Assessing non-Mendelian inheritance in inherited axonopathies.,Genetics in Medicine

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Assessing non-Mendelian inheritance in inherited axonopathies.
Genetics in Medicine ( IF 8.8 ) Pub Date : 2020-08-03 , DOI: 10.1038/s41436-020-0924-0
Dana M Bis-Brewer ₁ , Ziv Gan-Or _{2,

3,

4} , Patrick Sleiman ₅ , , Hakon Hakonarson ₅ , Sarah Fazal ₁ , Steve Courel ₁ , Vivian Cintra ₁ , Feifei Tao ₁ , Mehrdad A Estiar _{2,

3} , Mark Tarnopolsky ₆ , Kym M Boycott ₇ , Grace Yoon _{8,

9} , Oksana Suchowersky ₁₀ , Nicolas Dupré _{11,

12} , Andrew Cheng ₁₃ , Thomas E Lloyd ₁₃ , Guy Rouleau _{2,

3,

4} , Rebecca Schüle ₁₄ , Stephan Züchner ₁

Affiliation

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.
Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
Center for Applied Genomics, The Children's Hospital of Philadelphia; Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Neuromuscular and Neurometabolics Division, Department of Pediatrics, McMaster University, Hamilton, ON, Canada.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Department of Medicine, Medical Genetics and Pediatrics, University of Alberta, Edmonton, AB, Canada.
Division of Neurosciences, CHU de Québec, Université Laval, Québec City, QC, Canada.
Department of Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada.
Department of Neurology and Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Center for Neurology and Hertie Institute für Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, Tübingen, Germany.

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.

中文翻译：

评估遗传性轴突病中的非孟德尔遗传。

目的

遗传性轴突病 (IA) 是一种罕见的临床和遗传异质性疾病，可导致中枢（遗传性痉挛性截瘫 [HSP]）和外周（Charcot–Marie–Tooth 2 型 [CMT2]）神经系统中长轴突的长度依赖性退化. 超过 100 种不同基因中的孟德尔高外显率等位基因已被证明会导致 IA；然而，大约 50% 的 IA 病例没有接受基因诊断。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，以及寡基因多位点遗传。