Discovery of variants unmasked by hemizygous deletions

Hochstenbach, Ron; Poot, Martin; Nijman, Isaäc J; Renkens, Ivo; Duran, Karen; Slot, Ruben vanʼt; Binsbergen, Ellen van; Zwaag, Bert van der; Vogel, Maartje J.; Terhal, Paulien A; Amstel, Hans Kristian Ploos van; Kloosterman, Wigard P.; Cuppen, Edwin

doi:10.1038/ejhg.2011.263

Cited by 20 publications

(25 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…21 The coding regions of three patients with deletions encompassing one or more candidate genes, selected on the basis of their expression in the brain and their function, were further analyzed. No pathogenic variants were detected by sequencing of SMARCA2 and DOCK8 on the non-deleted allele of the girl with the 9p24 deletion.…”

Section: Resultsmentioning

confidence: 99%

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

et al. 2013

View full text Add to dashboard Cite

Copy number variants (CNVs) have repeatedly been found to cause or predispose to autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194 individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we also analyzed candidate genes located in inherited deletions to unmask autosomal recessive variants. Three CNVs, a de novo triplication of chromosome 15q11-q12 of paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were identified as the cause of the disorder in one individual each. An autosomal recessive cause was considered possible in two patients: a homozygous 1p31.1 deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated with a rare hemizygous missense variant. We also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents. Although highly penetrant CNVs or variants inherited in an autosomal recessive manner were detected in rare cases, our results mainly support the hypothesis that most CNVs contribute to ASDs in association with other CNVs or point variants located elsewhere in the genome. Identification of these genetic interactions in individuals with ASDs constitutes a formidable challenge.

show abstract

Section: Resultsmentioning

confidence: 99%

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The first two possibilities suggest that effects of these CNVs will only be revealed in genetic models carrying multiple simultaneous mutations, as has been observed for microcephaly (Golzio et al 2012), whereas the latter suggests that some disorder-relevant phenotypic similarities might be observed by apparently healthy individuals whose CNVs affect disease-relevant clusters to a lesser extent, as observed for autism (Bernier et al 2012). Finally, since the loss of a gene copy can act to reveal a recessive mutation in the remaining haplotype (Hochstenbach et al 2012), where a loss event occurs across a functional cluster, a single recessive mutation in any of the affected functionally similar genes may yield similar phenotypes, with larger CNVs more likely to reveal a mutation within a clustered gene.…”

Section: Discussionmentioning

confidence: 99%

The clustering of functionally related genes contributes to CNV-mediated disease

et al. 2015

View full text Add to dashboard Cite

Clusters of functionally related genes can be disrupted by a single copy number variant (CNV). We demonstrate that the simultaneous disruption of multiple functionally related genes is a frequent and significant characteristic of de novo CNVs in patients with developmental disorders (P = 1 × 10−3). Using three different functional networks, we identified unexpectedly large numbers of functionally related genes within de novo CNVs from two large independent cohorts of individuals with developmental disorders. The presence of multiple functionally related genes was a significant predictor of a CNV's pathogenicity when compared to CNVs from apparently healthy individuals and a better predictor than the presence of known disease or haploinsufficient genes for larger CNVs. The functionally related genes found in the de novo CNVs belonged to 70% of all clusters of functionally related genes found across the genome. De novo CNVs were more likely to affect functional clusters and affect them to a greater extent than benign CNVs (P = 6 × 10−4). Furthermore, such clusters of functionally related genes are phenotypically informative: Different patients possessing CNVs that affect the same cluster of functionally related genes exhibit more similar phenotypes than expected (P < 0.05). The spanning of multiple functionally similar genes by single CNVs contributes substantially to how these variants exert their pathogenic effects.

show abstract

“…A second mechanism may be the inheritance of 2 different, but overlapping, CNVs from 2 healthy parents [Hochstenbach et al, 2012]. Searching for gene mutations by transmitted deletions in a cohort of 20 cases, a single patient with severe mental retardation, lack of speech, microcephaly, cheilognathopalatoschisis, and bilateral hearing loss was found to have inherited 2 losses overlapping with respect to a single gene.…”

mentioning

confidence: 99%

“…Searching for gene mutations by transmitted deletions in a cohort of 20 cases, a single patient with severe mental retardation, lack of speech, microcephaly, cheilognathopalatoschisis, and bilateral hearing loss was found to have inherited 2 losses overlapping with respect to a single gene. Thus, the patient carried a loss of both alleles of the highly conserved heat shock factor binding protein 1 (HSBP1) gene [Hochstenbach et al, 2012].…”

mentioning

confidence: 99%

Late Breaking Chromosomes

Poot¹

2013

Mol Syndromol

View full text Add to dashboard Cite

Discovery of variants unmasked by hemizygous deletions

Cited by 20 publications

References 63 publications

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

The clustering of functionally related genes contributes to CNV-mediated disease

Late Breaking Chromosomes

Contact Info

Product

Resources

About