Genetics in medicine : official journal of the American College of Medical Genetics · 2020
Assessing non-Mendelian inheritance in inherited axonopathies.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Bis-Brewer Dana M, Gan-Or Ziv, Sleiman Patrick, Inherited Neuropathy Consortium, 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
Аннотация
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.
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.