目的：对1例发育迟缓患儿及其家系进行基因检测,了解其基因突变的类型和遗传模式,以对其进行临床诊断。方法：提取先证者及其家系成员的外周血DNA,利用高通量测序技术对先证者进行基因筛查,结合临床表型资料,寻找候选基因致病位点,结合Sanger测序技术对先证者及其家系成员进行致病位点验证。按照美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics, ACMG）变异分类指南判断致病性。结果：高通量测序结果发现, 先证者MECP2基因、PTPN11基因存在杂合错义变异,分别为第4号外显子c.398G>A,p.Arg133 His及第3号外显子c.188A>G,p.Tyr63Cys。Sanger测序结果显示,MECP2基因变异遗传自母亲,导致Rett综合征;PTPN11基因变异遗传自父亲,导致努南综合征（Noonan syndrome, NS）。这2个错义变异均为致病性变异,与先证者及其父母的临床表型相一致。结论：本研究通过高通量测序发现1例发育迟缓患儿存在2个不同基因的致病性变异,导致同患2种不同的遗传性综合征,提示遗传性疾病患者中可能同时存在2种或以上的疾病表型,需加以重视。
Objective: To identify the type and pattern of gene mutation of a developmental delayed child and her family members via gene mutation analysis for the accurate diagnosis of disease in this patient. Methods: Peripheral blood DNA was extracted from the proband as well as her family members - father and mother, and gene mutation screening was performed by high throughput sequencing. The pathogenic candidate genes were identified according to the clinical phenotype data combined with the results of gene mutation screening. Sanger sequencing technology was used to validate the pathogenic mutation sites of proband and her family pedigree. Results: Heterozygous missense variants in MECP2 gene and PTPN11 gene were identified in proband by high throughput sequencing, which were c.398G> A, p.Arg133His and c.188A> G, p.Tyr63Cys, respectively. Sanger sequencing revealed that the MECP2 gene mutation leading to Rett syndrome in proband was inherited from her mother and the PTPN11 gene mutation leading to Noonan syndrome was from her father. The two missense variations detected were pathogenic variants in concordance with the clinical phenotype of the proband, her mother and father, respectively. Conclusions: In this study, two pathogenetic variants are identified in the developmental delayed child by high-throughput sequencing, leading to the occurrence of two different hereditary syndrome in the same patient. It is suggested that two or more phenotypes of disease may be present in the same patient, and attention should be paid to this posibility.
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