and deafness) syndrome. Approximately, 10% of cases have no known genetic cause identified. We report a male child with clinical features of CHARGE syndrome and nondiagnostic genetic testing that included chromosomal microarray, CHD7 sequencing and deletion/duplication analysis, SEMA3E sequencing, and trio exome and whole‐genome sequencing (WGS). We used a comprehensive clinical assessment, genome‐wide methylation analysis (GMA), reanalysis of WGS data, and CHD7 RNA studies to discover a novel variant that causes CHD7 haploinsufficiency. The 7‐year‐old Hispanic male proband has typical phenotypic features of CHARGE syndrome. GMA revealed a CHD7‐associated epigenetic signature. Reanalysis of the WGS data with focused bioinformatic analysis of CHD7 detected a novel, de novo 15 base pair deletion in Intron 4 of CHD7 (c.2239‐20_2239‐6delGTCTTGGGTTTTTGT [NM_017780.3]). Using proband RNA, we confirmed that this novel deletion causes CHD7 haploinsufficiency by disrupting the canonical 3′ splice site and introducing a premature stop codon. Integrated genomic, epigenomic, and transcriptome analyses discovered a novel CHD7 variant that causes CHARGE syndrome.

中文翻译：

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通过综合组学分析发现一种新的 CHD7 CHARGE 综合征变体

染色质域解旋酶 DNA 结合蛋白 7 ( CHD7 ) 致病变异在 90% 以上的 CHARGE（虹膜、视网膜和/或视盘缺损；先天性心脏缺陷、后鼻孔闭锁、R生长发育迟缓、生殖器发育不全、特征性外耳和内耳异常和耳聋）综合征。大约 10% 的病例没有确定已知的遗传原因。我们报告了一名具有 CHARGE 综合征临床特征和非诊断性基因检测的男孩，包括染色体微阵列、CHD7测序和缺失/重复分析、SEMA3E测序，以及三外显子组和全基因组测序（WGS）。我们使用全面的临床评估、全基因组甲基化分析 (GMA)、WGS 数据的再分析和CHD7 RNA 研究来发现导致CHD7单倍体不足的新变体。这位 7 岁的西班牙裔男性先证者具有典型的 CHARGE 综合征表型特征。GMA 揭示了与CHD7相关的表观遗传特征。使用 CHD7的集中生物信息学分析对 WGS 数据进行重新分析，检测到CHD7的内含子 4 中的新的从头 15 个碱基对缺失（ c.2239-20_2239-6delGTCTTGGGTTTTTGT [NM_017780.3]）。使用先证者 RNA，我们证实这种新的缺失导致CHD7通过破坏规范的 3' 剪接位点并引入过早终止密码子来解决单倍体不足。综合基因组、表观基因组和转录组分析发现了一种导致 CHARGE 综合征的新型CHD7变体。