Genetic analysis and prenatal diagnosis of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type3 due to variants ofPIGT gene
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目的 探讨1例多发先天性畸形-肌张力低下-癫痫综合征3型(MCAHS3)患儿的临床特点及遗传学病因，为其母腹中胎儿提供产前诊断依据。 方法 选取2022年7月27日因"反复抽搐4年余"就诊于临沂市人民医院的1例女性MCAHS3患儿为研究对象，收集患儿的临床资料，抽取患儿及父母外周血样，提取基因组DNA进行家系全外显子组测序(WES)，采用Sanger测序对候选变异进行验证。并对其妊娠18周母亲进行羊水穿刺，提取胎儿DNA进行产前诊断。应用生物信息学软件分析构建蛋白模型变异位点的致病性。 结果 患儿为4岁女性，频繁癫痫发作，面容特殊，肌张力低下，重度发育迟缓。基因检测提示患儿PIGT基因上存在母源的c.1126del(p.H376Tfs*56)和父源的c.1285G>C(p.E429Q)复合杂合变异。根据美国医学遗传学与基因组学学会(ACMG)变异评级相关指南，位点c.1126del(p.H376Tfs*56)为致病性变异(PVS1+PM2_Supporting+PM4)，位点c.1285G>C(p.E429Q)为可能致病性变异(PM2_Supporting +PM3+PM4)。同时胎儿携带PIGT基因c.1126del(p.H376Tfs*56)和c.1285G>C(p.E429Q)复合杂合变异，考虑胎儿患病可能性大，引产胎儿。 结论 PIGT基因c.1126del(p.H376Tfs*56)和c.1285G>C(p.E429Q)位点复合杂合变异考虑为MCAHS3患儿的遗传学病因，经产前诊断避免了此类患儿的出生。 Objective To explore the clinical features and genetic etiology of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type 3 (MCAHS3) and provide prenatal diagnosis for her parents. Methods A female child who had presented at Linyi People′s Hospital on 27 July 2022 for recurrent convulsions for over 4 years was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples were taken from the child and her parents and subjected for whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out on amniotic fluid sample at 18 weeks′ gestation. Bioinformatic software was used to analyze the pathogenicity of the protein model for the variant loci. Results The child was a 4-year-old female with frequent seizures, peculiar facial appearance, hypotonia and severe developmental delay. Genetic analysis revealed that she has harbored compound heterozygous variants of the PIGT gene, namely c. 1126del (p.H376Tfs*56) and c. 1285G>C (p.E429Q), which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics, the c. 1126del (p.H376Tfs*56) variant was predicted to be pathogenic (PVS1+ PM2_Supporting+ PM4), and c. 1285G>C (p.E429Q) variant was predicted to be likely pathogenic (PM2_Supporting+ PM3+ PM4). Prenatal diagnosis suggested that the fetus also harbored the same compound heterozygous variants, and the pregnancy was terminated with induced labor. Conclusion The c. 1126del (p.H376Tfs*56) and c. 1285G>C (p.E429Q) compound heterozygous variants of thePIGT gene probably underlay the MCAHS3 in this patient, and prenatal diagnosis has prevented birth of further affected child in this family.
Objective To explore the clinical features and genetic etiology of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type 3 (MCAHS3) and provide prenatal diagnosis for her parents. Methods A female child who had presented at Linyi People′s Hospital on 27 July 2022 for recurrent convulsions for over 4 years was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples were taken from the child and her parents and subjected for whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out on amniotic fluid sample at 18 weeks′ gestation. Bioinformatic software was used to analyze the pathogenicity of the protein model for the variant loci. Results The child was a 4-year-old female with frequent seizures, peculiar facial appearance, hypotonia and severe developmental delay. Genetic analysis revealed that she has harbored compound heterozygous variants of the PIGT gene, namely c. 1126del (p.H376Tfs*56) and c. 1285G>C (p.E429Q), which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics, the c. 1126del (p.H376Tfs*56) variant was predicted to be pathogenic (PVS1+ PM2_Supporting+ PM4), and c. 1285G>C (p.E429Q) variant was predicted to be likely pathogenic (PM2_Supporting+ PM3+ PM4). Prenatal diagnosis suggested that the fetus also harbored the same compound heterozygous variants, and the pregnancy was terminated with induced labor. Conclusion The c. 1126del (p.H376Tfs*56) and c. 1285G>C (p.E429Q) compound heterozygous variants of thePIGT gene probably underlay the MCAHS3 in this patient, and prenatal diagnosis has prevented birth of further affected child in this family.
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