Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster

Abstract

Recent studies have shown that certain copy number variations (CNV) are associated with a wide range of neurodevelopmental disorders, including autism spectrum disorders (ASD), bipolar disorder and intellectual disabilities. Implicated regions and genes have comprised a variety of post synaptic complex proteins and neurotransmitter receptors, including gamma-amino butyric acid A (GABA A ). Clusters of GABA A receptor subunit genes are found on chromosomes 4p12, 5q34, 6q15 and 15q11-13. Maternally inherited 15q11-13 duplications among individuals with neurodevelopmental disorders are well described, but few case reports exist for the other regions. We describe a family with a 2.42 Mb duplication at chromosome 4p13 to 4p12, identified in the index case and other family members by oligonucleotide array comparative genomic hybridization, that contains 13 genes including a cluster of four GABA A receptor subunit genes. Fluorescent in-situ hybridization was used to confirm the duplication. The duplication segregates with a variety of neurodevelopmental disorders in this family, including ASD (index case), developmental delay, dyspraxia and ADHD (brother), global developmental delays (brother), learning disabilities (mother) and bipolar disorder (maternal grandmother). In addition, we identified and describe another individual unrelated to this family, with a similar duplication, who was diagnosed with ASD, ADHD and borderline intellectual disability. The 4p13 to 4p12 duplication appears to confer a susceptibility to a variety of neurodevelopmental disorders in these two families. We hypothesize that the duplication acts through a dosage effect of GABA A receptor subunit genes, adding evidence for alterations in the GABAergic system in the etiology of neurodevelopmental disorders.

Integrative analysis of genetic data sets reveals a shared innate immune component in autism spectrum disorder and its co-morbidities

“…In the leukocyte transendothelial migration pathway, the TXK gene, which is a non-receptor tyrosine kinase (with altered expression in ASD, ear infection, IBD, and bacterial and viral infections), specifically regulates IFN- γ gene transcription and the development, function, and differentiation of conventional T cells and nonconventional NKT cells. Mutation of the TXK gene has been identified to be a segregating factor for a number of neurodevelopmental disorders, including ASD, bipolar disorder, and intellectual disabilities [50]. …”

GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system

“…In addition, there is strong evidence for transcriptional regulation of GABA A R subunits by neurosteroids, as well as in a number of pathological conditions, including epilepsy, ethanol intoxication, Alzheimer's disease, and schizophrenia [reviewed in Steiger & Russek (2004) and Grabenstatter et al (2012)]. A recent genetic study identified a chromosomal duplication in a locus encoding four GABA A R subunits (4p12: a2, a4, b1, and c1) that is associated with neurodevelopmental disorders (Polan et al, 2013). In contrast, it is not well established whether the compensatory increase in subunit expression observed in some GABA A R subunit-KO mice (Box 1) reflects transcriptional control or is attributable to changes in mRNA stability and/or post-translational mechanisms (Peng et al, 2002;Kralic et al, 2006;Ogris et al, 2006).…”

The GABRB1 gene is associated with thalamus volume and modulates the association between thalamus volume and intelligence

“…First, additional molecular functional studies are needed to investigate the detailed biochemical mechanisms of the genetic effects found in this study. As identified in a recent genetic study, duplication of a cluster of four GABA A receptor genes located on chromosome 4p12 (i.e., GABRB1, GABRA4, GABRA2, GABRG1) was associated with neurodevelopment disorders (Polan et al, 2014). Due to the implications of GABRB1 in clinical samples characterized by reduced thalamus volume and abnormal intellectual performance, future research should explore potential associations between these GABA A receptor genes and thalamus volume and their interaction effect on intelligence in clinical samples, such as those with alcohol dependence, bipolar disorder, and schizophrenia.…”