Objectives: To analyze the clinical and genetic characteristics of children with autosomal dominant neurodevelopmental disorders caused by kinesin family member 1A (KIF1A) gene variation.
Methods: Clinical and genetic testing data of 6 children with KIF1A gene de novo heterozygous variation diagnosed in Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine from the year 2018 to 2020 were retrospectively analyzed. Pathogenic variants were identified based on whole exome sequencing, and verified by Sanger sequencing. Moreover, the effect of variants on three-dimensional structure and stability of protein was analyzed by bioinformatics.
Results: Among 6 patients there were 4 males and 2 females, and the age of consultation varied from 7 months to 18 years. All cases had varying degrees of motor developmental delay since childhood, and 4 of them had gait abnormalities or fell easily. In addition, 2 children were accompanied by delayed mental development, epilepsy and abnormal eye development. Genetic tests showed that all 6 cases had heterozygous de novo variations of KIF1A gene, including 4 missense mutations c.296C>T (p.T99M), c.761G>A (p.R254Q), c.326G>T (p.G109V), c.745C>G (p.L249V) and one splicing mutation c.798+1G>A, among which the last three variants have not been previously reported. Bioinformatics analysis showed that G109V and L249V may impair their interaction with the neighboring amino acid residues, thereby impacting protein function and reducing protein stability, and were assessed as "likely pathogenic". Meanwhile, c.798+1G>A may damage an alpha helix in the motor domain of the KIF1A protein, and was assessed as "likely pathogenic".
Conclusions: KIF1A-associated neurological diseases are clinically heterogeneous, with motor developmental delay and abnormal gait often being the most common clinical features. The clinical symptoms in T99M carriers are more severe, while those in R254Q carriers are relatively mild.
目的: 分析驱动蛋白家族成员1A（KIF1A）基因变异致常染色体显性遗传神经发育障碍患儿的临床和遗传学特点。方法: 收集并回顾性分析2018至2020年在上海交通大学医学院附属上海儿童医学中心就诊的6例KIF1A基因新生杂合变异患儿的临床及基因检测资料。致病性变异的确定基于对先证者行全外显子组基因测序，同时使用桑格测序对家系成员进行验证，并进一步采用生物信息学方法分析变异对蛋白三维结构以及稳定性的影响。结果: 6例患儿中男性4例，女性2例，确诊年龄7月龄~18岁。6例患儿自幼即有不同程度的大运动发育迟缓，其中4例可走路患儿存在步态异常或易摔倒；2例患儿同时合并智力发育迟缓、癫痫以及眼部发育异常。基因检测发现6例患儿均存在KIF1A基因杂合新生突变，包括4个错义突变和1个剪接突变。除c.296C>T（p.T99M）和c.761G>A（p.R254Q）外，c.326G>T（p.G109V）、c.745C>G（p.L249V）和c.798+1G>A均未曾报道。生物信息学分析表明G109V和L249V可损害其与邻近氨基酸残基的结合从而损害蛋白质功能，并降低蛋白质的稳定性，评估为“可能致病”；而c.798+1G>A可能导致KIF1A蛋白运动结构域中一个α螺旋结构严重受损，评估为“可能致病”。结论: KIF1A基因变异相关疾病临床异质性较强，大运动发育迟缓以及步态异常是临床常见的特征，其中T99M变异携带者的临床症状较重，R254Q变异携带者症状相对较轻。.
Keywords: Autosomal dominant; De novo mutation; KIF1A gene; Motor develop-mental delay.