三例CHARGE综合征患儿的临床表型和CHD7基因变异分析

目的对3例CHARGE综合征患者进行基因变异检测,明确其可能的遗传学病因。方法先证者及父母进行全外显子测序检测相关致病基因,对检出致病变异进行Sanger测序验证。结果3例患儿均有程度不同的眼部病变,包括小眼球、小角膜、虹膜缺损、晶状体混浊、视神经视网膜脉络膜缺损等。测序结果示例1的CHD7基因第2外显子存在c.1447delG(p.Val483Leufs*12)杂合移码变异;例2的CHD7基因第36外显子存在c.7957C>T(p.Arg2653*)杂合无义变异;例3的CHD7基因第2外显子存在c.1021_1048delAATCAGTCCGTACCAAGATACCCCAATG(p.Asn341Leufs*2)杂合移码变异,其中c.1447delG(p.Val483Leufs*12)和c.1021_1048delAATCAGTCCGTACCAAGATACCCCAATG(p.Asn341Leufs*2)变异未见报道,根据美国医学遗传学与基因组学学会遗传变异分类标准与指南,这两个均判定为致病性变异(PVS1+PM2+PM6);c.7957C>T(p.Arg2653*)变异为已报道的可能致病性变异(PVS1+PM2+PP4)。Sanger测序结果验证例1和例3的变异为新发变异(de novo),例2的变异为可疑新发变异。结论CHD7基因变异可能为3例CHARGE综合征患者的致病原因。

Clinical phenotype and analysis of CHD7 gene variants in three children patients with CHARGE syndrome

Objective To explore the genetic basis for three children patients with CHARGE syndrome.Methods The three children and their parents were subjected to whole exome sequencing,and candidate variants were verified by Sanger sequencing.Results All patients had ocular anomalies including microphthalmia,microcornea,lens opacity,and coloboma of iris,optic nerve,retina and choroid.And all were found to carry heterozygous variants of the CHD7 gene,which included two frameshifting variant,namely c.1447delG(p.Val483Leufs*12)and c.1021_1048delAATCAGTCCGTACCAAGATAC CCCAATG(p.Asn341Leufs*2)in exon 2,which were unreported previously and were pathogenic based on the American College of Medical Genetics and Genomics standards and guidelines(PVS1+PM2+PM6),and a nonsense variant c.7957C>T(p.Arg2653*)in exon 36,which was known to be likely pathogenic(PVS1+PM2+PP4).Sanger sequencing confirmed that the two frameshifting mutations were de novo,and the nonsense mutation was also suspected to be de novo.Conclusion Pathological variants of the CHD7 gene probably underlay the CHARGE syndrome in the three patients.