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

TitlePhenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases.
Publication TypeJournal Article
Year of Publication2020
AuthorsMontenegro-Garreaud, X, Hansen, AW, Khayat, MM, Chander, V, Grochowski, CM, Jiang, Y, Li, H, Mitani, T, Kessler, E, Jayaseelan, J, Shen, H, Gezdirici, A, Pehlivan, D, Meng, Q, Rosenfeld, JA, Jhangiani, SN, Madan-Khetarpal, S, Scott, DA, Abarca-Barriga, H, Trubnykova, M, Gingras, M-C, Muzny, DM, Posey, JE, Liu, P, Lupski, JR, Gibbs, RA
JournalHum Mutat
Date Published2020 Dec
KeywordsChild, Child, Preschool, Family, Female, Genes, Dominant, Genetic Predisposition to Disease, Humans, Kinesins, Male, Mutation, Pedigree, Peru, Phenotype

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.

Alternate JournalHum Mutat
PubMed ID32935419
PubMed Central IDPMC7903881
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States
UM1 HG008898 / HG / NHGRI NIH HHS / United States

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