Disruption at the
            <i>PTCHD1</i>
            Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability

Noor, Abdul; Whibley, Annabel; Marshall, Christian R.; Gianakopoulos, Peter J.; Piton, Amélie; Carson, Andrew R.; Orlic-Milacic, M; Lionel, Anath C.; Sato, Daisuke; Pinto, Dalila; Drmic, Irene; Noakes, Carolyn; Senman, Lili; Zhang, Xiaoyun; Mo, Rong; Gauthier, Julie; Crosbie, Jennifer; Pagnamenta, Alistair T.; Munson, Jeffrey; Estes, Annette; Fiebig, Andreas; Franke, André; Schreiber, Stefan; Stewart, Alexandre F.R.; Roberts, Robert J.; McPherson, Ruth; Guter, Stephen J.; Cook, Edwin H.; Dawson, Geraldine; Schellenberg, Gerard D.; Battaglia, Agatino; Maestrini, Elena; Jeng, Linda Jo Bone; Hutchison, Terry; Rajcan‐Separovic, Evica; Chudley, Albert E.; Sm, Lewis; Li, Xudong; Holden, J. J. A.; Fernandez, Bridget A.; Zwaigenbaum, Lonnie; Bryson, Susan E.; Roberts, Wendy; Szatmári, Péter; Gallagher, Louise; Stratton, Michael R.; Gécz, Jozef; Brady, Angela; Schwartz, Charles E.; Schachar, Russell; Monaco, Anthony P.; Rouleau, Guy A.; Hui, Chi‐chung; Raymond, F. Lucy; Scherer, Stephen W.; Vincent, John B.

doi:10.1126/scitranslmed.3001267

Cited by 170 publications

(189 citation statements)

References 38 publications

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“…In addition, some sex-specific factors have been shown in genetic or molecular analyses of ASD. For example, a recent study identified maternally inherited X-linked microdeletions and missense mutations in the PTCHD1 gene in only male ASD probands which were not observed in controls [Noor et al, 2010].Based on the hypothesis that affected males and females carry at least some distinct genetic components for ASD, several familybased linkage studies and/or subsequent follow-up studies of ASD divided families into two groups, those in which only males were affected (Male-only; MO) and those having at least one affected female (Female-containing; FC) [Stone et al, 2004;Stone et al, 2007;Alarcon et al, 2008;Strom et al, 2010]. These linkage studies tested the hypothesis of sex-predominant genetic heterogeneity by stratifying the analysis according to the sex of the affected individuals, and identified a male-specific linkage peak at chromosome 17q11.…”

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Sex‐specific association of a common variant of the XG gene with autism spectrum disorders

Chang

Pauls

Lange

et al. 2013

American J of Med Genetics Pt B

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Autism spectrum disorders (ASD) are much more common in males than in females. Studies using both linkage and candidate gene association approaches have identified genetic variants specific to families in which all affected cases were male, suggesting that sex may interact with or otherwise influence the expression of specific genes in association with ASD. In this study, we specifically evaluated the sex-specific genetic effects of ASD with a family-based genome-wide association study approach using the data from the Autism Genetic Resource Exchange repository. We evaluated the male-specific genetic effects of ASD in 374 multiplex families of European ancestry in which all affected were male (male-only; MO) and identified a novel genome-wide significant association in the pseudoautosomal boundary on chromosome Xp22.33/Yp11.31 in the MO families of predominantly paternal origin (rs2535443, p ¼ 3.8 Â 10 À8 ). Five markers that reside within a 550 kb intergenic region on chromosome 13q33.3, between the MYO16 and IRS2 genes, also showed suggestive association with ASD in the MO families (p ¼ 3.3 Â 10 À5 to 5.3 Â 10 À7 ). In contrast, none of these markers appeared to be associated with ASD in the families containing any affected females. Our results suggest that the pseudoautosomal boundary on Xp22.33/Yp11.31 may harbor male-specific genetic variants for ASD. Ó 2013 Wiley Periodicals, Inc.Key words: autism; GWAS; sex-specific; pseudoautosomal INTRODUCTIONAutism spectrum disorders (ASD) are neurodevelopmental disorders characterized by clinical symptoms of diverse impairments in social interactions, reciprocal communication, and repetitive and stereotyped patterns of behaviors and interests. Numerous studies have affirmed the heritability of ASDs. Evidence indicates that ASD has complex inheritance patterns [Bailey et al., 1995;Fombonne, 2005;Lauritsen et al., 2005;Freitag, 2007]. Yet despite the high heritability estimate of over 90% [Bailey et al., 1995], genetic variants that have been reported to be associated with ASD have either failed to be replicated or accounted for only a small proportion of cases [Santangelo and Tsatsanis, 2005]. Furthermore, the wide range of clinical manifestations of ASD suggests that it may in fact comprise multiple disorders that have separate etiologies but share behavioral commonalities. This phenotypic heterogeneity How to Cite this Article: 742Neuropsychiatric Genetics may imply genetic heterogeneity and may at least partially explain the limited success in consistently identifying common genetic variants of ASD in prior studies. Recent studies suggest that approximately 10-15% of ASD may be due to genetic syndromes with known comorbidities with ASD (e.g., fragile X syndrome, tuberous sclerosis) or rare chromosomal abnormalities [Folstein and Rosen-Sheidley, 2001;Freitag, 2007], while the etiology of the majority of familial ASD cases remains unclear. One potentially more efficient approach to identify susceptibility loci for ASD is to separate samples into more homogenous subgr...

