Recurrent 16p11.2 microdeletions in autism.

By Ravinesh A. Kumar, Samer Karamohamed, Jyotsna Sudi, D. Conrad, Camille W. Brune, J. Badner, T. Gilliam, N. Nowak, Edwin H. Cook Jr., W. Dobyns and 1 more. Human Molecular Genetics, 2007

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Autism is a childhood neurodevelopmental disorder with a strong genetic component, yet the identification of autism susceptibility loci remains elusive. We investigated 180 autism probands and 372 control subjects by array comparative genomic hybridization (aCGH) using a 19K whole-genome tiling path bacterial artificial chromosome microarray to identify submicroscopic chromosomal rearrangements specific to autism. We discovered a recurrent 16p11.2 microdeletion in two probands with autism and none in controls. The deletion spans approximately 500-kb and is flanked by approximately 147-kb segmental duplications (SDs) that are >99% identical, a common characteristic of genomic disorders. We assessed the frequency of this new autism genomic disorder by screening an additional 532 probands and 465 controls by quantitative PCR and identified two more patients but no controls with the microdeletion, indicating a combined frequency of 0.6% (4/712 autism versus 0/837 controls; Fisher exact test P = 0.044). We confirmed all 16p11.2 deletions using fluorescence in situ hybridization, microsatellite analyses and aCGH, and mapped the approximate deletion breakpoints to the edges of the flanking SDs using a custom-designed high-density oligonucleotide microarray. Bioinformatic analysis localized 12 of the 25 genes within the microdeletion to nodes in one interaction network. We performed phenotype analyses and found no striking features that distinguish patients with the 16p11.2 microdeletion as a distinct autism subtype. Our work reports the first frequency, breakpoint, bioinformatic and phenotypic analyses of a de novo 16p11.2 microdeletion that represents one of the most common recurrent genomic disorders associated with autism to date.

Subfields: Cognitive Neuroscience, Genetics, Plant Science

View Paper: https://www.semanticscholar.org/paper/b66f8b3bd03821d2d36ec038c1627fefd70bcb61

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Citations in the corpus

Uncovering the roles of rare variants in common disease through whole-genome sequencing (2010, background): “The CNVs that have recently been implicated in many common diseases generally have population frequencies that are considerably below this threshol”
Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci (2015, background): “All eight loci (Table 2) have previously been implicated in ASD (Bucan et al., 2009; Kumar et al., 2008; Leblond et al., 2014; Marshall et al., 2008; Mefford et al., 2008; Moreno-De-Luca et al., 2013b; Sanders et al., 2011; Weiss et al., 2008).”
Whole population, genome-wide mapping of hidden relatedness. (2009, neutral): “Human genome length taken from ( Kong, Murphy, Raj, He, White and Matise 2004 )”
A recurrent 16p12.1 microdeletion suggests a two-hit model for severe developmental delay (2010, background): “2 associated with autism-spectrum disorders and intellectual disabilit”
Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. (2011, background): “Given the strong male predominance and increased rates of ASD in monogenic X-linked intellectual disability syndromes, we paid particular attention to rare de novo CNVs on the X chromosome but found only 2 events: one genic deletion present in a male at the gene DDX53 and a duplication involving 6 g”
Heritability in the Era of Molecular Genetics: Some Thoughts for Understanding Genetic Influences on Behavioural Traits (2011, background): “Their involvement is increasingly suspected in major behavioural disorders such as schizophrenia and autism (Sebat et al., 2007; International Schizophrenia Consortium, 2008; Kumar et al., 2008; Morrow et al., 2008; Stefansson et al., 2008; Walsh et al., 2008; Xu et al., 2008).”
Human genetic variation and its contribution to complex traits (2009, background): “2 that was observed in multiple unrelated individuals with autism and was estimated to account for 1% of the case”