Contactin 4 as an autism susceptibility locus

Cottrell, Catherine E.; Bir, Natalie; Varga, Elizabeth; Álvarez, Carlos E.; Bouyain, Samuel; Zernzach, Randall; Thrush, Devon Lamb; Evans, Johnna; Trimarchi, Michael; Butter, Eric; Cunningham, David; Gastier‐Foster, Julie M.; McBride, Kim L.; Herman, Gail E.

doi:10.1002/aur.184

Cited by 60 publications

(41 citation statements)

References 46 publications

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“…Families were recruited as previously reported (Cottrell et al, 2011; Smith et al, 2014). Caucasian participants with ADI-R scores and genetic material were used for the current analyses (74 boys, 14 girls, N=88).…”

Section: Methodsmentioning

confidence: 99%

Testing Genetic Modifiers of Behavior and Response to Atomoxetine in Autism Spectrum Disorder with ADHD

et al. 2018

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Background Frequent non-pathogenic genetic variants may act as moderators of phenotypic severity for complex disorders such as autism spectrum disorder (ASD). We previously identified polymorphisms affecting mRNA expression of candidate genes, including tryptophan hydroxylase 2 (TPH2), dopamine beta hydroxylase (DBH), and dopamine transporter (DAT, SLC6A3). Method We compare genotypes and (1) clinical response to atomoxetine, (2) scores from the Autism Diagnostic Interview-Revised (ADI-R), and (3) severity of Attention Deficit Hyperactivity Disorder (ADHD) symptoms in a cohort of patients with ASD from multiple study sites. Results There was no association between CYP2D6 metabolizer status and atomoxetine response. TPH2 rs7305115 genotype was associated with ADI-R Restrictive/Repetitive Behavior score (p=0.03). DBH rs1611115 genotype was associated with ADI-R Social score (p=0.002) and Restrictive/Repetitive Behavior score (p=0.04). The DAT intron 8 5/6 repeat was associated with ADHD symptoms (ABC Hyperactivity p=0.01 and SNAP ADHD p=0.03), replicating a previous finding. Conclusions We find associations between ASD phenotypes and regulatory variants in catecholamine biosynthesis genes. This work may help guide future genetics studies related to ASD.

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Section: Methodsmentioning

confidence: 99%

Testing Genetic Modifiers of Behavior and Response to Atomoxetine in Autism Spectrum Disorder with ADHD

et al. 2018

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“…CNTN4 lies within the region deleted in 3pÀ syndrome (MIM 613792), and rearrangements involving CNTN4 have been described in children with developmental delay, speech delay, or ASD. [34][35][36] EGL527's referring diagnosis of cleft palate is probably due to loss of function of TCOF1, which causes autosomaldominant Treacher Collins syndrome (MIM 606847).…”

Section: Gene Fusions and Phenotypesmentioning

confidence: 99%

Next-Generation Sequencing of Duplication CNVs Reveals that Most Are Tandem and Some Create Fusion Genes at Breakpoints

Newman

Hermetz

Weckselblatt

et al. 2015

The American Journal of Human Genetics

147

127

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Interpreting the genomic and phenotypic consequences of copy-number variation (CNV) is essential to understanding the etiology of genetic disorders. Whereas deletion CNVs lead obviously to haploinsufficiency, duplications might cause disease through triplosensitivity, gene disruption, or gene fusion at breakpoints. The mutational spectrum of duplications has been studied at certain loci, and in some cases these copy-number gains are complex chromosome rearrangements involving triplications and/or inversions. However, the organization of clinically relevant duplications throughout the genome has yet to be investigated on a large scale. Here we fine-mapped 184 germline duplications (14.7 kb-25.3 Mb; median 532 kb) ascertained from individuals referred for diagnostic cytogenetics testing. We performed next-generation sequencing (NGS) and whole-genome sequencing (WGS) to sequence 130 breakpoints from 112 subjects with 119 CNVs and found that most (83%) were tandem duplications in direct orientation. The remainder were triplications embedded within duplications (8.4%), adjacent duplications (4.2%), insertional translocations (2.5%), or other complex rearrangements (1.7%). Moreover, we predicted six in-frame fusion genes at sequenced duplication breakpoints; four gene fusions were formed by tandem duplications, one by two interconnected duplications, and one by duplication inserted at another locus. These unique fusion genes could be related to clinical phenotypes and warrant further study. Although most duplications are positioned head-to-tail adjacent to the original locus, those that are inverted, triplicated, or inserted can disrupt or fuse genes in a manner that might not be predicted by conventional copy-number assays. Therefore, interpreting the genetic consequences of duplication CNVs requires breakpoint-level analysis.

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“…Structural and sequence variations in several members of the contactin gene family were associated with neuropsychiatric disorders (e.g. schizophrenia and autism) (Fernandez et al 2008;Burbach and van der Zwaag 2009;Cottrell et al 2011).…”

Section: Candidate Novel Cnvsmentioning

confidence: 99%

Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

Ghani

Pinto

Lee

et al. 2012

G3 Genes|Genomes|Genetics

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Recently genome-wide association studies have identified significant association between Alzheimer's disease (AD) and variations in CLU, PICALM, BIN1, CR1, MS4A4/MS4A6E, CD2AP, CD33, EPHA1, and ABCA7. However, the pathogenic variants in these loci have not yet been found. We conducted a genome-wide scan for large copy number variation (CNV) in a dataset of Caribbean Hispanic origin (554 controls and 559 AD cases that were previously investigated in a SNP-based genome-wide association study using Illumina HumanHap 650Y platform). We ran four CNV calling algorithms to obtain high-confidence calls for large CNVs (.100 kb) that were detected by at least two algorithms. Global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications, total or average CNV size; or number of genes affected by CNVs. However, we observed a nominal association between AD and a 470 kb duplication on chromosome 15q11.2 (P = 0.037). This duplication, encompassing up to five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1, and WHAMML1) was present in 10 cases (2.6%) and 3 controls (0.8%). The dosage increase of CYFIP1 and NIPA1 genes was further confirmed by quantitative PCR. The current study did not detect CNVs that affect novel AD loci identified by recent genome-wide association studies. However, because the array technology used in our study has limitations in detecting small CNVs, future studies must carefully assess novel AD genes for the presence of disease-related CNVs. Alzheimer's disease (AD) is the most common form of dementia, affecting 30% of individuals over 80 years of age (Mayeux 2003). The hallmark of AD brain pathology is characterized by the accumulation of a neurotoxic proteolytic derivative of the amyloid precursor protein (APP; Ab peptides) and the formation of intraneuronal tau-associated neurofibrillary tangles. The majority of AD cases are sporadic (95%), with onset after 65 years of age. One half of the genetic variance is attributable to mutations in APP, PSEN1, PSEN2, and the APOE e4-allele, and they have been shown to cause the overproduction or reduced clearance of Ab (Rogaeva et al. 2006). More recently, it was demonstrated that single nucleotide polymorphisms (SNP) in SORL1 are significantly associated with late-onset AD in several independent cohorts (Rogaeva et al. 2007;Reitz et al. 2011). In addition,

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Contactin 4 as an autism susceptibility locus

Cited by 60 publications

References 46 publications

Testing Genetic Modifiers of Behavior and Response to Atomoxetine in Autism Spectrum Disorder with ADHD

Testing Genetic Modifiers of Behavior and Response to Atomoxetine in Autism Spectrum Disorder with ADHD

Next-Generation Sequencing of Duplication CNVs Reveals that Most Are Tandem and Some Create Fusion Genes at Breakpoints

Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

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