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Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases.

ABSTRACT: KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus.

SUBMITTER: Montenegro-Garreaud X

PROVIDER: S-EPMC7903881 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases.

Montenegro-Garreaud Ximena X Hansen Adam W AW Khayat Michael M MM Chander Varuna V Grochowski Christopher M CM Jiang Yunyun Y Li He H Mitani Tadahiro T Kessler Elena E Jayaseelan Joy J Shen Hua H Gezdirici Alper A Pehlivan Davut D Meng Qingchang Q Rosenfeld Jill A JA Jhangiani Shalini N SN Madan-Khetarpal Suneeta S Scott Daryl A DA Abarca-Barriga Hugo H Trubnykova Milana M Gingras Marie-Claude MC Muzny Donna M DM Posey Jennifer E JE Liu Pengfei P Lupski James R JR Gibbs Richard A RA

Human mutation 20201008 12

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional ca ...[more]

PMID: 32935419

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Project description:ObjectivesTo analyze the clinical and genetic characteristics of children with autosomal dominant neurodevelopmental disorders caused by kinesin family member 1A (KIF1A) gene variation.MethodsClinical 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.ResultsAmong 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".ConclusionsKIF1A-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.

Dataset Information

Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases.

Publications

Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases.

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