Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

O’Roak, Brian J.; Vives, Laura; Fu, Wenqing; Egertson, Jarrett D.; Stanaway, Ian B.; Phelps, Ian G.; Carvill, Gemma L.; Kumar, Akash; Lee, Choli; Ankenman, Katy; Munson, Jeff; Hiatt, Joseph; Turner, Emily H.; Levy, Roie; O’Day, Diana R.; Krumm, Niklas; Coe, Bradley P.; Martin, Beth; Borenstein, Elhanan; Nickerson, Deborah A.; Mefford, Heather C; Doherty, Dan; Akey, Joshua M.; Bernier, Raphael; Eichler, Evan E.; Shendure, Jay

doi:10.1126/science.1227764

Cited by 1,153 publications

(1,256 citation statements)

References 96 publications

Supporting

Mentioning

1,216

Contrasting

Unclassified

Order By: Relevance

“…20,21 Targeted resequencing of WAC Upon identification of the de novo mutation in Individual 1, targeted resequencing was performed on a cohort of 2326 patients with unexplained ID using molecular inversion probes (MIPs) as described previously. 7 This cohort was selected from the in-house collection of the Department of Human Genetics of Radboud University Medical Center (Nijmegen, The Netherlands) containing patients with unexplained ID. Candidate loss-of-function mutations as well as highly conserved missense mutations (PhyloP45) were validated by standard Sanger sequencing approaches on DNA extracted from peripheral blood.…”

Section: Diagnostic Exome Sequencingmentioning

confidence: 99%

“…Targeted resequencing of WAC in an ID cohort identifies additional de novo mutations On the identification of multiple de novo loss-of-function mutations in WAC, we performed targeted resequencing of this gene in a cohort of over 2300 individuals with unexplained ID using MIPs as described before. 7 This cohort was selected from the in-house collection of the Department of Human Genetics of Radboud University Medical Center containing individuals with unexplained ID. All candidate loss-of-function mutations as well as highly conserved missense mutations (PhyloP45) were validated by standard Sanger sequencing approaches.…”

Section: Identification Of Individuals With De Novo Cnvs Affecting Wacmentioning

confidence: 99%

“…To establish the pathogenicity of mutations in such candidate ID genes, it is essential to identify additional individuals with an overlapping phenotype and a mutation in the same gene. [3][4][5] With increasing availability of WES in routine diagnostics 6 as well as technological advances facilitating targeted resequencing of candidate ID genes in larger cohorts of samples, 7 chances of finding such additional individuals are increasing. Furthermore, supporting evidence and insights into underlying mechanisms can be obtained from functional studies in cell or animal models.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

et al. 2016

Self Cite

View full text Add to dashboard Cite

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.

show abstract

Section: Diagnostic Exome Sequencingmentioning

confidence: 99%

Section: Identification Of Individuals With De Novo Cnvs Affecting Wacmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…The other syndrome results from mutations in TBR1, which is involved in cortical development and is co-expressed with FOXP2 in layer 6 of the cortex (Hevner et al 2001;Willsey et al 2013). Both syndromes are characterized by global developmental delay, ID, speech delay and varying degrees of language deficits (O'Roak et al 2011;Traylor et al 2012;Palumbo et al 2013;Palumbo et al 2014;O'Roak et al 2012;Belengeanu et al 2014;Le Fevre et al 2013;Bacon and Rappold 2012). In addition, autistic behaviors are found in all cases with TBR1 disruptions and in some individuals with FOXP1 mutations.…”

Section: Intellectual Disability and Autism Spectrum Disordersmentioning

confidence: 99%

Insights into the Genetic Foundations of Human Communication

2015

View full text Add to dashboard Cite

The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior.

show abstract

“…For example, sequencing was performed on 2446 families with autistic patients from SSC to identify 44 candidate genes. In 6 genes, including CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1, recurrent disruptive mutations were detected (Table 3) [177]. Following this study, almost 3500 probands and their unaffected siblings were resequenced for 64 candidate genes in a case-control design.…”

Section: De Novo Snvs In Asdmentioning

confidence: 99%

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

et al. 2015

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

show abstract

Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

Cited by 1,153 publications

References 96 publications

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

Insights into the Genetic Foundations of Human Communication

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

Contact Info

Product

Resources

About