Refining analyses of copy number variation identifies specific genes associated with developmental delay

By Bradley P. Coe, Kali T. Witherspoon, J. Rosenfeld, B. V. van Bon, A. V. Vulto-van Silfhout, P. Bosco, K. Friend, Carl A. Baker, S. Buono, L. M. Vissers and 29 more. Nature Genetics, 2014

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Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0d99ea9a69f47b761e7535cf0f890ee92b88cbe3

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Citations in the corpus

Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations. (2016, background): “Similarly, for the same deletion, Coe et al.19 reported a population frequency of 17/ 13,347 samples (MAF 0.06%, 17/26,694 alleles), including 8,822 of presumed European ethnicity (ARIC and Wellcome Trust Case Control Consortium, WTCCC2 project samples from National Blood Donors).”
Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci (2015, methodology): “Neu The majority of these CNV loci are also associated with developmental delay (Coe et al., 2014) and, to a lesser extent, schizophrenia.”
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2019, methodology): “4 locus have been observed in NDD, ASD, and otodental dysplasia (Coe et al., 2014; Cooper et al., 2011).”