Strong Association of De Novo Copy Number Mutations with Autism

Sebat, Jonathan; Lakshmi, B.; Malhotra, Dheeraj; Troge, Jennifer; Lese-Martin, Christa; Walsh, Tom; Yamrom, Boris; Yoon, Seungtai; Krasnitz, A.; Kendall, Jude; Leotta, Anthony; Pai, Deepa; Zhang, Ray; Lee, Yoonha; Hicks, James; Spence, Sarah; Lee, Annette T.; Puura, Kaija; Lehtimäki, Terho; Ledbetter, David H.; Gregersen, Peter K.; Bregman, Joel D.; Sutcliffe, James S.; Jobanputra, Vaidehi; Chung, Wendy K.; Warburton, Dorothy; King, Mary Claire; Skuse, David; Geschwind, Daniel H.; Gilliam, T. Conrad; Ye, Kenny; Wigler, Michael

doi:10.1126/science.1138659

Cited by 2,553 publications

(2,190 citation statements)

References 30 publications

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“…[35][36][37][38][39][40][41][42][43] Within our associated region, a segmental duplication is reported, 44 which is situated between the two associated regions on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background and caused a 223-kb gap not genotyped in our study. This segmental duplication has, to our knowledge, not been studied regarding human diseases.…”

Section: Discussionmentioning

confidence: 58%

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

et al. 2009

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The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1*0401-DQA1*03-DQB1*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.

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Section: Discussionmentioning

confidence: 58%

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

et al. 2009

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“…These cytogenetic abnormalities are observed in chromosomes 5p15, 15q11–q13, 17p11, and 22q11.2 (Jacquemont et al., 2006; Sebat et al., 2007). Abnormalities affecting the 15q11–q13 region represent the most frequent variation associated with ASD accounting for close to 1% of all ASD cases (Badescu et al., 2016).…”

Section: Reviewmentioning

confidence: 99%

“…Besides structural rearrangements, other abnormalities of chromosomal numbers or aneuploidies are detected in ASD including trisomy 21, Turner syndrome (45, X), and Klinefelter syndrome (47, XXY; Devlin & Scherer, 2012). Thanks to the comparative genomic hybridization (CGH) technique or SNPs array, CNVs were also found in multiple chromosomal regions at 1q21.1, 16p11.2, 17q12, and 22q11.2 (Jacquemont et al., 2006; Marshall et al., 2008; Matsunami et al., 2013; O'Roak et al., 2012; Pinto et al., 2010; Sebat et al., 2007). Further studies supported the association with ASD of two recurrent de novo CNVs at 16p11.2 (duplication and deletion) and 7q11.23 (duplication; Levy et al., 2011; Sanders Stephan et al., 2011).…”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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“…6,7 New molecular techniques, such as array comparative genomic hybridization (CGH), seem to help increase the rate of genetic diagnosis, particularly in individuals where autism is accompanied by malformations or dysmorphic features. 8 Moreover, the deletions and duplications detected in ASD patients may point to new disease genes involved in non-syndromic cases 9 and it has been shown that functional de novo mutations occur in ASDs at higher frequency than expected. 10 ASD is sometimes associated with fragile X syndrome (MIM #300624), tuberous sclerosis (MIM #191100), and cytogenetically detectable chromosome abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

et al. 2012

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Autism spectrum disorders (ASDs) include three main conditions: autistic disorder (AD), pervasive developmental disorder, not otherwise specified (PDD-NOS), and Asperger syndrome. It has been shown that many genes associated with ASDs are involved in the neuroligin-neurexin interaction at the glutamate synapse: NLGN3, NLGN4, NRXN1, CNTNAP2, and SHANK3. We screened this last gene in two cohorts of ASD patients (133 patients from US and 88 from Italy). We found 5/221 (2.3%) cases with pathogenic alterations: a 106 kb deletion encompassing the SHANK3 gene, two frameshift mutations leading to premature stop codons, a missense mutation (p.Pro141Ala), and a splicing mutation (c.1820-4 G4A). Additionally, in 17 patients (7.7%) we detected a c.1304 þ 48C4T transition affecting a methylated cytosine in a CpG island. This variant is reported as SNP rs76224556 and was found in both US and Italian controls, but it results significantly more frequent in our cases than in the control cohorts. The variant is also significantly more common among PDD-NOS cases than in AD cases. We also screened this gene in an independent replication cohort of 104 US patients with ASDs, in which we found a missense mutation (p.Ala1468Ser) in 1 patient (0.9%), and in 8 patients (7.7%) we detected the c.1304 þ 48C4T transition. While SHANK3 variants are present in any ASD subtype, the SNP rs76224556 appears to be significantly associated with PDD-NOS cases. This represents the first evidence of a genotype-phenotype correlation in ASDs and highlights the importance of a detailed clinical-neuropsychiatric evaluation for the effective genetic screening of ASD patients.

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Strong Association of De Novo Copy Number Mutations with Autism

Cited by 2,553 publications

References 30 publications

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

Autism throughout genetics: Perusal of the implication of ion channels

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

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