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

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  • 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.


  • Bis-Brewer, Dana M
  • Gan-Or, Ziv
  • Sleiman, Patrick
  • 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

  • August 3, 2020