Abstract:

Objective　To explore the clinical features and genetic variants in a case of KRAS gene mutation-induced Noonan syndrome type 3, and to provide some references for its diagnosis. Methods　We selected a case of a 15-year-and-2-month-old male patient with Noonan syndrome type 3 who visited Dongying People's Hospital in August 2024. The patient's clinical data were retrospectively collected. Whole-exome sequencing was performed on the peripheral blood samples from the patient and his parents. The candidate variants were validated by Sanger sequencing, and analyzed by the bioinformatics tools. The pathogenicity of the identified variant was classified according to the standards and guidelines for the interpretation of sequence variants established by the American College of Medical Genetics and Genomics (ACMG). Results　The patient's clinical features included short stature, growth and developmental delay, facial dysmorphism, and electrocardiographic abnormalities. The whole-exome sequencing revealed a de novo pathogenic point mutation in the KRAS gene: NM_004985.4: c.40G>A (p.Val14Ile). According to the ACMG guidelines, the variant was classified as pathogenic (PS2_VeryStrong+PS3+PS4+PM1+PP2+PM2_Supporting). Conclusions　The de novo variant in the KRAS gene is considered the genetic etiology of Noonan syndrome type 3 in this patient. For children with short stature, growth and developmental delay, facial dysmorphism, or electrocardiographic abnormalities, clinical suspicion for Noonan syndrome type 3 should be raised, and early genetic testing is recommended to confirm the diagnosis. The findings of this study also expand the known variant spectrum of the KRAS gene.

Key words:

Noonan syndrome type 3, KRAS , gene, Phenotype spectrum

摘要：

目的　探讨1例KRAS基因变异致Noonan综合征3型的临床特征和基因变异情况，为该病诊断提供参考。方法　选择2024年8月在东营市人民医院就诊的1例15岁2个月的Noonan综合征3型男性患者。采用回顾性研究方法，收集患者的相关临床资料，对患者及其父母外周血样进行全外显子测序，对候选变异进行Sanger测序验证和生物信息学分析。根据美国医学遗传学与基因学学会（American College of Medical Genetics and Genomic，ACMG）制定的《遗传变异分类标准与指南》，对该变异进行致病性评级。结果　患者临床特征为身材矮小、生长发育迟缓、面部畸形、心电图异常等。全外显子测序显示KRAS基因为新发致病性点突变：NM_004985.4：c.40G>A（Val14Ile）。根据ACMG相关指南评判为致病变异（PS2_VeryStrong+PS3+PS4+PM1+PP2+PM2_Supporting）。结论　KRAS基因新发变异考虑为Noonan综合征3型患者的遗传学病因。对身材矮小、生长发育迟缓、面部畸形、心电图异常的患者，应警惕Noonan综合征3型的可能，通过基因检测尽早明确诊断。本研究的发现亦扩展了KRAS基因的变异谱。

关键词:

Noonan综合征3型, KRAS基因, 表型谱