Assessing non-Mendelian inheritance in inherited axonopathies

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.

Keywords: Charcot–Marie–Tooth disease; hereditary spastic paraplegia; inherited axonopathy; mutational burden; oligogenic inheritance.

Figure 1.

Risk allele and multilocus inheritance in inherited axonopathies. (A-C) CMT gene-based rare variant association analysis. (A) qq plot of the observed p-values from C-alpha gene-based association analysis. Blue line indicates multiple testing correction threshold. Known CMT genes with nominal significance are annotated; (B) Transcript model of EXOC4 annotated with variant positions and counts (green bubble); and (C) Heterozygous carrier risk for CMT at gene and variant level. (D-E) Cumulative mutational burden across disease genes. Distribution of the average count of qualifying variants in known HSP and CMT disease genes per case at 1% and 0.1% ExAC MAF for (D) non-synonymous and (E) loss-of-function variation. Difference in case/control distribution tested with Mann-Whitney U Test (*p-value <= 0.05). (F-I) Multilocus variant counts across disease genes. Proportion (F-G) and absolute counts (H-I) of cases carrying non-synonymous (F,H) and loss-of-function (G,I) variants in the indicated number of mutated disease genes (1, 2, 2+, or 3+) at 0.1% and 1% ExAC MAF.