TY - JOUR
T1 - Assessing non-Mendelian inheritance in inherited axonopathies
AU - Inherited Neuropathy Consortium
AU - Bis-Brewer, Dana M.
AU - Gan-Or, Ziv
AU - Sleiman, Patrick
AU - Rodriguez, Aixa
AU - Bacha, Alexa
AU - Kosikowski, Ashley
AU - Wood, Beth
AU - McCray, Brett
AU - Blume, Brianna
AU - Siskind, Carly
AU - Sumner, Charlotte
AU - Calabrese, Daniela
AU - Walk, David
AU - Vujovic, Dragan
AU - Park, Eun
AU - Muntoni, Francesco
AU - Donlevy, Gabrielle
AU - Acsadi, Gyula
AU - Day, John
AU - Burns, Joshua
AU - Li, Jun
AU - Krajewski, Karen
AU - Eichinger, Kate
AU - Cornett, Kayla
AU - Mullen, Krista
AU - Perez, Laura
AU - Gutmann, Laurie
AU - Barrett, Maria
AU - Saporta, Mario
AU - Skorupinska, Mariola
AU - Grant, Natalie
AU - Bray, Paula
AU - Seyedsadjadi, Reza
AU - Zuccarino, Riccardo
AU - Finkel, Richard
AU - Lewis, Richard
AU - Yum, Sabrina
AU - Hilbert, Sarah
AU - Thomas, Simone
AU - Behrens-Spraggins, Steffen
AU - Jones, Tara
AU - Grider, Tiffany
AU - Estilow, Tim
AU - Fridman, Vera
AU - Reilly, Mary M.
AU - Shy, Michael E.
AU - Bacon, Chelsea J.
AU - Feely, Shawna M.E.
AU - Rossor, Alexander M.
AU - Herrmann, David N.
N1 - Funding Information:
We thank the patients and their families for their participation. This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) (U54NS065712-12 to S.Z. as site principal investigator [PI], R01NS105755 to S.Z., R01NS072248 to S.Z.), the Charcot–Marie–Tooth Association, the Hereditary Neuropathy Foundation, and the Muscular Dystrophy Association. This work was done as a part of a Canadian collaboration to study HSP (CanHSP). The CanHSP cohort was funded by Canadian Institutes of Health Research (CIHR) Emerging Team Grant, in collaboration with the Canadian Organization for Rare Disorders (CORD), grant number RN127580–260005.
Publisher Copyright:
© 2020, American College of Medical Genetics and Genomics.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
KW - Charcot–Marie–Tooth disease
KW - hereditary spastic paraplegia
KW - inherited axonopathy
KW - mutational burden
KW - oligogenic inheritance
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U2 - 10.1038/s41436-020-0924-0
DO - 10.1038/s41436-020-0924-0
M3 - Article
C2 - 32741968
AN - SCOPUS:85088839630
SN - 1098-3600
VL - 22
SP - 2114
EP - 2119
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 12
ER -