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

Ximena Montenegro-Garreaud, Adam W. Hansen, Michael M. Khayat, Varuna Chander, Christopher M. Grochowski, Yunyun Jiang, He Li, Tadahiro Mitani, Elena Kessler, Joy Jayaseelan, Hua Shen, Alper Gezdirici, Davut Pehlivan, Qingchang Meng, Jill A. Rosenfeld, Shalini N. Jhangiani, Suneeta Madan-Khetarpal, Daryl A. Scott, Hugo Abarca-Barriga, Milana TrubnykovaMarie Claude Gingras, Donna M. Muzny, Jennifer E. Posey, Pengfei Liu, James R. Lupski, Richard A. Gibbs

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish
Pages (from-to)2094-2104
Number of pages11
JournalHuman Mutation
Issue number12
StatePublished - Dec 2020


  • KIF1A
  • data lake
  • genocentric
  • germline mosaicism
  • in-frame deletion
  • literature review


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