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Phenotypic expansion in KIF1A ‐related dominant disorders: A description of novel variants and review of published cases
Author(s) -
MontenegroGarreaud Ximena,
Hansen Adam W.,
Khayat Michael M.,
Chander Varuna,
Grochowski Christopher M.,
Jiang Yunyun,
Li He,
Mitani Tadahiro,
Kessler Elena,
Jayaseelan Joy,
Shen Hua,
Gezdirici Alper,
Pehlivan Davut,
Meng Qingchang,
Rosenfeld Jill A.,
Jhangiani Shalini N.,
MadanKhetarpal Suneeta,
Scott Daryl A.,
AbarcaBarriga Hugo,
Trubnykova Milana,
Gingras MarieClaude,
Muzny Donna M.,
Posey Jennifer E.,
Liu Pengfei,
Lupski James R.,
Gibbs Richard A.
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24118
Subject(s) - phenocopy , biology , phenotype , genetics , exome sequencing , locus (genetics) , haplotype , allele , gene
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.

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