Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation |
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Authors: | Mahmoud Aarabi Elena Kessler Suneeta Madan-Khetarpal Urvashi Surti Daniel Bellissimo Aleksandar Rajkovic Svetlana A. Yatsenko |
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Affiliation: | 1. Medical Genetics & Genomics Laboratories, Magee-Womens Hospital of UPMC, Pittsburgh, PA, Unitetd States;2. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, Unitetd States;3. Medical Genetics, Children''s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, Unitetd States;4. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, Unitetd States;5. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, Unitetd States;6. Magee-Womens Research Institute, Pittsburgh, PA, Unitetd States |
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Abstract: | Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1. ARHGEF9 alterations, some inherited from unaffected mothers, have been reported in males with autism, seizures and severe neurodevelopmental abnormalities. In females, a spectrum of mild to moderate phenotype has been detected. We report two unrelated females with autism and mild intellectual disability. High resolution X-chromosome microarray analysis revealed de novo intragenic deletions in ARHGEF9 of 24?kb and 56?kb involving exons 5–8 and exons 3–8 and leading to truncated forms of collybistin. Peripheral blood samples revealed random X-chromosome inactivation in both patients. To explain phenotypic variability in female patients, we propose a model for disruption of collybistin and various irregular interactions in post-synaptic neurons based on X inactivation patterns. Our findings highlight the importance of ARHGEF9 integrity and suggest further research on its correlation with autism and neurobehavioral problems. |
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Keywords: | Collybistin Microdeletion Autism X-chromosome inactivation |
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