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Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies

Chen, Z; Maroofian, R; Başak, AN; Shingavi, L; Karakaya, M; Efthymiou, S; Gustavsson, EK; ... Sarraf, P; + view all (2021) Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies. European Journal of Neurology , 28 (4) pp. 1344-1355. 10.1111/ene.14649. Green open access

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Abstract

BACKGROUND: Pathogenic variants in PLEKHG5 have been reported, to date, to be causative in three unrelated families with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMT) and in one consanguineous family with spinal muscular atrophy (SMA). PLEKHG5 is known to be expressed in the human peripheral nervous system and previous studies have shown its function in axon terminal autophagy of synaptic vesicles lending support to its underlying pathogenetic mechanism. Despite this, there is limited knowledge of the clinical and genetic spectrum of disease. METHODS: We leverage the diagnostic utility of exome and genome sequencing and describe novel biallelic variants in PLEKHG5 in thirteen individuals from nine unrelated families originating from four different countries. We compare our phenotypic and genotypic findings with a comprehensive review of cases previously described in the literature. RESULTS: We found that patients presented with variable disease severity at different ages of onset (8 to 25 years). In our cases, weakness usually started proximally, progressing distally, and can be associated with intermediate slow conduction velocities and minor clinical sensory involvement. We report three novel nonsense and four novel missense pathogenic variants associated with these PLEKHG5-associated neuropathies which are phenotypically SMA or intermediate CMT. CONCLUSIONS: Therefore, PLEKHG5-associated neuropathies should be considered as an important differential in non-5q SMAs even in the presence of mild sensory impairment and a candidate causative gene for a wide range of hereditary neuropathies. We present this series of cases to further the understanding of the phenotypic and molecular spectrum of PLEKHG5-associated diseases.

Type: Article
Title: Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/ene.14649
Publisher version: https://doi.org/10.1111/ene.14649
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Charcot-Marie-Tooth disease, genotype-phenotype association, hereditary motor neuropathy, hereditary sensory and motor neuropathy, peripheral nerve disease, spinal muscular atrophy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10115793
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