Assessing non-Mendelian inheritance in inherited axonopathies.

Alleles Charcot-Marie-Tooth Disease / diagnosis Humans Mutation Spastic Paraplegia, Hereditary / diagnosis Exome Sequencing
Charcot–Marie–Tooth disease hereditary spastic paraplegia inherited axonopathy mutational burden oligogenic inheritance

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
12 2020
Historique:
received: 10 02 2020
accepted: 22 07 2020
revised: 22 07 2020
pubmed: 4 8 2020
medline: 28 4 2021
entrez: 4 8 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41436-020-0924-0 PMID: 32741968 PMC: PMC7710562
pubmed: 32741968
doi: 10.1038/s41436-020-0924-0
pii: S1098-3600(21)00817-0
pmc: PMC7710562
mid: NIHMS1619685
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2114-2119

Subventions

Organisme : NINDS NIH HHS
ID : U54 NS065712
Pays : United States
Organisme : NINDS NIH HHS
ID : U54NS065712-12
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS072248
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS105755
Pays : United States
Organisme : CIHR
Pays : Canada

Investigateurs

Aixa Rodriguez (A)
Alexa Bacha (A)
Ashley Kosikowski (A)
Beth Wood (B)
Brett McCray (B)
Brianna Blume (B)
Carly Siskind (C)
Charlotte Sumner (C)
Daniela Calabrese (D)
David Walk (D)
Dragan Vujovic (D)
Eun Park (E)
Francesco Muntoni (F)
Gabrielle Donlevy (G)
Gyula Acsadi (G)
John Day (J)
Joshua Burns (J)
Jun Li (J)
Karen Krajewski (K)
Kate Eichinger (K)
Kayla Cornett (K)
Krista Mullen (K)
Laura Perez (L)
Laurie Gutmann (L)
Maria Barrett (M)
Mario Saporta (M)
Mariola Skorupinska (M)
Natalie Grant (N)
Paula Bray (P)
Reza Seyedsadjadi (R)
Riccardo Zuccarino (R)
Richard Finkel (R)
Richard Lewis (R)
Sabrina Yum (S)
Sarah Hilbert (S)
Simone Thomas (S)
Steffen Behrens-Spraggins (S)
Tara Jones (T)
Tiffany Grider (T)
Tim Estilow (T)
Vera Fridman (V)
Mary M Reilly (MM)
Michael E Shy (ME)
Chelsea J Bacon (CJ)
Shawna M E Feely (SME)
Alexander M Rossor (AM)
David N Herrmann (DN)

Références

Cortese A, Wilcox JE, Polke JM, et al. Targeted next-generation sequencing panels in the diagnosis of Charcot–Marie–Tooth disease. Neurology. 2020;94:51.
doi: 10.1212/WNL.0000000000008672
Frésard L, Montgomery SB. Diagnosing rare diseases after the exome. Cold Spring Harb Mol Case Stud. 2018;4:a003392.
doi: 10.1101/mcs.a003392
Eldomery MK, Coban-Akdemir Z, Harel T, et al. Lessons learned from additional research analyses of unsolved clinical exome cases. Genome Med. 2017;9:26.
doi: 10.1186/s13073-017-0412-6
Bis-Brewer DM, Zuchner S. Genetics modifiers and non-Mendelian aspects of CMT. Brain Res. 2020;1726:146459.
doi: 10.1016/j.brainres.2019.146459
Bis-Brewer DM, Zuchner S. Perspectives on the genomics of HSP beyond Mendelian inheritance. Front Neurol. 2018;9:11.
doi: 10.3389/fneur.2018.00958
Kiezun A, Garimella K, Do R, et al. Exome sequencing and the genetic basis of complex traits. Nat Genet. 2012;44:623–630.
doi: 10.1038/ng.2303
Bolis A, Coviello S, Visigalli I, et al. Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in Schwann cell myelination. J Neurosci. 2009;29:8858–8870.
doi: 10.1523/JNEUROSCI.1423-09.2009
Liebl FL, Chen K, Karr J, Sheng Q, Featherstone DE. Increased synaptic microtubules and altered synapse development in Drosophila sec8 mutants. BMC Biol. 2005;3:27.
doi: 10.1186/1741-7007-3-27
Anitei M. A role for Sec8 in oligodendrocyte morphological differentiation. J Cell Sci. 2006;119:807–818.
doi: 10.1242/jcs.02785
Auer-Grumbach M, Toegel S, Schabhüttl M, et al. Rare variants in MME, encoding metalloprotease neprilysin, are linked to late-onset autosomal-dominant axonal polyneuropathies. Am J Hum Genet. 2016;99:607–623.
doi: 10.1016/j.ajhg.2016.07.008
Pounraja VJ, Jayakar G, Jensen M, et al. A machine-learning approach for accurate detection of copy number variants from exome sequencing. Genome Res. 2019;29:1134–1143.
doi: 10.1101/gr.245928.118
Zuchner S, Mersiyanova I, Muglia M, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot–Marie–Tooth neuropathy type 2A. Nat Genet. 2004;36:449–451.
doi: 10.1038/ng1341
Cirulli ET, Lasseigne BN, Petrovski S, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015;347:1436–1441.
doi: 10.1126/science.aaa3650
Gonzaga-Jauregui C, Harel T, Gambin T, et al. Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Rep. 2015;12:1169–1183.
doi: 10.1016/j.celrep.2015.07.023
Posey JE, O’Donnell-Luria AH, Chong JX, et al. Insights into genetics, human biology and disease gleaned from family based genomic studies. Genet Med. 2019;21:798–812.
doi: 10.1038/s41436-018-0408-7
Ji W, Foo J, O’Roak BJ, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40:592–599.
doi: 10.1038/ng.118

Auteurs

Dana M Bis-Brewer (DM)

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.edu.
ORCID: 0000-0002-4953-3487

Ziv Gan-Or (Z)

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.

Patrick Sleiman (P)

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.

Hakon Hakonarson (H)

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.

Sarah Fazal (S)

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.

Steve Courel (S)

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.

Vivian Cintra (V)

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.

Feifei Tao (F)

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.

Mehrdad A Estiar (MA)

Department of Human Genetics, McGill University, Montréal, QC, Canada.
Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.

Mark Tarnopolsky (M)

Neuromuscular and Neurometabolics Division, Department of Pediatrics, McMaster University, Hamilton, ON, Canada.

Kym M Boycott (KM)

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.

Grace Yoon (G)

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.

Oksana Suchowersky (O)

Department of Medicine, Medical Genetics and Pediatrics, University of Alberta, Edmonton, AB, Canada.

Nicolas Dupré (N)

Division of Neurosciences, CHU de Québec, Université Laval, Québec City, QC, Canada.
Department of Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada.

Andrew Cheng (A)

Department of Neurology and Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.

Thomas E Lloyd (TE)

Department of Neurology and Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.

Guy Rouleau (G)

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.

Rebecca Schüle (R)

Center for Neurology and Hertie Institute für Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, Tübingen, Germany.

Stephan Züchner (S)

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.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Allèles › Assessing non-Mendelian inheritance in...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Maladies neurodégénératives héréditaires › Neuropathie héréditaire motrice et sensitive › Maladie de Charcot-Marie-Tooth › Assessing non-Mendelian inheritance in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Assessing non-Mendelian inheritance in...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Assessing non-Mendelian inheritance in...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Maladies neurodégénératives héréditaires › Neuropathie héréditaire motrice et sensitive › Paraplégie spasmodique héréditaire › Assessing non-Mendelian inheritance in...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Séquençage de l'exome › Assessing non-Mendelian inheritance in...