The genetic variability and commonality of neurodevelopmental disease

Coe, Bradley P.; Girirajan, Santhosh; Eichler, Evan E.

doi:10.1002/ajmg.c.31327

Cited by 106 publications

(97 citation statements)

References 86 publications

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“…De novo CNVs observed in patients with developmental abnormalities are considered likely pathogenic Coe et al 2012;Malhotra and Sebat 2014). We obtained 626 de novo CNVs and the respective patient phenotypes, compiled from a consortium of clinical genetics laboratories, and we identified on a variety of arrays from the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER) (Firth et al 2009).…”

Section: Methods De Novo Cnv Data Setsmentioning

confidence: 99%

The clustering of functionally related genes contributes to CNV-mediated disease

et al. 2015

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Clusters of functionally related genes can be disrupted by a single copy number variant (CNV). We demonstrate that the simultaneous disruption of multiple functionally related genes is a frequent and significant characteristic of de novo CNVs in patients with developmental disorders (P = 1 × 10−3). Using three different functional networks, we identified unexpectedly large numbers of functionally related genes within de novo CNVs from two large independent cohorts of individuals with developmental disorders. The presence of multiple functionally related genes was a significant predictor of a CNV's pathogenicity when compared to CNVs from apparently healthy individuals and a better predictor than the presence of known disease or haploinsufficient genes for larger CNVs. The functionally related genes found in the de novo CNVs belonged to 70% of all clusters of functionally related genes found across the genome. De novo CNVs were more likely to affect functional clusters and affect them to a greater extent than benign CNVs (P = 6 × 10−4). Furthermore, such clusters of functionally related genes are phenotypically informative: Different patients possessing CNVs that affect the same cluster of functionally related genes exhibit more similar phenotypes than expected (P < 0.05). The spanning of multiple functionally similar genes by single CNVs contributes substantially to how these variants exert their pathogenic effects.

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Section: Methods De Novo Cnv Data Setsmentioning

confidence: 99%

The clustering of functionally related genes contributes to CNV-mediated disease

et al. 2015

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“…Some children with ASDs are described as having behavioral differences (eg, in reactivity and social orienting) from the earliest months of life, whereas others present with speech delay in the second year, and still others are described as becoming withdrawn and losing skills after a period of relatively typical development into the second year of life. [22][23][24] There is also heterogeneity at an etiologic level, with hundreds of susceptibility genes 25 and potentially a wide range of environmental and/or epigenetic factors [26][27][28] implicated in ASD causation. The variability in behavioral profiles, developmental course, and underlying etiologic factors must be taken into account when synthesizing findings across studies.…”

Section: Summary Statementsmentioning

confidence: 99%

Early Identification of Autism Spectrum Disorder: Recommendations for Practice and Research

Zwaigenbaum

Bauman

Stone³

et al. 2015

Pediatrics

319

243

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Early identification of autism spectrum disorder (ASD) is essential to ensure that children can access specialized evidence-based interventions that can help to optimize long-term outcomes. Early identification also helps shorten the stressful "diagnostic odyssey" that many families experience before diagnosis. There have been important advances in research into the early development of ASDs, incorporating prospective designs and new technologies aimed at more precisely delineating the early emergence of ASD. Thus, an updated review of the state of the science of early identification of ASD was needed to inform best practice. These issues were the focus of a multidisciplinary panel of clinical practitioners and researchers who completed a literature review and reached consensus on current evidence addressing the question "What are the earliest signs and symptoms of ASD in children aged #24 months that can be used for early identification?" Summary statements address current knowledge on early signs of ASD, potential contributions and limitations of prospective research with high-risk infants, and priorities for promoting the incorporation of this knowledge into clinical practice and future research. Pediatrics 2015;136:S10-S40

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“…Most likely, there are other factors affecting the final phenotype, a concept that is becoming more evident with a number of publications noting more than one CNV among individuals with neurodevelopmental phenotypes. 17 In summary, we report a family with a duplication of 4p13 to 4p12 that appears to segregate with a variable neurodevelopmental phenotype, and an unrelated individual with autism and ADHD with the same duplication. We surmise this is due to duplication of a GABA A receptor subunit gene cluster.…”

Section: Discussionmentioning

confidence: 79%

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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The genetic variability and commonality of neurodevelopmental disease

Cited by 106 publications

References 86 publications

The clustering of functionally related genes contributes to CNV-mediated disease

The clustering of functionally related genes contributes to CNV-mediated disease

Early Identification of Autism Spectrum Disorder: Recommendations for Practice and Research

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

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