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Int. J. Mol. Sci. 2015, 16(4), 7627-7643; doi:10.3390/ijms16047627

Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
2
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
*
Author to whom correspondence should be addressed.
Academic Editor: Merlin G. Butler
Received: 21 January 2015 / Revised: 19 March 2015 / Accepted: 19 March 2015 / Published: 7 April 2015
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Abstract

Roughly 20% of autism spectrum disorders (ASD) are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5) is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention. View Full-Text
Keywords: MBD5; ASD; networks; overlapping phenotypes; UBE3A; TCF4; MEF2C; EHMT1; RAI1; transcriptional regulation; pathways; network analysis MBD5; ASD; networks; overlapping phenotypes; UBE3A; TCF4; MEF2C; EHMT1; RAI1; transcriptional regulation; pathways; network analysis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Mullegama, S.V.; Alaimo, J.T.; Chen, L.; Elsea, S.H. Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder. Int. J. Mol. Sci. 2015, 16, 7627-7643.

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