Dataset Information

Association of copy number variants with specific ultrasonographically detected fetal anomalies.

ABSTRACT: To evaluate the association of other-than-common benign copy number variants with specific fetal abnormalities detected by ultrasonogram.Fetuses with structural anomalies were compared with fetuses without detected abnormalities for the frequency of other-than-common benign copy number variants. This is a secondary analysis from the previously published National Institute of Child Health and Human Development microarray trial. Ultrasound reports were reviewed and details of structural anomalies were entered into a nonhierarchical web-based database. The frequency of other-than-common benign copy number variants (ie, either pathogenic or variants of uncertain significance) not detected by karyotype was calculated for each anomaly in isolation and in the presence of other anomalies and compared with the frequency in fetuses without detected abnormalities.Of 1,082 fetuses with anomalies detected on ultrasound scan, 752 had a normal karyotype. Other-than-common benign copy number variants were present in 61 (8.1%) of these euploid fetuses. Fetuses with anomalies in more than one system had a 13.0% frequency of other-than-common benign copy number variants, which was significantly higher (P<.001) than the frequency (3.6%) in fetuses without anomalies (n=1,966). Specific organ systems in which isolated anomalies were nominally significantly associated with other-than-common benign copy number variants were the renal (P=.036) and cardiac systems (P=.012) but did not meet significance after the adjustment.When a fetal anomaly is detected on ultrasonogram, chromosomal microarray offers additional information over karyotype, the degree of which depends on the organ system involved.: II.

SUBMITTER: Donnelly JC

PROVIDER: S-EPMC4111105 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Association of copy number variants with specific ultrasonographically detected fetal anomalies.

Donnelly Jennifer C JC Platt Lawrence D LD Rebarber Andrei A Zachary Julia J Grobman William A WA Wapner Ronald J RJ

Obstetrics and gynecology 20140701 1

<h4>Objective</h4>To evaluate the association of other-than-common benign copy number variants with specific fetal abnormalities detected by ultrasonogram.<h4>Methods</h4>Fetuses with structural anomalies were compared with fetuses without detected abnormalities for the frequency of other-than-common benign copy number variants. This is a secondary analysis from the previously published National Institute of Child Health and Human Development microarray trial. Ultrasound reports were reviewed an ...[more]

PMID: 24901266

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Project description:Copy number variants (CNVs) are a type of polymorphism found to underlie phenotypic variation, both in humans and livestock. Most surveys of CNV in livestock have been conducted in the cattle genome, and often utilise only a single approach for the detection of copy number differences. Here we performed a study of CNV in sheep, using multiple methods to identify and characterise copy number changes. Comprehensive information from small pedigrees (trios) was collected using multiple platforms (array CGH, SNP chip and whole genome sequence data), with these data then analysed via multiple approaches to identify and verify CNVs.In total, 3,488 autosomal CNV regions (CNVRs) were identified in this study, which substantially builds on an initial survey of the sheep genome that identified 135 CNVRs. The average length of the identified CNVRs was 19 kb (range of 1 kb to 3.6 Mb), with shorter CNVRs being more frequent than longer CNVRs. The total length of all CNVRs was 67.6Mbps, which equates to 2.7 % of the sheep autosomes. For individuals this value ranged from 0.24 to 0.55 %, and the majority of CNVRs were identified in single animals. Rather than being uniformly distributed throughout the genome, CNVRs tended to be clustered. Application of three independent approaches for CNVR detection facilitated a comparison of validation rates. CNVs identified on the Roche-NimbleGen 2.1M CGH array generally had low validation rates with lower density arrays, while whole genome sequence data had the highest validation rate (>60 %).This study represents the first comprehensive survey of the distribution, prevalence and characteristics of CNVR in sheep. Multiple approaches were used to detect CNV regions and it appears that the best method for verifying CNVR on a large scale involves using a combination of detection methodologies. The characteristics of the 3,488 autosomal CNV regions identified in this study are comparable to other CNV regions reported in the literature and provide a valuable and sizeable addition to the small subset of published sheep CNVs.

