Assessing non-Mendelian inheritance in inherited axonopathies

Inherited Neuropathy Consortium

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2114-2119
Number of pages6
JournalGenetics in Medicine
Issue number12
StatePublished - Dec 2020


  • Charcot–Marie–Tooth disease
  • hereditary spastic paraplegia
  • inherited axonopathy
  • mutational burden
  • oligogenic inheritance

ASJC Scopus subject areas

  • Genetics(clinical)


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