Journal Article

DZNE-2021-00228

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Assessing non-Mendelian inheritance in inherited axonopathies.

Bis-Brewer, D. M. ; Gan-Or, Z. ; Sleiman, P. ; Consortium, I. N. (Collaboration Author) ; Hakonarson, H. ; Fazal, S. ; Courel, S. ; Cintra, V. ; Tao, F. ; Estiar, M. A. ; Tarnopolsky, M. ; Boycott, K. M. ; Yoon, G. ; Suchowersky, O. ; Dupré, N. ; Cheng, A. ; Lloyd, T. E. ; Rouleau, G. ; Schüle, R.DZNE* ; Züchner, S. (Corresponding author) ; Rodriguez, A. ; Bacha, A. ; Kosikowski, A. ; Wood, B. ; McCray, B. ; Blume, B. ; Siskind, C. ; Sumner, C. ; Calabrese, D. ; Walk, D. ; Vujovic, D. ; Park, E. ; Muntoni, F. ; Donlevy, G. ; Acsadi, G. ; Day, J. ; Burns, J. ; Li, J. ; Krajewski, K. ; Eichinger, K. ; Cornett, K. ; Mullen, K. ; Perez, L. ; Gutmann, L. ; Barrett, M. ; Saporta, M. ; Skorupinska, M. ; Grant, N. ; Bray, P. ; Seyedsadjadi, R. ; Zuccarino, R. ; Finkel, R. ; Lewis, R. ; Yum, S. ; Hilbert, S. ; Thomas, S. ; Behrens-Spraggins, S. ; Jones, T. ; Grider, T. ; Estilow, T. ; Fridman, V. ; Reilly, M. M. ; Shy, M. E. ; Bacon, C. J. ; Feely, S. M. E. ; Rossor, A. M. ; Herrmann, D. N.

2020
Springer Nature London, UK

This record in other databases:    

Please use a persistent id in citations: doi:10.1038/s41436-020-0924-0

Abstract: 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.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.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.Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders.

Keyword(s): Alleles (MeSH) ; Charcot-Marie-Tooth Disease: diagnosis (MeSH) ; Charcot-Marie-Tooth Disease: genetics (MeSH) ; Humans (MeSH) ; Mutation (MeSH) ; Spastic Paraplegia, Hereditary: diagnosis (MeSH) ; Spastic Paraplegia, Hereditary: genetics (MeSH) ; Exome Sequencing (MeSH) ; Charcot–Marie–Tooth disease ; hereditary spastic paraplegia ; inherited axonopathy ; mutational burden ; oligogenic inheritance

Note: ISSN 1530-0366 not unique: **3 hits**.

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Contributing Institute(s):

1. Functional Neurogeriatrics (AG Maetzler)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2020

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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