scholarly journals Residual risk for clinically significant copy number variants in low-risk pregnancies with a normal NIPS result: does it have clinical value?

2021 ◽  
Author(s):  
Qi Tian ◽  
Dong-Zhi Li
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Low Risk ◽  
Residual Risk ◽  
Clinical Value ◽  
Clinically Significant

scholarly journals Trio-Based Low-Pass Genome Sequencing Reveals Characteristics and Significance of Rare Copy Number Variants in Prenatal Diagnosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Matthew Hoi Kin Chau ◽  
Jicheng Qian ◽  
Zihan Chen ◽  
Ying Li ◽  
Yu Zheng ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Genome Sequencing ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Recurrence Risk ◽  
Rare Cnvs ◽  
Pathogenic Cnvs ◽  
Low Pass ◽  
Clinically Significant

Background: Low-pass genome sequencing (GS) detects clinically significant copy number variants (CNVs) in prenatal diagnosis. However, detection at improved resolutions leads to an increase in the number of CNVs identified, increasing the difficulty of clinical interpretation and management.Methods: Trio-based low-pass GS was performed in 315 pregnancies undergoing invasive testing. Rare CNVs detected in the fetuses were investigated. The characteristics of rare CNVs were described and compared to curated CNVs in other studies.Results: A total of 603 rare CNVs, namely, 597 constitutional and 6 mosaic CNVs, were detected in 272 fetuses (272/315, 86.3%), providing 1.9 rare CNVs per fetus (603/315). Most CNVs were smaller than 1 Mb (562/603, 93.2%), while 1% (6/603) were mosaic. Forty-six de novo (7.6%, 46/603) CNVs were detected in 11.4% (36/315) of the cases. Eighty-four CNVs (74 fetuses, 23.5%) involved disease-causing genes of which the mode of inheritance was crucial for interpretation and assessment of recurrence risk. Overall, 31 pathogenic/likely pathogenic CNVs were detected, among which 25.8% (8/31) were small (<100 kb; n = 3) or mosaic CNVs (n = 5).Conclusion: We examined the landscape of rare CNVs with parental inheritance assignment and demonstrated that they occur frequently in prenatal diagnosis. This information has clinical implications regarding genetic counseling and consideration for trio-based CNV analysis.

scholarly journals Copy number variants in clinical WGS: deployment and interpretation for rare and undiagnosed disease

2018 ◽  
Author(s):  
Andrew M Gross ◽  
Subramanian S. Ajay ◽  
Vani Rajan ◽  
Carolyn Brown ◽  
Krista Bluske ◽  
...  
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Genetic Disorders ◽  
Diagnostic Testing ◽  
Copy Number Variants ◽  
Uniparental Disomy ◽  
Copy Number Variant ◽  
Break Point ◽  
Clinically Significant ◽  
Family Based

AbstractPurposeCurrent diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, whole genome sequencing (WGS) has the potential to detect all genomic mutation types on a single platform and workflow. Here we sought to evaluate copy number variant (CNV) calling as part of a clinically accredited WGS test.MethodsUsing a depth-based copy number caller we performed analytical validation of CNV calling on a reference panel of 17 samples, compared the sensitivity of WGS-based variants to those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis, annotation, filtering, visualization of WGS based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases.ResultsWe found that CNV calls from WGS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed. This pipeline also enabled identification of cases of uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of some CNVs enabled break-point level resolution of genomic rearrangements and phasing of de-novo CNVs.ConclusionRobust identification of CNVs by WGS is possible within a clinical testing environment, and further developments will bring improvements in resolution of smaller and more complex CNVs.

scholarly journals Polygenic risk scores in schizophrenia with clinically significant copy number variants

2019 ◽  
Vol 74 (1) ◽  
pp. 35-39 ◽  
Author(s):  
Satoru Taniguchi ◽  
Kohei Ninomiya ◽  
Itaru Kushima ◽  
Takeo Saito ◽  
Ayu Shimasaki ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Clinically Significant

Copy Number Alterations at Polymorphic Loci May Be Acquired Somatically in Patients with Myelodysplastic Syndromes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2782-2782
Author(s):  
Daniel T. Starczynowski ◽  
Suzanne Vercauteren ◽  
Sandy Sung ◽  
Angela Brooks-Wilson ◽  
Wan L Lam ◽  
...  
Keyword(s):  
Copy Number ◽  
Conflicts Of Interest ◽  
Normal Population ◽  
Copy Number Variants ◽  
Low Risk ◽  
Comparative Genomic ◽  
Copy Number Alterations ◽  
Polymorphic Loci ◽  
Cd34 Cells ◽  
Somatic Alterations

