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Assessing non-Mendelian inheritance in inherited axonopathies

2020; Elsevier BV; Volume: 22; Issue: 12 Linguagem: Inglês

10.1038/s41436-020-0924-0

1530-0366

Dana M. Bis‐Brewer, Ziv Gan‐Or, Patrick Sleiman, Aixa Rodríguez, Alexa Bacha, Ashley Kosikowski, Beth Wood, Brett A. McCray, Brianna Blume, Carly E. Siskind, Charlotte J. Sumner, Daniela Calabrese, David Walk, Dragan Vujović, Eun Hye Park, Francesco Muntoni, Gabrielle Donlevy, Gyula Acsádi, John Day, Joshua Burns, Jun Li, Karen Krajewski, Kate Eichinger, Kayla Cornett, Krista Mullen, Laura Pérez, Laurie Gutmann, Maria Barrett, Mario Saporta, Mariola Skorupinska, Natalie Grant, Paula Bray, Reza Sadjadi, Riccardo Zuccarino, Richard S. Finkel, Richard A. Lewis, Sabrina W. Yum, Sarah Hilbert, Simone Thomas, Steffen Behrens‐Spraggins, Tara Jones, Tiffany Grider, Tim Estilow, Vera Fridman, Mary M. Reilly, Michael E. Shy, Chelsea J. Bacon, Shawna Feely, Alexander M. Rossor, David N. Herrmann, Hákon Hákonarson, Sarah Fazal, Steve Courel, Vívian Pedigone Cintra, Feifei Tao, Mehrdad A. Estiar, Mark A. Tarnopolsky, Kym M. Boycott, Grace Yoon, Oksana Suchowersky, Nicolas Dupré, Andrew Cheng, Thomas E. Lloyd, Guy A. Rouleau, Rebecca Schüle, Stephan Züchner,

RNA regulation and disease

PurposeInherited 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.MethodsThrough 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.ResultsWe 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.ConclusionOur results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders.