scholarly journals Critical exon indexing improves clinical interpretation of copy number variants in neurodevelopmental disorders

2019 ◽  
Vol 5 (6) ◽  
pp. e378 ◽  
Author(s):  
E. Robert Wassman ◽  
Karen S. Ho ◽  
Diana Bertrand ◽  
Kyle W. Davis ◽  
Megan M. Martin ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Relevant Literature ◽  
Copy Number Variants ◽  
Mendelian Inheritance ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Variants Of Unknown Significance ◽  
Pathogenic Cnvs ◽  
Highly Correlated

ObjectiveTo evaluate a new tool to aid interpretation of copy number variants (CNVs) in individuals with neurodevelopmental disabilities.MethodsCritical exon indexing (CEI) was used to identify genes with critical exons (CEGs) from clinically reported CNVs, which may contribute to neurodevelopmental disorders (NDDs). The 742 pathogenic CNVs and 1,363 variants of unknown significance (VUS) identified by chromosomal microarray analysis in 5,487 individuals with NDDs were subjected to CEI to identify CEGs. CEGs identified in a subsequent random series of VUS were evaluated for relevance to CNV interpretation.ResultsCEI identified a total of 2,492 unique CEGs in pathogenic CNVs and 953 in VUS compared with 259 CEGs in 6,965 CNVs from 873 controls. These differences are highly significant (p < 0.00001) whether compared as frequency, average, or normalized by CNV size. Twenty-one percent of VUS CEGs were not represented in Online Mendelian Inheritance in Man, highlighting limitations of existing resources for identifying potentially impactful genes within CNVs. CEGs were highly correlated with other indices and known pathways of relevance. Separately, 136 random VUS reports were reevaluated, and 76% of CEGs had not been commented on. In multiple cases, further investigation yielded additional relevant literature aiding interpretation. As one specific example, we discuss GTF2I as a CEG, which likely alters interpretation of several reported duplication VUS in the Williams-Beuren region.ConclusionsApplication of CEI to CNVs in individuals with NDDs can identify genes of potential clinical relevance, aid laboratories in effectively searching the clinical literature, and support the clinical reporting of poorly annotated VUS.

scholarly journals Clinical Performance of an Ultrahigh Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Karen S. Ho ◽  
Hope Twede ◽  
Rena Vanzo ◽  
Erin Harward ◽  
Charles H. Hensel ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Detection Rate ◽  
Clinical Performance ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Ultrahigh Resolution ◽  
Significant Difference

Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.8-million probe custom CMA optimized for the detection of CNVs associated with neurodevelopmental disorders. We report an overall detection rate of 29.4% in our neurodevelopmental cohort, which rises to nearly 33% when cases with DD/ID and/or MCA only are considered. The detection rate for the ASD cohort is also significant, at 25%. Additionally, we find that detection rate and pathogenic yield of CMA vary significantly depending on the primary indications for testing, the age of the individuals tested, and the specialty of the ordering doctor. We also report a significant difference between the detection rate on the ultrahigh resolution optimized array in comparison to the array from which it originated. This increase in detection can significantly contribute to the efficient and effective medical management of neurodevelopmental conditions in the clinic.

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.

Genomic Syndromes in Schizophrenia

2013 ◽  
pp. 247-255
Author(s):  
George Kirov ◽  
Michael C. O’Donovan ◽  
Michael J. Owen
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Individual Risk ◽  
Genomic Deletions ◽  
Pathogenic Cnvs ◽  
Cognition And Learning

Several submicroscopic genomic deletions and duplications known as copy number variants (CNVs) have been reported to increase susceptibility to schizophrenia. Those for which the evidence is particularly strong include deletions at chromosomal segments 1q21.1, 3q29, 15q11.2, 15q13.3, 17q12 and 22q11.2, duplications at 15q11.2-q13.1, 16p13.1, and 16p11.2, and deletions atthe gene NRXN1. The effect of each on individual risk is relatively large, but it does not appear that any of them is alone sufficient to cause disorder in carriers. These CNVs often arise as new mutations(de novo). Analyses of genes enriched among schizophrenia implicated CNVs highlight the involvement in the disorder of post-synaptic processes relevant to glutamatergicsignalling, cognition and learning. CNVs that contribute to schizophrenia risk also contribute to other neurodevelopmental disorders, including intellectual disability, developmental delay and autism. As a result of selection, all known pathogenic CNVs are rare, and none makes a sizeable contribution to overall population risk of schizophrenia, although the study of these mutations is nevertheless providing important insights into the origins of the disorder.

scholarly journals Comprehensive Evaluation of Non-invasive Prenatal Screening to Detect Fetal Copy Number Variations

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Wang ◽  
Bin Zhang ◽  
Lingna Zhou ◽  
Qin Zhou ◽  
Yingping Chen ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Pregnant Women ◽  
Copy Number ◽  
Prenatal Screening ◽  
Comprehensive Evaluation ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Non Invasive ◽  
Pathogenic Cnvs

ObjectiveTo evaluate the effectiveness of non-invasive prenatal screening (NIPS) in prenatal screening of fetal pathogenic copy number variants (CNVs).Materials and MethodsWe evaluated the prenatal screening capacity using traditional and retrospective approaches. For the traditional method, we evaluated 24,613 pregnant women who underwent NIPS; cases which fetal CNVs were suggested underwent prenatal diagnosis with chromosomal microarray analysis (CMA). For the retrospective method, we retrospectively evaluated 47 cases with fetal pathogenic CNVs by NIPS. A systematic literature search was performed to compare the evaluation efficiency.ResultsAmong the 24,613 pregnant women who received NIPS, 124 (0.50%) were suspected to have fetal CNVs. Of these, 66 women underwent prenatal diagnosis with CMA and 13 had true-positive results. The positive predictive value (PPV) of NIPS for fetal CNVs was 19.7%. Among 1,161 women who did not receive NIPS and underwent prenatal diagnosis by CMA, 47 were confirmed to have fetal pathogenic CNVs. Retesting with NIPS indicated that 24 of these 47 cases could also be detected by NIPS, representing a detection rate (DR) of 51.1%. In total, 10 publications, namely, six retrospective studies and four prospective studies, met our criteria and were selected for a detailed full-text review. The reported DRs were 61.10–97.70% and the PPVs were 36.11–80.56%. The sizes of CNVs were closely related to the accuracy of NIPS detection. The DR was 41.9% (13/31) in fetuses with CNVs ≤ 3 Mb, but was 55.0% (11/20) in fetuses with CNVs &gt; 3 Mb. Finally, to intuitively show the CNVs accurately detected by NIPS, we mapped all CNVs to chromosomes according to their location, size, and characteristics. NIPS detected fetal CNVs in 2q13 and 4q35.ConclusionThe DR and PPV of NIPS for fetal CNVs were approximately 51.1% and 19.7%, respectively. Follow-up molecular prenatal diagnosis is recommended in cases where NIPS suggests fetal CNVs.

scholarly journals Detection of Clinically Relevant Copy Number Variations and Genes in a Bangladeshi Cohort of Neurodevelopmental Disorders

2021 ◽  
Author(s):  
Hosneara Akter ◽  
Muhammad Mizanur Rahman ◽  
Shaoli Sarker ◽  
Mohammed Basiruzzaman ◽  
Mazharul Islam ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Critical Role ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Chromosomal Microarray Analysis ◽  
Potential Candidate ◽  
Female Ratio ◽  
Pathogenic Cnvs

Abstract Background: Copy number variations (CNVs) play a critical role into the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh. Methods: We have conducted genome-wide chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare chromosomal abnormalities (deletion /duplication/ rearrangements). To identify candidate genes within the rare CNVs, multiple gene constraint metrics (i.e. “Critical-Exon Genes (CEGs)”) were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using R package. Results: In our cohort, the head circumference of males are significantly greater than females (p=0.0002). Of all samples assayed, 12.26% (26/212) and 47.17% (100/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. 2.83% (6/212) pathogenic CNVs are located at the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs in comparison to males (OR=4.2; p=0.0007). ADOS-2 subset show severe social communication deficit (p=0.014) and overall ASD symptoms severity (p=0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs and identified PSMC3 gene as a potential candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability. Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis therapeutics and management of NDD patients.

scholarly journals Chromosomal Microarray Analysis in Children with Unexplained Developmental Delay/Intellectual Disability

2018 ◽  
Vol 08 (01) ◽  
pp. 001-009
Author(s):  
Pinar Arican ◽  
Berk Ozyilmaz ◽  
Dilek Cavusoglu ◽  
Pinar Gencpinar ◽  
Kadri Erdogan ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
De Novo ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Genetic Syndromes ◽  
Pathogenic Cnvs ◽  
Spectrum Disorders

AbstractChromosomal microarray (CMA) analysis for discovery of copy number variants (CNVs) is now recommended as a first-line diagnostic tool in patients with unexplained developmental delay/intellectual disability (DD/ID) and autism spectrum disorders. In this study, we present the results of CMA analysis in patients with DD/ID. Of 210 patients, pathogenic CNVs were detected in 26 (12%) and variants of uncertain clinical significance in 36 (17%) children. The diagnosis of well-recognized genetic syndromes was achieved in 12 patients. CMA analysis revealed pathogenic de novo CNVs, such as 11p13 duplication with new clinical features. Our results support the utility of CMA as a routine diagnostic test for unexplained DD/ID.

Sign in / Sign up

Export Citation Format

Share Document