一例BRAF基因突变导致的Noonan综合征遗传学分析

Genetic analysis of a case of Noonan syndrome caused by BRAF gene mutation

目的 分析1例由BRAF基因突变所致Noonan综合征患儿的临床表型及遗传学特点,为该病的临床诊断和遗传咨询提供参考依据。方法 获取患儿的临床资料,对患儿血液DNA样本进行全外显子组测序以检测可疑致病基因变异,通过Sanger DNA测序,在患儿及其父母中进行突变位点的验证分析,并采用生物信息学分析方法预测基因突变的有害性。结果 患儿为12岁2个月男性,主要临床表现为特殊面容、癫痫发作、隐睾症、智力发育障碍,双手指关节增粗等。全外显子组测序结果显示患儿携带BRAF基因(NM 004333)c.722C>G(p.Thr241Arg)杂合错义变异。Sanger DNA测序结果显示患儿父亲及母亲均未携带该突变,表明该突变为新发变异,且为致病性变异(PS2+PS4+PM1+PM2+PP3)。结论 BRAF基因c.722C>G(p.Thr241Arg)杂合错义变异为该患儿Noonan综合征的致病原因,本研究提供了BRAF基因变异导致的Noonan综合征患儿的临床表型数据,丰富了Noonan综合征的基因突变谱和临床表型谱,为该病的临床诊断,鉴别诊断和遗传咨询提供了参考依据。

Objective To analyze the clinical phenotype and genetic characteristics of a child with Noonan syndrome caused by BRAF gene mutation, and provide reference for clinical diagnosis and genetic consultation. Methods Obtain the clinical data of the child, perform whole-exome sequencing of the blood DNA sample of the child to detect the suspected pathogenic gene mutation. We use Sanger DNA sequencing to verify the mutation site in the child and his parents, and bioinformatics analysis methods are used to predict the harmfulness of gene mutations. Results The child is a boy under 13years old, he suffers from special facial appearance, seizures, cryptorchidism, mental retardation, and his fingers’ joints is thickening. The whole exome sequencing results showed that the child carried the BRAF gene(NM 004333) c.722C>G(p.Thr241Arg) heterozygous missense mutation. Sanger DNA sequencing results showed that his parents did not carry the mutation, indicating that the mutation is a de novo mutation,which was considered a pathogenic variant(PS2+PS4+PM1+PM2+PP3). Conclusion The heterozygous missense mutation of BRAF gene c.722c>G(p.Thr241Arg) is the cause of Noonan syndrome. This study provides the clinical phenotype data of the child with Noonan syndrome caused by BRAF gene mutation, enriches the gene mutation spectrum and clinical phenotype spectrum of Noonan syndrome, and provides reference for clinical diagnosis, differential diagnosis and genetic counseling of the disease.