Abstract：
CHARGE syndrome is a rare autosomal dominant (AD) multi-system disorder with a broad and variable clinical manifestation and occurs in approximately 1/10,000 newborns in the world. Mutations in the CHD7 gene are the genetic cause of over 90% of patients with typical CHARGE syndrome. The present study reported a novel variant in the CHD7 gene in a Chinese family with an abnormal fetus.
Routine prenatal ultrasound screening showed fetal heart abnormality and left foot varus. Chromosomal microarray analysis (CMA) and fetus-parent whole-exome sequencing (trio-WES) were performed to determine the genetic cause of the fetus. The candidate variant was further verified using Sanger sequencing.
CMA analysis revealed normal results. However, WES analysis identified a de novo heterozygous variant of c.2919_2922del (NM_017780.4) on exon 11 of CHD7 gene, resulting in a premature truncation of the CHD7 protein (p.Gly975*). The variant was classified as Pathogenic (PVS1 + PS2_Moderate + PM2_Supporting) based on the ACMG guidelines. Combined with the clinical phenotype of fetal heart abnormalities, it was confirmed CHARGE syndrome.
We identified a novel heterozygous variant c.2919_2922del in CHD7 of a Chinese fetus with CHARGE syndrome, enriching the genotype-phenotype spectrum of CHD7. These results suggest that genetic testing could help facilitate prenatal diagnosis of CHARGE syndrome, thus promoting the appropriate genetic counseling.
Routine prenatal ultrasound screening showed fetal heart abnormality and left foot varus. Chromosomal microarray analysis (CMA) and fetus-parent whole-exome sequencing (trio-WES) were performed to determine the genetic cause of the fetus. The candidate variant was further verified using Sanger sequencing.
CMA analysis revealed normal results. However, WES analysis identified a de novo heterozygous variant of c.2919_2922del (NM_017780.4) on exon 11 of CHD7 gene, resulting in a premature truncation of the CHD7 protein (p.Gly975*). The variant was classified as Pathogenic (PVS1 + PS2_Moderate + PM2_Supporting) based on the ACMG guidelines. Combined with the clinical phenotype of fetal heart abnormalities, it was confirmed CHARGE syndrome.
We identified a novel heterozygous variant c.2919_2922del in CHD7 of a Chinese fetus with CHARGE syndrome, enriching the genotype-phenotype spectrum of CHD7. These results suggest that genetic testing could help facilitate prenatal diagnosis of CHARGE syndrome, thus promoting the appropriate genetic counseling.
摘要：
目的：CHARGE综合征是一种罕见的常染色体显性遗传（AD）多系统疾病，临床表现广泛且多变，在世界上约有1/10,000的新生儿中发生。CHD7基因突变是超过90%的典型CHARGE综合征患者的遗传原因。本研究报道了一个胎儿异常的中国家庭中CHD7基因的新变体。
方法：常规产前超声筛查显示胎儿心脏异常和左足内翻。进行染色体微阵列分析（CMA）和胎儿-亲本全外显子组测序（trio-WES）以确定胎儿的遗传原因。使用Sanger测序进一步验证候选变体。
结果：CMA分析显示结果正常。然而,WES分析确定了CHD7基因外显子11上c.2919_2922del（NM_017780.4）的从头杂合变体，导致CHD7蛋白的过早截短（p。Gly975*）。基于ACMG指南,该变体被分类为致病性(PVS1+PS2_中度+PM2_支持)。结合胎儿心脏异常的临床表型，它被证实为CHARGE综合征。
结论：我们在CHARGE综合征的中国胎儿CHD7中发现了一种新的杂合变体c.2919_2922del，丰富CHD7的基因型-表型谱。这些结果表明，基因检测可以帮助促进CHARGE综合征的产前诊断，从而促进适当的遗传咨询。
方法：常规产前超声筛查显示胎儿心脏异常和左足内翻。进行染色体微阵列分析（CMA）和胎儿-亲本全外显子组测序（trio-WES）以确定胎儿的遗传原因。使用Sanger测序进一步验证候选变体。
结果：CMA分析显示结果正常。然而,WES分析确定了CHD7基因外显子11上c.2919_2922del（NM_017780.4）的从头杂合变体，导致CHD7蛋白的过早截短（p。Gly975*）。基于ACMG指南,该变体被分类为致病性(PVS1+PS2_中度+PM2_支持)。结合胎儿心脏异常的临床表型，它被证实为CHARGE综合征。
结论：我们在CHARGE综合征的中国胎儿CHD7中发现了一种新的杂合变体c.2919_2922del，丰富CHD7的基因型-表型谱。这些结果表明，基因检测可以帮助促进CHARGE综合征的产前诊断，从而促进适当的遗传咨询。
