Rare heterozygous de novo variants in RAPGEF2 are associated with a neurodevelopmental disorder

Ali H. Bereshneh, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Kirkland A. Wilson, Children's National Medical Center and George Washington University, Washington, DC, USA.
Xueyang Pan, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Shabab B. Hannan, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
Megan A. Cooper, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Jullianne Diaz, Children's National Medical Center and George Washington University, Washington, DC, USA.
Eyby Leon, Children's National Medical Center and George Washington University, Washington, DC, USA.
Tiana M. Moses, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Mahshid S. Azamian, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Daryl A. Scott, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Ping Yee Billie Au, Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Juan Pablo Appendino, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Pediatrics, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, AB. Canada.
Ingrid E. Scheffer, Department of Medicine, University of Melbourne, Austin Health and Department of Paediatrics, Royal Children's Hospital, Melbourne, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Australia.
Antony Kaspi, Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Parkville, Australia.
Melanie Bahlo, Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Parkville, Australia.
Michael S. Hildebrand, Department of Medicine, University of Melbourne, Austin Health and Department of Paediatrics, Royal Children's Hospital, Melbourne, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Australia.
Angela T. Morgan, Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Australia.
Ekanem Ekure, Department of Pediatrics, University of Lagos, Lagos, Nigeria.

Document Type

Journal Article

Publication Date

1-16-2026

Journal

Genetics in medicine : official journal of the American College of Medical Genetics

DOI

10.1016/j.gim.2026.101685

Keywords

PDZ-GEF; RAPGEF2; global developmental delay; microtubule stability; synaptic overgrowth

Abstract

PURPOSE: RAPGEF2 encodes a guanine nucleotide exchange factor (GEF) that activates small GTPases and has not been linked to a Mendelian disorder. RAPGEF2 is highly intolerant to loss-of-function variants. We report five de novo heterozygous variants in RAPGEF2 in unrelated individuals with developmental delay, attention deficit hyperactivity disorder, epilepsy, dysmorphic features, or other manifestations. We used a Drosophila model to assess the functional impact of the identified human variants. METHODS: We generated a Kozak-GAL4 null allele of the Drosophila ortholog of RAPGEF2, PDZ-GEF, and used the allele to determine the gene expression pattern as well as the LoF phenotypes. We expressed the reference and variant RAPGEF2 in PDZ-GEF mutant background to conduct "humanization" studies. RESULTS: Our experiments show that PDZ-GEF is expressed in the central nervous system. Loss of PDZ-GEF leads to severe locomotion defects, aberrant microtubular stability in motor neuron axons, and synaptic overgrowth at neuromuscular junctions in third instar larvae. Mutant animals are lethal at various developmental stages. Importantly, the neurodevelopmental phenotypes can be rescued by expression of the human RAPGEF2 reference cDNA but not by any of the variants. CONCLUSION: Our findings provide functional evidence that the tested RAPGEF2 variants are LoF alleles and that the RAPGEF2 variants are associated with a neurodevelopmental disorder.

Department

Pediatrics

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