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Assessing non-Mendelian inheritance in inherited axonopathies

Bis-Brewer, DM; Gan-Or, Z; Sleiman, P; Rodriguez, A; Bacha, A; Kosikowski, A; Wood, B; ... Züchner, S; + view all (2020) Assessing non-Mendelian inheritance in inherited axonopathies. Genetics in Medicine , 22 pp. 2114-2119. 10.1038/s41436-020-0924-0. Green open access

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Abstract

PURPOSE: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot–Marie–Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance. METHODS: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis. RESULTS: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA. CONCLUSION: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders.

Type: Article
Title: Assessing non-Mendelian inheritance in inherited axonopathies
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41436-020-0924-0
Publisher version: https://doi.org/10.1038/s41436-020-0924-0
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, hereditary spastic paraplegia, inherited axonopathy, mutational burden, oligogenic inheritance
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 Population Health Sciences
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 > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10113629
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