Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity
Autor: | Jennifer E. Posey, Arthur Sorlin, Fatema Al Zahrani, Jérôme Govin, Nathalie Marle, Thomas Besnard, Anne-Sophie Denommé-Pichon, Sebastien Moutton, Jill A. Madden, Patrick Callier, Christophe Philippe, Eleina M. England, Julian Delanne, Benjamin Cogné, Ange-Line Bruel, Pankaj B. Agrawal, Maria Iascone, Tabib Dabir, Solène Conrad, Thierry Gautier, Quentin Thomas, Nebal Waill Saadi, Lydie Burglen, Laurence Duplomb, Fowzan S. Alkuraya, Yannis Duffourd, Sylvie Nguyen, Siddharth Banka, Dana Marafi, Marjolaine Willems, Christel Thauvin-Robinet, Philippine Garret, Laurence Faivre, Frédéric Tran Mau-Them, Antonio Vitobello, James R. Lupski, Adam Jackson, Diana Rodriguez, Alice Masurel, Romano Tenconi, Martin Chevarin, Bertand Isidor |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Genetics Candidate gene Heterozygote Epilepsy ADP ribosylation factor In silico Heterozygote advantage Haploinsufficiency 030105 genetics & heredity Biology medicine.disease 03 medical and health sciences 030104 developmental biology Intellectual Disability medicine Guanine Nucleotide Exchange Factors Humans Guanine nucleotide exchange factor Genetics (clinical) Minigene |
Zdroj: | Genetics in Medicine Thomas, Q, Gautier, T, Marafi, D, Besnard, T, Willems, M, Moutton, S, Isidor, B, Cogné, B, Conrad, S, Tenconi, R, Iascone, M, Sorlin, A, Masurel, A, Dabir, T, Jackson, A, Banka, S, Delanne, J, Lupski, J R, Saadi, N W, Alkuraya, F S, Zahrani, F A, Agrawal, P B, England, E, Madden, J A, Posey, J E, Burglen, L, Rodriguez, D, Chevarin, M, Nguyen, S, Mau-Them, F T, Duffourd, Y, Garret, P, Bruel, A-L, Callier, P, Marle, N, Denomme-Pichon, A-S, Duplomb, L, Philippe, C, Thauvin-Robinet, C, Govin, J, Faivre, L & Vitobello, A 2021, ' Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity ', Genetics in medicine : official journal of the American College of Medical Genetics . https://doi.org/10.1038/s41436-021-01218-6 |
ISSN: | 1098-3600 |
DOI: | 10.1038/s41436-021-01218-6 |
Popis: | PURPOSE: ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.METHODS: International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing.RESULTS: We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity.CONCLUSION: We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy. |
Databáze: | OpenAIRE |
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