Abstract Abstract 2782 Poster Board II-758 Myelodysplastic (MDS) clones are thought to arise from a primitive CD34+ hematopoietic cell as a result of disrupted genomic integrity. Although approximately 50% of low-risk MDS patients do not exhibit karyotypic alterations, recent studies have identified submegabase copy number alterations in a proportion (18–68%) of cytogenetically normal cases using genomic array platforms. Recently, we observed disease-associated copy number alterations in low-risk MDS patients that overlapped common loci known to be sites of copy number variants (CNV). These CNV or copy number polymorphisms are a source of structural variation in the genome of a normal population, and widely assumed to be constitutional and not relevant findings in malignant tissue. Here we show by whole genome array comparative genomic hybridization that copy number changes in the CD34+ MDS clone that occur at polymorphic loci are frequently somatic alterations rather than constitutional variants. Further, the extent of copy number variation is increased in CD34+ cells of MDS patients compared to CD34+ cells of age-matched controls. This increase in disease-associated copy number alterations at polymorphic loci shows a trend toward association with poorer overall survival. Our findings demonstrate that copy number alterations at known polymorphic loci in CD34+ cells from lower-risk MDS patients are frequently due to somatic changes rather than constitutional polymorphisms. Further, alterations in copy number at these sites are likely not benign, regardless of whether they represent constitutional or somatic alterations, and may contribute to disease progression. Disclosures: No relevant conflicts of interest to declare.

M84 POLYGENIC RISK SCORES IN SCHIZOPHRENIA WITH CLINICALLY SIGNIFICANT COPY NUMBER VARIANTS

2019 ◽  
Vol 29 ◽  
pp. S211-S212
Author(s):  
Satoru Taniguchi ◽  
Kohei Ninomiya ◽  
Itaru Kushima ◽  
Tomo Okochi ◽  
Takeo Saito ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Clinically Significant

scholarly journals Assessment of emotions and behaviour by the Developmental Behaviour Checklist in young people with neurodevelopmental CNVs

2020 ◽  
pp. 1-13
Author(s):  
Adam C. Cunningham ◽  
Jeremy Hall ◽  
Stewart Einfeld ◽  
Michael J. Owen ◽  
Marianne B. M. van den Bree ◽  
...  
Keyword(s):  
Young People ◽  
Copy Number ◽  
Cognitive Impairments ◽  
Copy Number Variants ◽  
Learning Difficulties ◽  
Behaviour Problems ◽  
22Q11.2 Deletion ◽  
Clinically Significant ◽  
1Q21.1 Deletion ◽  
Developmental Behaviour Checklist

Abstract Background A number of genomic conditions caused by copy number variants (CNVs) are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Although these patients also tend to have cognitive impairments, few studies have investigated the range of emotion and behaviour problems in young people with ND-CNVs using measures that are suitable for those with learning difficulties. Methods A total of 322 young people with 13 ND-CNVs across eight loci (mean age: 9.79 years, range: 6.02–17.91, 66.5% male) took part in the study. Primary carers completed the Developmental Behaviour Checklist (DBC). Results Of the total, 69% of individuals with an ND-CNV screened positive for clinically significant difficulties. Young people from families with higher incomes (OR = 0.71, CI = 0.55–0.91, p = .008) were less likely to screen positive. The rate of difficulties differed depending on ND-CNV genotype (χ2 = 39.99, p < 0.001), with the lowest rate in young people with 22q11.2 deletion (45.7%) and the highest in those with 1q21.1 deletion (93.8%). Specific patterns of strengths and weaknesses were found for different ND-CNV genotypes. However, ND-CNV genotype explained no more than 9–16% of the variance, depending on DBC subdomain. Conclusions Emotion and behaviour problems are common in young people with ND-CNVs. The ND-CNV specific patterns we find can provide a basis for more tailored support. More research is needed to better understand the variation in emotion and behaviour problems not accounted for by genotype.

Chromosomal microarray findings in pregnancies with an isolated pelvic kidney

2018 ◽  
Vol 47 (1) ◽  
pp. 30-34
Author(s):  
Lena Sagi-Dain ◽  
Amihood Singer ◽  
Ayala Frumkin ◽  
Adel Shalata ◽  
Arie Koifman ◽  
...  
Keyword(s):  
Copy Number ◽  
Risk Estimation ◽  
Copy Number Variants ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Pelvic Kidney ◽  
Local Data ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Clinically Significant

Abstract Objective To examine the risk for abnormal chromosomal microarray analysis (CMA) results among fetuses with an apparently isolated pelvic kidney. Methods Data from all CMA analyses performed due to an isolated pelvic kidney reported to the Israeli Ministry of Health between January 2013 and September 2016 were retrospectively obtained. Risk estimation was performed comparing the rate of abnormal observed CMA findings to the general population risk, based on a systematic review encompassing 9272 cases and on local data of 5541 cases. Results Of 120 pregnancies with an isolated pelvic kidney, two gain-of-copy number variants suggesting microduplication syndromes were demonstrated (1.67%). In addition, three variants of unknown significance were detected (2.5%). Conclusion The risk for clinically significant CMA findings among pregnancies with an isolated single pelvic kidney was not significantly different compared to both control populations. The results of our study question the practice of routine CMA analysis in fetuses with an isolated pelvic kidney.

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