Journal article
Assessing non-Mendelian inheritance in inherited axonopathies
Genetics in medicine, Vol.22(12), pp.2114-2119
12/2020
DOI: 10.1038/s41436-020-0924-0
PMCID: PMC7710562
PMID: 32741968
Abstract
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.
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.
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.
Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders.
Details
- Title: Subtitle
- Assessing non-Mendelian inheritance in inherited axonopathies
- Creators
- Dana M Bis-Brewer - 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. dmb107@miami.eduZiv Gan-Or - Department of Neurology and Neurosurgery, McGill University, Montréal, QC, CanadaPatrick Sleiman - 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, USAHakon Hakonarson - 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, USASarah Fazal - 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, USASteve Courel - 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, USAVivian Cintra - 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, USAFeifei Tao - 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, USAMehrdad A Estiar - Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, CanadaMark Tarnopolsky - Neuromuscular and Neurometabolics Division, Department of Pediatrics, McMaster University, Hamilton, ON, CanadaKym M Boycott - Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, CanadaGrace Yoon - Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, CanadaOksana Suchowersky - Department of Medicine, Medical Genetics and Pediatrics, University of Alberta, Edmonton, AB, CanadaNicolas Dupré - Department of Medicine, Faculty of Medicine, Université Laval, Québec City, QC, CanadaAndrew Cheng - Department of Neurology and Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USAThomas E Lloyd - Department of Neurology and Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USAGuy Rouleau - Department of Neurology and Neurosurgery, McGill University, Montréal, QC, CanadaRebecca Schüle - Center for Neurology and Hertie Institute für Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, Tübingen, GermanyStephan Züchner - 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, USAInherited Neuropathy Consortium
- Contributors
- Michael E Shy (Contributor) - University of Iowa, Neurology
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.22(12), pp.2114-2119
- DOI
- 10.1038/s41436-020-0924-0
- PMID
- 32741968
- PMCID
- PMC7710562
- NLM abbreviation
- Genet Med
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Publisher
- United States
- Grant note
- R01 NS105755 / NINDS NIH HHS\r\nU54NS065712-12 / NINDS NIH HHS\r\nCIHR\r\nU54 NS065712 / NINDS NIH HHS\r\nR01 NS072248 / NINDS NIH HHS
- Language
- English
- Date published
- 12/2020
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984070708002771
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