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Review
. 2020 Dec;41(12):2094-2104.
doi: 10.1002/humu.24118. Epub 2020 Oct 8.

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

Ximena Montenegro-Garreaud  1   2   3 , Adam W Hansen  3   4 , Michael M Khayat  3   4 , Varuna Chander  3   4 , Christopher M Grochowski  4 , Yunyun Jiang  3 , He Li  3 , Tadahiro Mitani  4 , Elena Kessler  5 , Joy Jayaseelan  3 , Hua Shen  3 , Alper Gezdirici  6 , Davut Pehlivan  4   7 , Qingchang Meng  3 , Jill A Rosenfeld  4 , Shalini N Jhangiani  3 , Suneeta Madan-Khetarpal  5 , Daryl A Scott  4   8 , Hugo Abarca-Barriga  1   9 , Milana Trubnykova  1   10 , Marie-Claude Gingras  3   4   11 , Donna M Muzny  3   4 , Jennifer E Posey  4 , Pengfei Liu  4   12 , James R Lupski  3   4   13   14 , Richard A Gibbs  3   4
Affiliations
Review

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

Ximena Montenegro-Garreaud et al. Hum Mutat. 2020 Dec.

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.

Keywords: KIF1A; data lake; genocentric; germline mosaicism; in-frame deletion; literature review.

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Conflict of interest statement

Declaration of Interests

JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Baylor Genetics Laboratory (http://baylorgenetics.com).

Figures

Figure 1 –
Figure 1 –. Peruvian Index Family and KIF1A Kinesin Motor Domain Non-truncating Variants.
A) Siblings affected with dominant KIF1A-related disorder inherited from a germline mosaic, unaffected parent. Asterisk indicates possession of pathogenic p.Asn272del variant. Both the proband (PERU1) and unaffected sister (PERU2) present with strabismus and nystagmus. B-C) Brain MRIs obtained at 11 years of age for subject PERU1 (B) and 1 year of age for subject PERU2 (C) revealed severe cerebellar atrophy. D) The p.Asn272del (N272del) variant observed in subjects PERU1 and PERU2 is shown in pink. Other putatively pathogenic missense variants in previously unpublished cases (Table 1) within the kinesin motor domain from local cases are shown in green. Previously published pathogenic non-truncating variants in the motor domain are shown at the bottom in yellow.
See this image and copyright information in PMC

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