评估遗传性轴索神经病中的非孟德尔遗传。

Assessing non-Mendelian inheritance in inherited axonopathies.

机构信息

Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

出版信息

Genet Med. 2020 Dec;22(12):2114-2119. doi: 10.1038/s41436-020-0924-0. Epub 2020 Aug 3.

DOI:10.1038/s41436-020-0924-0

PMID:32741968

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7710562/

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.

摘要

目的

遗传性轴索神经病（IA）是罕见的、临床表现和遗传异质性的疾病，导致中枢神经系统（遗传性痉挛性截瘫[HSP]）和周围神经系统（Charcot-Marie-Tooth 型 2 [CMT2]）中的长轴突进行性退化。已经证实超过 100 个不同基因中的孟德尔高外显率等位基因可导致 IA；然而，约 50%的 IA 病例未得到遗传诊断。因此，需要更全面的致病基因和等位基因谱，包括致病和风险等位基因，以及多基因多部位遗传。