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



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.


International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing.


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.


We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy.

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Fig. 1: Family trees and visual representation of ARFGEF1 variants on a protein model.
Fig. 2: Pictures of six affected individuals carrying ARFGEF1 expected pathogenic variants showing mild morphological particularities including large, low-set ears, large mouth, high forehead, and bulbous nose-tip.
Fig. 3: Brain magnetic resonance image (MRI) affected individuals carrying expected-pathogenic variants in ARFGEF1.
Fig. 4: In silico analyses regarding the missense p.Asp798Asn and western blot analyses.

Data availability

Data are available upon request.


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We thank the families and patients for taking part in the study. We thank the University of Burgundy Centre de Calcul (CCuB) for technical support and management of the informatics platform, and the GeneMatcher platform for data sharing. We thank the Centre de Ressources Biologiques Ferdinand Cabanne (CHU Dijon) for sample biobanking. This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR) and the European Union through the FEDER programs. Also supported in part by the US National Institutes of Health, National Human Genome Research Institute (NHGRI) to the Baylor Hopkins Center for Mendelian Genomics (UM1HG006542). This work was supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre. The Deciphering Developmental Disorders (DDD) study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009–003). This study makes use of DECIPHER (, which is funded by the Wellcome. See Nature PMID 25533962 or for full acknowledgement. D.M. is also supported by a Medical Genetics Research Fellowship Program through the United States National Institute of Health (T32 GM007526–42). Several authors of this publication are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA) A.J., A-S.D-P., and A.V. are supported by Solve-RD. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. J.E.P. was supported by NHGRI K08 HG008986.

Author information




Conceptualization: A.V., C.T.-R., L.F., L.D. Data curation: Q.T., A.V., Y.D., P.G. Investigation: Q.T., D.M., M.W., S.M., B.I., B.C., S.C., R.T., M.I., A.S., A.M., T.D., A.J., S.B., J.D., N.S., F.A., F.AZ., P.A., E.E., J.M. L.B., D.R., F.TM-T. A-L.B., P.C., N.M., A-S.D-P., C.P. Methodology: A.V., L.D., M.C., S.N., T.B., T.G., J.G. Supervision: Q.T., A.V., D.M. Visualization: T.G., Q.T., A.V, Writing - original draft: Q.T., A.V., L.F., C.T.-R. Writing – review & editing: all authors.

Corresponding authors

Correspondence to Quentin Thomas or Antonio Vitobello.

Ethics declarations

Ethics declaration

All affected individuals or their legal representative gave informed consent for the sequencing procedures and the publication of their results along with clinical and molecular data. Special consent forms were signed authorizing publication of pictures when relevant. The study was performed within the framework of the GAD (“Génétique des Anomalies du Développement”) collection and approved by the appropriate institutional review board of Dijon University Hospital (DC2011‐1332).

Competing interests

J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. The other authors declare no competing interests.

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Thomas, Q., Gautier, T., Marafi, D. et al. Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity. Genet Med (2021).

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