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 - 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 -