Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome

Mlynarski, Elisabeth E.; Xie, Michael; Taylor, Deanne; Sheridan, Molly B.; Guo, Tingwei; Racedo, Silvia E.; McDonald‐McGinn, Donna M.; Chow, Eva W.C.; Vorstman, Jacob; Swillen, Ann; Devriendt, Koen; Breckpot, Jeroen; Digilio, María Cristina; Marino, Bruno; Dallapiccola, Bruno; Philip, Nicole; Simon, Tony J.; Roberts, Amy; Piotrowicz, Małgorzata; Bearden, Carrie E.; Eliez, Stéphan; Gothelf, Doron; Coleman, Karlene; Kates, Wendy R.; Devoto, Marcella; Zackai, Elaine H.; Suñer, Damian Heine-; Goldmuntz, Elizabeth; Bassett, Anne S.; Morrow, Bernice E.; Emanuel, Beverly S.

doi:10.1007/s00439-015-1623-9

Cited by 50 publications

(72 citation statements)

References 54 publications

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“…Recent evidence suggests a role for additional genetic variants that modify risk for congenital heart defects in some patients with the deletion [22]. Conversely, other studies have found no evidence of an increase in novel genome-wide CNVs in patients with the 22q11.2 deletion [23].…”

Section: Discussionmentioning

confidence: 99%

Incidence of the 22q11.2 deletion in a large cohort of miscarriage samples

et al. 2017

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BackgroundThe 22q11.2 deletion syndrome is the most common microdeletion syndrome in livebirths, but data regarding its incidence in other populations is limited and also include ascertainment bias. This study was designed to determine the incidence of the 22q11.2 deletion in miscarriage samples sent for clinical molecular cytogenetic testing.ResultsTwenty-six thousand one hundred one fresh product of conception (POC) samples were sent to a CLIA- certified, CAP-accredited laboratory from April 2010–-May 2016 for molecular cytogenetic miscarriage testing using a single-nucleotide polymorphism (SNP)-based microarray platform. A retrospective review determined the incidence of the 22q11.2 deletion in this sample set. Fetal results were obtained in 22,451 (86%) cases, of which, 15 (0.07%) had a microdeletion in the 22q11.2 region (incidence, 1/1497). Of those, 12 (80%) cases were found in samples that were normal at the resolution of traditional karyotyping (i.e., had no chromosome abnormalities above 10 Mb in size) and three (20%) cases had additional findings (Trisomy 15, Trisomy 16, XXY). Ten (67%) cases with a 22q11.2 deletion had the common ~3 Mb deletion; the remaining 5 cases had deletions ranging in size from 0.65 to 1.5 Mb. A majority (12/15) of cases had a deletion on the maternally inherited chromosome. No significant relationship between maternal age and presence of a fetal 22q11.2 deletion was observed.ConclusionsThe observed incidence of 1/1497 for the 22q11.2 deletion in miscarriage samples is higher than the reported general population prevalence (1/4000–1/6000). Further research is needed to determine whether the 22q11.2 deletion is a causal factor for miscarriage.

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Section: Discussionmentioning

confidence: 99%

Incidence of the 22q11.2 deletion in a large cohort of miscarriage samples

et al. 2017

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“…Subjects with a presumed 22q11.2 deletion were recruited from 22 international sites (Table S1) and provided DNA samples that were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0 at the Albert Einstein College of Medicine (13). Informed consent was obtained from all subjects and/or their legal guardian.…”

Section: Methodsmentioning

confidence: 99%

“…A goal of the International 22q11.2DS Brain and Behavior Consortium (IBBC) (12) is to discover additional genetic factors that contribute to the high risk for schizophrenia in the 22q11.2DS population. Emerging research suggests that additional rare CNVs elsewhere in the genome may shape the expression of cardiac phenotypes associated with 22q11.2DS (13). In the current study, we used high-resolution genome-wide microarrays and proven CNV detection methods (14) to identify rare CNVs that may be involved in the expression of schizophrenia in 22q11.2DS.…”

Section: Introductionmentioning

confidence: 99%

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome

Bassett¹,

Lowther²,

Merico³

et al. 2017

AJP

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Objective 22q11.2 deletion syndrome (22q11.2DS) is associated with a >20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., “second hits”) that may contribute to schizophrenia expression. Methods Through an international consortium we obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), we compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: with and, at age ≥25 years, without a psychotic disorder. We assessed whether genes overlapped by rare CNVs were over-represented in functional pathways relevant to schizophrenia. Results Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene-sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a step-wise logistic regression model (p=0.00062) and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had on average more genes overlapped (p=0.0058). The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. Conclusions The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness, and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

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“…One of the most compelling theories considers the influence of the anomalies in genes from the intact 22q11.2 region, as well as additional modifying variants located outside the 22q11.2 region, involving both proteincoding genes and regulatory mechanisms (Goldmuntz et al, 2009). For example, studies evaluating common and rare copy number variants and single nucleotide polymorphisms (SNPs), found that duplications of the glucose transporter gene SLC2A3 have been demonstrated to increase the risk of CHD in patients with 22q11.2DS (Mlynarski et al, 2015, 2016). Another study suggested that rare deleterious SNPs in histone modification-related genes might modify the cardiovascular phenotype in 22q11.2DS (Guo et al, 2015).…”

Section: Genes and Pathogenesis Of The Cardiovascular Phenotypementioning

confidence: 99%

Congenital heart diseases and cardiovascular abnormalities in 22q11.2 deletion syndrome: From well‐established knowledge to new frontiers

Unolt

Versacci

Anaclerio

et al. 2018

American J of Med Genetics Pt A

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Congenital heart diseases (CHDs) and cardiovascular abnormalities are one of the pillars of clinical diagnosis of 22q11.2 deletion syndrome (22q11.2DS) and still represent the main cause of mortality in the affected children. In the past 30 years, much progress has been made in describing the anatomical patterns of CHD, in improving their diagnosis, medical treatment, and surgical procedures for these conditions, as well as in understanding the underlying genetic and developmental mechanisms. However, further studies are still needed to better determine the true prevalence of CHDs in 22q11.2DS, including data from prenatal studies and on the adult population, to further clarify the genetic mechanisms behind the high variability of phenotypic expression of 22q11.2DS, and to fully understand the mechanism responsible for the increased postoperative morbidity and for the premature death of these patients. Moreover, the increased life expectancy of persons with 22q11.2DS allowed the expansion of the adult population that poses new challenges for clinicians such as acquired cardiovascular problems and complexity related to multisystemic comorbidity. In this review, we provide a comprehensive review of the existing literature about 22q11.2DS in order to summarize the knowledge gained in the past years of clinical experience and research, as well as to identify the remaining gaps in comprehension of this syndrome and the possible future research directions.

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Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome

Cited by 50 publications

References 54 publications

Incidence of the 22q11.2 deletion in a large cohort of miscarriage samples

Incidence of the 22q11.2 deletion in a large cohort of miscarriage samples

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome

Congenital heart diseases and cardiovascular abnormalities in 22q11.2 deletion syndrome: From well‐established knowledge to new frontiers

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