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Sex‐specific association of a common variant of the XG gene with autism spectrum disorders

Chang

Pauls

Lange

et al. 2013

American J of Med Genetics Pt B

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“…Locus disruptions in the PTCHD1 gene have been associated with several forms of autism (Filges 2011;Noor 2010). Currently, several other genes are being researched, as the pathogenesis of autism likely involves the derailment of some of the processes of synaptic plasticity, maturation of neuron signaling, myelination, and neurite outgrowth during development.…”

Section: The Second Neurogenetic Phase: the Continuum Of Neuron-basedmentioning

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The Neurogenetic Substructures of Human Consciousness

Grandy¹

2014

Essays Philos

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There are many interpretations of what consciousness is. In the past decade materialist and reductionist theories have gained in popularity as many neurological correlates of consciousness have been identified experimentally. This article presents a neurogenetic account of the underpinnings of neuron-based consciousness. In this paradigm, human consciousness is supported by genes that are involved in three distinct neurogenetic phases: 1) the emergence of neuron-based consciousness, 2) the continuum of neuronbased consciousness, and 3) the neurodegeneration of human consciousness. The methodology implemented to establish these three neurogenetic phases was a systematic search and evaluation of genes that have been proven to support an active role in one or more of these three phases. This article demonstrates that there is a substructure of gene-based correlates that functions in the three neurogenetic phases. These phases work in tandem with the conscious experience. Consequently, it is established that explanations of human consciousness that rely solely on regions of the brain and neurons are deficient without taking into consideration the neurogenetic element of human consciousness. This presentation of the neurogenetic dimensions of human consciousness is the first of its kind.

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“…PTCHD1 maps on chromosome Xp22.11 and encodes the patched domain containing protein 1 (PTCHD1), which is mainly expressed in the developing brain and in adult brain tissues, with the highest expression in the cerebellum. 24 PTCHD1 has been suggested to be implicated in Hedgehog (Hh) signalling, inhibiting Gli-dependent transcription in a similar way as its homologues PTCH1 and PTCH2. 24 Deletions spanning the gene have been reported in ASD and ID patients.…”

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confidence: 99%

Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability

et al. 2015

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Recent findings revealed rare copy number variants and missense changes in the X-linked gene PTCHD1 in autism spectrum disorder (ASD) and intellectual disability (ID). Here, we aim to explore the contribution of common PTCHD1 variants in ASD and gain additional evidence for the role of rare variants of this gene in ASD and ID. A two-stage case-control association study investigated 28 tag single nucleotide polymorphisms (SNPs) in 994 ASD cases and 1035 controls from four European populations. Mutation screening was performed in 673 individuals who included 240 ASD cases, 183 ID patients and 250 controls. The case-control association study showed a significant association with rs7052177 (P = 6.13E-4) in the ASD discovery sample that was replicated in an independent sample (P = 0.03). A Mantel-Haenszel meta-analysis for rs7052177T considering the four European populations showed an odds ratio of 0.58 (P = 7E-05). This SNP is predicted to be located in a transcription factor binding site. No rare missense PTCHD1 variants were found in our ASD cohort and only one was identified in the ID sample. A duplication (27 bp) in the promoter region, absent from 590 controls, was found in three ASD patients (Fisher exact test, P = 0.024). A gene reporter assay showed a significant decrease in the transcriptional activity (26%) driven by this variant. Moreover, we found that the longest allele of a trinucleotide repeat located upstream from PTCHD1 was associated with ASD (P = 0.003, permP = 0.0186). Our results further support the involvement of PTCHD1 in ASD, suggesting that both common and rare variants contribute to the disorder. INTRODUCTIONAutism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by impairments in reciprocal social interaction, verbal and non-verbal communication and stereotyped patterns of behavior. The prevalence for ASD is estimated to be about 0.5-1%, and it is approximately four times more frequent in males than in females. [1][2][3] Family and twin studies in recent decades have provided strong evidence showing that ASD is one of the most heritable neuropsychiatric disorders. Sibling recurrence risk is approximately 20%, and concordance among twins may range from 76 to 88% for monozygotic twins and from 0 to 31% for dizygotic twins, depending on phenotypic criteria. 4,5 The genetic model for idiopathic autism is complex. Recent studies suggest that at least 1000 genes contribute to the disorder, with a combination of common variants of small to moderate effect and rare variants with potential larger effect sizes. 6,7

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Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability

Abstract: Mutations of the X-linked gene PTCHD1 are associated with autism spectrum disorders and intellectual disability.

Cited by 170 publications

References 38 publications

Sex‐specific association of a common variant of the XG gene with autism spectrum disorders

Sex‐specific association of a common variant of the XG gene with autism spectrum disorders

The Neurogenetic Substructures of Human Consciousness

Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability

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