De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and ph
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De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females Marcello Scala 1,2 & Evelien Zonneveld-Huijssoon 3 & Marianna Brienza 4 & Oriano Mecarelli 4 & Annemarie H. van der Hout 3 & Elena Zambrelli 5 & Katherine Turner 5 & Federico Zara 2,6 & Angela Peron 7,8,9 & Aglaia Vignoli 7,8 & Pasquale Striano 1,2 Received: 17 May 2020 / Accepted: 21 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Individuals harboring pathogenic variants in ARHGEF9, encoding an essential submembrane protein for gamma-aminobutyric acid (GABA)–ergic synapses named collybistin, show intellectual disability (ID), facial dysmorphism, behavioral disorders, and epilepsy. Only few affected females carrying large chromosomal rearrangements involving ARHGEF9 have been reported so far. Through next-generation sequencing (NGS)–based panels, we identified two single nucleotide variants (SNVs) in ARHGEF9 in two females with neurodevelopmental features. Sanger sequencing revealed that these variants were de novo. The X-inactivation pattern in peripheral blood cells was random. We report the first affected females harboring de novo SNVs in ARHGEF9, expanding the genotypic and phenotypic spectrum of ARHGEF9-related neurodevelopmental disorder in females. Keywords ARHGEF9 . De novo . Neurodevelopmental disorder . Autism spectrum disorder . Epilepsy . X-inactivation
Introduction ARHGEF9 (OMIM *300429) maps to Xq11.1 and encodes collybistin, a submembrane protein involved in the formation of inhibitory gamma-aminobutyric acid (GABA)–ergic synapses.1 Arhgef9 knockout mice exhibit deficient hippocampal
synaptic plasticity, behavioral disturbances, cognitive defects, and seizures [1, 2]. In humans, ARHGEF9 pathogenic variants cause a recognizable neurologic disorder characterized by the variable association of intellectual disability (ID), dysmorphic features, hyperekplexia, anxiety, and epilepsy [3–5]. The large phenotypic spectrum encompasses non-epileptic mildly
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10048-020-00622-5) contains supplementary material, which is available to authorized users. * Marcello Scala [email protected] 1
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
2
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
3
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
4
Department of Human Neurosciences, Policlinico Umberto I Hospital, Sapienza University, Rome, Italy
5
Epilepsy Center - Sleep Medicine Center, San Paolo Hospital, Milan, Italy
6
Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
7
Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Milan, Italy
8
Department of Health Scienc
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