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Autosomal dominant neurodevelopmental disorders associated with KIF1A gene variants in 6 pediatric patients
Jingqi Lin1, Niu Li2, Ru'en Yao3
1Central Laboratory, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. lin_j7@sjtu.edu.cn.
Insights
KIF1A gene variations cause diverse neurodevelopmental disorders in children, primarily affecting motor development and gait. Severity varies by specific KIF1A mutation, with some new variants identified.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Kinesin family member 1A (KIF1A) plays a crucial role in neuronal development and function.
- Variations in KIF1A are associated with autosomal dominant neurodevelopmental disorders.
- Understanding KIF1A mutations is key to diagnosing and managing these complex conditions.
Purpose of the Study:
- To investigate the clinical manifestations and genetic underpinnings of KIF1A-related neurodevelopmental disorders in pediatric patients.
- To identify and characterize novel KIF1A gene variations.
- To analyze the impact of identified variants on KIF1A protein structure and function.
Main Methods:
- Retrospective analysis of clinical and genetic data from 6 children diagnosed with KIF1A gene variations.
- Whole exome sequencing for variant identification, confirmed by Sanger sequencing.
- Bioinformatic analysis to predict the structural and functional consequences of KIF1A variants.
Main Results:
- Six children (4 male, 2 female) aged 7 months to 18 years presented with motor developmental delay and gait abnormalities.
- Two children exhibited delayed mental development, epilepsy, and abnormal eye development.
- Four novel heterozygous de novo KIF1A variations (3 missense, 1 splicing) were identified, with bioinformatics predicting likely pathogenic effects on protein stability and function.
Conclusions:
- KIF1A-associated neurological diseases present with significant clinical heterogeneity, predominantly featuring motor delay and gait issues.
- Specific KIF1A mutations, such as T99M, are linked to more severe clinical phenotypes compared to others like R254Q.
- This study highlights the importance of genetic analysis for diagnosing KIF1A-related disorders and identifies novel pathogenic variants.
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.
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