A de novo variant in RAC3 causes severe global developmental delay and a middle interhemispheric variant of holoprosencephaly
- 16 August 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Human Genetics
- Vol. 64 (11), 1127-1132
- https://doi.org/10.1038/s10038-019-0656-7
Abstract
RAC3 is a member of the Rho GTPases family, which has important regulatory functions in aspects of neuronal morphogenesis. Rho GTPases show a conformational change in two regions (switch I and II) through GTP binding, which provides a platform for selective interactions with functionally diverse proteins. Missense variants in the switch I and II regions of RAC3 were recently suggested to cause severe intellectual disability and brain malformations. Here, we report an individual with a novel de novo RAC3 variant (c.101 C>G, p.(Pro34Arg)), which substitutes for an evolutionarily conserved amino acid within the switch I region. The patient showed severe global developmental delay, intellectual disability, epilepsy, and laryngeal dystonia. An imaging study revealed characteristic brain dysplasia, including coexistence of the middle interhemispheric variant of holoprosencephaly and brainstem dysmorphism. Our study supports that RAC3 variants cause syndromic neurodevelopmental disorders and brain structural abnormality, and expands the phenotypic spectrum of RAC3-related disorders.Keywords
Funding Information
- Grant-in-Aid from Hamamatsu University School of Medicine
- Ministry of Health, Labour and Welfare (H29- nanchitou-ippan-025)
- Intramural Research Grant (30-6) for Neurological and Psychiatric Disorders of NCNP
- MEXT | Japan Society for the Promotion of Science (JP16H05160)
- Japan Agency for Medical Research and Development (JP18ek0109297)
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