title: 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 (GABAA). Clusters of GABAA 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 GABAA 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 GABAA receptor subunit genes, adding evidence for alterations in the GABAergic system in the etiology of neurodevelopmental disorders.
authors.affiliation: Division of Molecular and Human Genetics, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Polan
authors.affiliation: 1] Division of Molecular and Human Genetics, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA [2] Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Pastore
authors.affiliation: 1] Department of Pediatrics, The Ohio State University, Columbus, OH, USA [2] Division of Behavioral Pediatrics, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Steingass
authors.affiliation: Department of Pathology and Laboratory Medicine, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA [2] Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Devon L
authors.initials: DL
authors.lastname: Thrush
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA [2] Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Pyatt
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA [2] Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Reshmi
authors.affiliation: 1] Department of Pediatrics, The Ohio State University, Columbus, OH, USA [2] Department of Pathology and Laboratory Medicine, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA [3] Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA [2] Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Astbury
authors.affiliation: 1] Division of Molecular and Human Genetics, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA [2] Department of Pediatrics, The Ohio State University, Columbus, OH, USA [3] Center for Cardiovascular and Pulmonary Research, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
mesh_terms: D000328:Adult; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D002658:Developmental Disabilities / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D020440:Gene Duplication; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D010375:Pedigree; D010641:Phenotype; D011963:Receptors, GABA-A / Q000235:genetics*
chemical_list: D011963:Receptors, GABA-A