Assessing non-Mendelian inheritance in inherited axonopathies Academic Article uri icon

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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.

authors

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

publication date

  • December 2020