Project description:ImportanceThe role of large, rare copy number variants (CNVs) in neuropsychiatric disorders is well established, but their association with common psychiatric disorders, such as depression, remains unclear.ObjectiveTo examine the association of a group of 53 CNVs associated with neurodevelopmental disorders and burden of rare CNVs with risk of depression.Design, setting, and participantsThis case-control study used data from the UK Biobank study sample, which comprised 502 534 individuals living in the United Kingdom. Individuals with autism spectrum disorder, intellectual disability, attention-deficit/hyperactivity disorder, schizophrenia, or bipolar affective disorder diagnoses were excluded. Analyses were further restricted to individuals of European genetic ancestry (n = 407 074). The study was conducted from January 2017 to September 2018.ExposuresCNV carrier status.Main outcomes and measuresFor the primary outcome, individuals who reported that a physician had told them they had a depression diagnosis were defined as cases. Analyses were repeated using 2 alternative depression definitions: self-reported lifetime depression with current antidepressant prescription at the time of visit 1, and hospital discharge diagnosis of depression.ResultsCopy number variants were identified in 488 366 individuals aged 37 to 73 years. In total, 407 074 individuals with European genetic ancestry (220 201 female [54.1%]; mean [SD] age of 56.9 [8.0] years) were included in the study. Of these individuals, 23 979 (5.9%) had self-reported lifetime depression and 383 095 (94.1%) reported no lifetime depression. The group of 53 neurodevelopmental CNVs was associated with self-reported depression (odds ratio [OR], 1.34; 95% CI, 1.19-1.49, uncorrected P = 1.38 × 10-7), and these results were consistent when using 2 alternative definitions of depression. This association was partially explained by physical health, educational attainment, social deprivation, smoking status, and alcohol consumption. A strong independent association remained between the neurodevelopmental CNVs and depression in analyses that incorporated these other measures (OR, 1.26; 95% CI, 1.11-1.43; P = 2.87 × 10-4). Eight individual CNVs were nominally associated with risk of depression, and 3 of these 8 CNVs (1q21.1 duplication, Prader-Willi syndrome duplication, and 16p11.2 duplication) survived Bonferroni correction for the 53 CNVs tested. After the exclusion of carriers of neurodevelopmental CNVs, no association was found between measures of CNV burden and depression.Conclusions and relevanceNeurodevelopmental CNVs appear to be associated with depression, extending the spectrum of clinical phenotypes that are associated with CNV carrier status.

Project description:ImportanceAt least 11 rare copy number variants (CNVs) have been shown to be major risk factors for schizophrenia (SZ). These CNVs also increase the risk for other neurodevelopmental disorders, such as intellectual disability. It is possible that additional intellectual disability-associated CNVs increase the risk for SZ but have not yet been implicated in SZ because of previous studies being underpowered.ObjectiveTo examine whether additional CNVs implicated in intellectual disability represent novel SZ risk loci.Design, setting, and participantsWe used single-nucleotide polymorphism (SNP) array data to evaluate a set of 51 CNVs implicated in intellectual disability (excluding the known SZ loci) in a large data set of patients with SZ and healthy persons serving as controls recruited in a variety of settings. We analyzed a new sample of 6934 individuals with SZ and 8751 controls and combined those data with previously published large data sets for a total of 20 403 cases of SZ and 26 628 controls.Main outcomes and measuresBurden analysis of CNVs implicated in intellectual disability (excluding known SZ CNVs) for association with SZ. Association of individual intellectual disability CNV loci with SZ.ResultsOf data on the 20 403 cases (6151 [30.15%] female) and 26 628 controls (14 252 [53.52%] female), 51 intellectual disability CNVs were analyzed. Collectively, intellectual disability CNVs were significantly enriched for SZ (P = 1.0 × 10-6; odds ratio [OR], 1.9 [95% CI, 1.46-2.49]). Of the 51 CNVs tested, 19 (37%) were more common in SZ cases; only 4 (8%) were more common in controls (no observations were made for the remaining 28 [55%] loci). One novel locus, deletion at 16p12.1, was significantly associated with SZ after correction for multiple testing (rate in SZ, 33 [0.16%]; rate in controls, 12 [0.05%]; corrected P = .017; OR, 3.3; 95% CI, 1.61-7.05), and 2 loci reached nominal levels of significance (deletions at 2q11.2: 6 [0.03%] vs 1 [0.004%]; OR, 9.3; 95% CI, 1.03-447.76; corrected P > .99; and duplications at 10q11.21q11.23: 5 [0.2%] vs 0 [0.03%]; OR, infinity; 95% CI, 1.26-infinity; corrected P = .71). Our new data set also provided independent support for the 11 SZ risk loci previously reported to be associated with the disorder and for the protective effect of 22q11.2 duplication.Conclusions and relevanceA large proportion of CNV loci implicated in intellectual disability are risk factors for SZ, but the available sample size precludes statistical confirmation for additional individual loci.

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Association of copy number variants with specific ultrasonographically detected fetal anomalies.

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Association of copy number variants with specific ultrasonographically detected fetal anomalies.

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