Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity.

TitleHaploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity.
Publication TypeJournal Article
Year of Publication2021
AuthorsThomas, 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, JR, Saadi, NWaill, Alkuraya, FS, Zahrani, FAl, Agrawal, PB, England, E, Madden, JA, Posey, JE, Burglen, L, Rodriguez, D, Chevarin, M, Nguyen, S, Mau-Them, FTran, Duffourd, Y, Garret, P, Bruel, A-L, Callier, P, Marle, N, Denommé-Pichon, A-S, Duplomb, L, Philippe, C, Thauvin-Robinet, C, Govin, J, Faivre, L, Vitobello, A
JournalGenet Med
Date Published2021 Oct
KeywordsEpilepsy, Guanine Nucleotide Exchange Factors, Haploinsufficiency, Heterozygote, Humans, Intellectual Disability

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.

Alternate JournalGenet Med
PubMed ID34113008
PubMed Central ID6352689
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States

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