A CGG-Repeat Expansion Mutation in<i>ZNF713</i>Causes FRA7A: Association with Autistic Spectrum Disorder in two Families

Metsu, Sofie; Rainger, Jacqueline K.; Debacker, Kim; Bernhard, Birgitta; Rooms, Liesbeth; Grafodatskaya, Daria; Weksberg, Rosanna; Fombonne, Éric; Taylor, Martin S.; Scherer, Stephen W.; Kooy, R. Frank; FitzPatrick, David R.

doi:10.1002/humu.22683

Cited by 27 publications

(32 citation statements)

References 20 publications

(26 reference statements)

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“…In the field of autism, point mutation is the top priority in the researches related with pathological genetic characteristics [24][25][26]. Several human syndromes derived from a single gene mutation increase the risk for ASD: such as fragile X-chromosome syndrome…”

Section: Discussionmentioning

confidence: 99%

Copy number variations independently induce autism spectrum disorder

et al. 2017

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Correspondence : Sun Xiaofang (xiaofangsun@hotmail.com) The examination of copy number variation (CNV) is critical to understand the etiology of the CNV-related autism spectrum disorders (ASD). DNA samples were obtained from 64 ASD probands, which were genotyped on an Affymetrix CytoScan HD platform. qPCR or FISH were used as a validation for some novel recurrent CNVs. We further compared the clinical phenotypes of the genes in the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER) database with these overlapping genes. Using vast, readily available databases with previously reported clinically relevant CNVs from human populations, the genes were evaluated using Enrichment Analysis and GO Slim Classification. By using the Ploysearch2 software, we identified the interaction relationship between significant genes and known ASD genes. A total of 29 CNVs, overlapping with 520 genes, including 315 OMIM genes, were identified. Additionally, myocyte enhancer factor 2 family (MEF2C) with two cases of CNV overlapping were also identified. Enrichment analysis showed that the 520 genes are most likely to be related to membrane components with protein-binding functions involved in metabolic processes. In the interaction network of those genes, the known ASD genes are mostly at the core position and the significant genes found in our samples are closely related to the known ASD genes. CNVs should be an independent factor to induce autism. With the strategy of our study, we could find the ASDs candidate genes by CNV data and review certain pathogenesis of this disorder. Those CNVs were associated with ASD and they may contribute to ASD by affecting the ASD-related genes.

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Section: Discussionmentioning

confidence: 99%

Copy number variations independently induce autism spectrum disorder

et al. 2017

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“… 3 A firm link has yet to be established between the repeat expansion mutation and symptoms of autism spectrum disorder reported in 2 families [141]. …”

Section: Figmentioning

confidence: 99%

The Repeat Expansion Diseases: The dark side of DNA repair

Zhao

Usdin

2015

DNA Repair

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DNA repair normally protects the genome against mutations that threaten genome integrity and thus cell viability. However, growing evidence suggests that in the case of the Repeat Expansion Diseases, disorders that result from an increase in the size of a disease-specific microsatellite, the disease-causing mutation is actually the result of aberrant DNA repair. A variety of proteins from different DNA repair pathways have thus far been implicated in this process. This review will summarize recent findings from patients and from mouse models of these diseases that shed light on how these pathways may interact to cause repeat expansion.

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“…To investigate whether these epivariations were attributable to expansions of an underlying TR, we obtained DNA samples from four individuals in whom we had identified hypermethylated epivariations overlapping putatively unstable CGG repeats and performed long-read WGS using either Pacific Biosciences SMRT sequencing or Oxford Nanopore Technology (ONT). In all four samples tested, we confirmed the presence of a heterozygous TR expansion comprising several hundred copies of CGG at the epivariation ( Figure 6, Table S10) FRA16A (XYLT1), FRAXA (FMR1), FRAXE (AFF2), and FRAXF (TMEM185A) 16,17,45,[18][19][20]37,40,41,43,44 . We thus hypothesized that novel CGG expansions might underlie other FSFS.…”

Section: Prediction and Validation Of Novel Cgg Expansions At Hypermementioning

confidence: 54%

A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and novel CGG expansions

Garg

Jadhav

Rodriguez

et al. 2020

Preprint

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There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ~1 in 3,000 and ~1 in 6,000 respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of SNV data and monozygous twin pairs suggests that approximately two thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one third are likely sproradic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, and validated the presence of novel CGG expansions at several of these, identifying the molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many novel hypermethylated CGG repeat expansions.

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A CGG-Repeat Expansion Mutation inZNF713Causes FRA7A: Association with Autistic Spectrum Disorder in two Families

Cited by 27 publications

References 20 publications

Copy number variations independently induce autism spectrum disorder

Copy number variations independently induce autism spectrum disorder

The Repeat Expansion Diseases: The dark side of DNA repair

A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and novel CGG expansions

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