Variation in GABA‐A subunit gene copy number in an autistic patient with mosaic 4 p duplication (p12p16)

Kakinuma, Hiroaki; Ozaki, Mamoru; Sato, Hitoshi; Takahashi, Hiroaki

doi:10.1002/ajmg.b.30663

Cited by 31 publications

(21 citation statements)

References 14 publications

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“…Maybe it has also to be considered that the mosaicism present in the reported case could also be responsible for the lack of symptoms, as it has recently been shown that different body tissues can vary significantly in mosaic-expression of sSMC carriers [Fickelscher et al, 2007]. Overall, apart from the case reported here, there is no comparable case in the literature with such a small imbalance in 4p; there is only a larger one which includes 4p16 to 4p12 reported by Kakinuma et al [2008]. Thus, we have to wait for further reports on duplications to clarify the question if proximal 4q may harbor a UBCA.…”

contrasting

confidence: 45%

Is There a Yet Unreported Unbalanced Chromosomal Abnormality without Phenotypic Consequences in Proximal 4p?

Liehr

Bartels²,

Zoll³

et al. 2010

Cytogenet Genome Res

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Unbalanced chromosomal abnormalities (UBCA) are reported for >50 euchromatic regions of almost all human autosomes. UBCA are comprised of a few megabases of DNA, and carriers are in many cases clinically healthy. Here we report on a partial trisomy of chromosome 4 of the centromere-near region of the short arm of chromosome 4 present as a small supernumerary marker chromosome (sSMC). The sSMC was present in >70% of amnion cells and in 60% of placenta. Further delineation of the size of the duplicated region was done by molecular cytogenetics and array comparative genomic hybridization. Even though the sSMC lead to a partial trisomy of ∼9 megabase pairs, a healthy child was born, developing normally at 1 year of age. No comparable cases are available in the literature. Thus, we discuss here the possibility of having found a yet unrecognized chromosomal region subject to UBCA.

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contrasting

confidence: 45%

Is There a Yet Unreported Unbalanced Chromosomal Abnormality without Phenotypic Consequences in Proximal 4p?

Liehr

Bartels²,

Zoll³

et al. 2010

Cytogenet Genome Res

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show abstract

“…CNV may also act as a susceptibility factor as has been described at the 7q11.23 segmental duplications for the Williams-Beuren syndrome deletion (30, 70). Microdeletions and microduplications in genes have been associated with autism (30, 108,116,186,237,384).…”

Section: Aneuploidy Syndromes and Phenotypic Variabilitymentioning

confidence: 99%

Aneuploidy: From a Physiological Mechanism of Variance to Down Syndrome

Dierssen¹,

Hérault²,

Estivill³

2009

Physiological Reviews

124

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Quantitative differences in gene expression emerge as a significant source of variation in natural populations, representing an important substrate for evolution and accounting for a considerable fraction of phenotypic diversity. However, perturbation of gene expression is also the main factor in determining the molecular pathogenesis of numerous aneuploid disorders. In this review, we focus on Down syndrome (DS) as the prototype of "genomic disorder" induced by copy number change. The understanding of the pathogenicity of the extra genomic material in trisomy 21 has accelerated in the last years due to the recent advances in genome sequencing, comparative genome analysis, functional genome exploration, and the use of model organisms. We present recent data on the role of genome-altering processes in the generation of diversity in DS neural phenotypes focusing on the impact of trisomy on brain structure and mental retardation and on biological pathways and cell types in target brain regions (including prefrontal cortex, hippocampus, cerebellum, and basal ganglia). We also review the potential that genetically engineered mouse models of DS bring into the understanding of the molecular biology of human learning disorders.

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“…This chromosomal abnormality was found to be a de novo alteration because both her parents were healthy and have normal chromosomes. 5 Another case report describes two brothers, 12 and 11-years-old, with autism and a maternally inherited paracentric inversion of a short arm of chromosome 4 [46,XY,inv(4)(p12p15.3)mat] disrupting the GABRG1 receptor gene, which was inherited from their mother. 6 Last, there is one case report of an 18-year-old female with autistic disorder, intellectual disability and a duplication of 4p13 to 4p12 [46,XX,dup(4)(p12p13)].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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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.

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Variation in GABA‐A subunit gene copy number in an autistic patient with mosaic 4 p duplication (p12p16)

Cited by 31 publications

References 14 publications

Is There a Yet Unreported Unbalanced Chromosomal Abnormality without Phenotypic Consequences in Proximal 4p?

Is There a Yet Unreported Unbalanced Chromosomal Abnormality without Phenotypic Consequences in Proximal 4p?

Aneuploidy: From a Physiological Mechanism of Variance to Down Syndrome

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

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