Autosomal dominant neurodevelopmental disorders associated with KIF1A gene variants in 6 pediatric patients.
10.3724/zdxbyxb-2023-0457
- VernacularTitle:六例KIF1A基因变异相关常染色体显性遗传神经发育障碍患儿临床和遗传学分析
- Author:
Jingqi LIN
1
;
Niu LI
2
;
Ru'en YAO
3
;
Tingting YU
3
;
Xiumin WANG
4
;
Jian WANG
5
Author Information
1. Central Laboratory, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. lin_j7@sjtu.edu.cn.
2. Central Laboratory, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
3. Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
4. Department of Endocrinology and Metabolism, Shanghai Children's Medical Center,Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
5. Central Laboratory, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. labwangjian@shsmu.edu.cn.
- Publication Type:Journal Article
- Keywords:
Autosomal dominant;
De novo mutation;
KIF1A gene;
Motor develop-mental delay
- MeSH:
Male;
Female;
Humans;
Child;
Retrospective Studies;
China;
Mutation;
Epilepsy/genetics*;
Neurodevelopmental Disorders/genetics*;
Kinesins/genetics*
- From:
Journal of Zhejiang University. Medical sciences
2023;52(6):693-700
- CountryChina
- Language:English
-
Abstract:
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.
