Phenotypic spectrum associated with <i><scp>PTCHD1</scp></i> deletions and truncating mutations includes intellectual disability and autism spectrum disorder

Chaudhry, Ayeshah; Noor, Abdul; Degagne, Bryan; Baker, Kate; Bok, Levinus A.; Brady, Angela; Chitayat, David; Chung, Brian Hon‐Yin; Cytrynbaum, Cheryl; Dyment, David A.; Filges, Isabel; Helm, Benjamin M.; Hutchison, H. T.; Jeng, Linda Jo Bone; Laumonnier, Frédéric; Marshall, Christian R.; Menzel, M.; Parkash, Sandhya; Parker, Michael; Raymond, Lucy; Rideout, Andrea L.; Roberts, Wendy; Rupps, Rosemarie; Schanze, Ina; Schrander-Stumpel, C. T. R. M.; Speevak, Marsha; Stavropoulos, Dimitri J.; Stevens, Servi J.C.; Thomas, Elizabeth R.; Toutain, Annick; Vergano, Samantha A. Schrier; Weksberg, Rosanna; Scherer, Stephen W.; Vincent, John B.; Carter, M. T.

doi:10.1111/cge.12482

Cited by 67 publications

(90 citation statements)

References 8 publications

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“…Supporting this possibility, the Hh acyltransferase HHAT has been identified as mutated in whole-exon sequencing and proposed as a candidate gene for ID (Agha et al, 2014). Similarly, PTCHD1, which shares high homology with the Patched receptors, has been suggested as a candidate gene for ASD and ID (Noor et al, 2010;Filges et al, 2011;Chaudhry et al, 2015).…”

Section: Discussionmentioning

confidence: 98%

JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling

et al. 2017

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Components of the KDM7 family of histone demethylases are implicated in neuronal development and one member, PHF8, is often found to be mutated in cases of X-linked mental retardation. However, how PHF8 regulates neurodevelopmental processes and contributes to the disease is still largely unknown. Here, we show that the catalytic activity of a PHF8 homolog in Caenorhabditis elegans, JMJD-1.2, is required non-cell-autonomously for proper axon guidance. Loss of JMJD-1.2 dysregulates transcription of the Hedgehog-related genes wrt-8 and grl-16, the overexpression of which is sufficient to induce the axonal defects. Deficiency of either wrt-8 or grl-16, or reduced expression of homologs of genes promoting Hedgehog signaling, restores correct axon guidance in jmjd-1.2 mutants. Genetic and overexpression data indicate that Hedgehog-related genes act on axon guidance through actin remodelers. Thus, our study highlights a novel function of jmjd-1.2 in axon guidance that might be relevant for the onset of X-linked mental retardation and provides compelling evidence of a conserved function of the Hedgehog pathway in C. elegans axon migration.

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Section: Discussionmentioning

confidence: 98%

JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling

et al. 2017

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“…30 Given our results, we speculate that other variants of modest effect in the gene, located in regulatory regions, may contribute to the susceptibility to ASD.…”

Section: Discussionmentioning

confidence: 53%

“…Although several reports have confirmed a clear involvement of rare deletions or coding indels of PTCHD1 in ASD and ID, 24,25,27,30 it remains unclear whether rare missense variants of this gene may also contribute to the etiology of these disorders. In our study, we screened a Spanish sample of 240 ASD and 183 ID patients for variants in the PTCHD1 gene.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a systematic clinical description of 23 individuals with truncating variants or deletions involving PTCHD1 suggested that these are highly penetrant genetic factors that may cause infantile hypotonia, motor coordination problems, subtle dysmorphic features and a wide range of neurodevelopmental conditions, including ID, ASD and attention deficit hyperactivity disorder. 30 Here, we performed the first analysis of PTCHD1 common variants in ASD through a two-stage case-control association study of 28 SNPs in 994 ASD cases and 1035 controls. Moreover, we aimed to gain additional evidence for the role of rare variants of PTCHD1 in ASD and ID by performing a mutational screening of this gene in a Spanish sample of 240 ASD cases, 183 ID patients and 250 controls.…”

Section: Introductionmentioning

confidence: 99%

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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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“…We identified the following rearrangements: a duplication of NPHP1 gene in 2q13 [8]; a de novo 7q32.3 gain involving PLXNA4 [9]; a 9p24.3 duplication involving KANK1 gene [10]; a duplication of PTCH1 in 9q22 [11]; a 5.8 Mb deletion on 12p12.2p12.1 including SOX5 [12]; a duplication of the 16q24.2 region [13]; an inherited 20p12.1 deletion interrupting the MACROD2 gene [14]; a Xp11.22 duplication involving KDM5C and IQSEC2 [15]; a duplication in Xp22.12 including the RPS6KA3 gene [16]; and the deletion of PTCHD1 in Xp22.11 [17]. …”

Section: Cnvs Affecting Asd/id Associated Genesmentioning

confidence: 99%

A Genome Wide Copy Number Variations Analysis in Autism Spectrum Disorder (Asd) and Intellectual Disability (Id) in Italian Families

Mucciolo¹,

Marco²,

Canitano³

et al. 2016

J Genet Syndr Gene Ther

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Background: Autism Spectrum Disorders (ASD) and Intellectual Disability (ID) represent lifelong conditions with severe impact on behavior and lifestyle of patients and their families. Array comparative genomic hybridization (array-CGH) has clarified the underlying genetic causes of ASD and ID by CNVs identification in several chromosomal regions with susceptibility to different levels of severity of ASD or ID in up to 1% of patients. Methods:Using oligo array-CGH we analyzed 476 unrelated subjects with ASD or ID, thoroughly investigated by both child neuropsychiatrists and clinical geneticists. The inheritance of the CNV was tested in the majority of cases (82% of positive cases).Results: A total of 198 rearrangements were identified in 154 cases. CNVs were classified in three groups: i-CNVs previously known to be associated with ASD or ID (28/198, 14%), including 16p11.2, 15q13.3, 17p12 and 17q12; ii-CNVs including genes known to be associated with either ASD or ID (9/198, 4.5%); iii-CNVs of unknown significance (161/198, 81.3%). Conclusion:Our study confirmed that array-CGH analysis is able to detect the underlying genetic cause in about 18% of ASD or ID patients, highlighting it as an essential diagnostic tool for patient's assessment. Overall, a prevalence of duplications with respect to deletions was observed (62% and 38%, respectively) but among the deleted cases an enrichment of microdeletions in ASD cases (p=0.03) is present. Furthermore, we shown a prevalence of multiple CNVs in ASD cases compared to ID (p=0.05), pointing out the complex nature of ASD.

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Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder

Cited by 67 publications

References 8 publications

JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling

JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling

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

A Genome Wide Copy Number Variations Analysis in Autism Spectrum Disorder (Asd) and Intellectual Disability (Id) in Italian Families

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