scholarly journals The prenatal diagnosis and clinical outcomes of fetuses with 15q11.2 copy number variants: a case series of 36 patients

2021 ◽  
Author(s):  
Jessica Kang ◽  
Chien Nan Lee ◽  
Yi-Ning Su ◽  
Ming-Wei Lin ◽  
Yi-Yun Tai ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Developmental Delay ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Case Series ◽  
Copy Number Variant ◽  
University Hospital ◽  
Limited Information ◽  
Ultrasound Findings

Objective: The prenatal genetic counseling of fetus diagnosed with the 15q11.2 copy number variant (CNV) involving the BP1-BP2 region has been difficult due to limited information and controversial opinion on prognosis. Design: Case series. Setting: This study uses data from National Taiwan University Hospital. Sample: Data of 36 pregnant women who underwent prenatal microarray analysis from 2012 to 2017 and were assessed at National Taiwan University Hospital. Methods: Data were collected by reviewing patients’ medical record. Comparison of patient characteristics, prenatal ultrasound findings and postnatal outcomes between different cases involving the 15q11.2 BP1-BP2 region were presented. Main outcome measured: Postnatal prognosis. Results: Out of the 36 patients diagnosed with CNVs involving the BP1-BP2 region, 5 were diagnosed with microduplication and 31 with microdeletion. Abnormal ultrasound findings were recorded in 12 cases prenatally. De novo microduplications were observed in 25% of the cases and microdeletions were found in 14%. Amongst the cases, 10 pregnant women received termination of pregnancy and 26 gave birth to healthy individuals (27 babies in total). Conclusion: The prognoses of 15q11.2 CNVs were controversial and recent studies have revealed its connection with developmental delay and autism. In our study, no obvious developmental delay or neurological disorders were detected postnatally in the 1 case of 15q11.2 microduplication and 25 cases of microdeletion.

scholarly journals The Prenatal Diagnosis and Clinical Outcomes of Fetuses With 15q11.2 Copy Number Variants: A Case Series of 36 Patients

2021 ◽  
Vol 8 ◽  
Author(s):  
Jessica Kang ◽  
Chien-Nan Lee ◽  
Yi-Ning Su ◽  
Ming-Wei Lin ◽  
Yi-Yun Tai ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Neurological Disorders ◽  
Copy Number ◽  
Copy Number Variants ◽  
Case Series ◽  
University Hospital ◽  
Limited Information ◽  
Maternal Characteristics ◽  
Ultrasound Findings ◽  
Hospital Comparison

Prenatal genetic counseling of fetuses diagnosed with 15q11.2 copy number variants (CNVs) involving the BP1–BP2 region is difficult due to limited information and controversial opinion on prognosis. In total, we collected the data of 36 pregnant women who underwent prenatal microarray analysis from 2010 to 2017 and were assessed at National Taiwan University Hospital. Comparison of the maternal characteristics, prenatal ultrasound findings, and postnatal outcomes among the different cases involving the 15q11.2 BP1–BP2 region were presented. Out of the 36 fetuses diagnosed with CNVs involving the BP1–BP2 region, five were diagnosed with microduplications and 31 with microdeletions. Among the participants, 10 pregnant women received termination of pregnancy and 26 gave birth to healthy individuals (27 babies in total). The prognoses of 15q11.2 CNVs were controversial and recent studies have revealed its low pathogenicity. In our study, the prenatal abnormal ultrasound findings were recorded in 12 participants and were associated with 15q11.2 deletions. No obvious developmental delay or neurological disorders were detected in early childhood.

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 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 Expansion of the Genotypic and Phenotypic Spectrum of WASF1-Related Neurodevelopmental Disorder

2021 ◽  
Vol 11 (7) ◽  
pp. 931
Author(s):  
Siddharth Srivastava ◽  
Erica L. Macke ◽  
Lindsay C. Swanson ◽  
David Coulter ◽  
Eric W. Klee ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Case Series ◽  
Monozygotic Twins ◽  
Copy Number Variant ◽  
Limited Information ◽  
Phenotypic Spectrum ◽  
New Variant ◽  
Genetic Landscape ◽  
Syndrome Protein

In humans, de novo truncating variants in WASF1 (Wiskott–Aldrich syndrome protein family member 1) have been linked to presentations of moderate-to-profound intellectual disability (ID), autistic features, and epilepsy. Apart from one case series, there is limited information on the phenotypic spectrum and genetic landscape of WASF1-related neurodevelopmental disorder (NDD). In this report, we describe detailed clinical characteristics of six individuals with WASF1-related NDD. We demonstrate a broader spectrum of neurodevelopmental impairment including more mildly affected individuals. Further, we report new variant types, including a copy number variant (CNV), resulting in the partial deletion of WASF1 in monozygotic twins, and three missense variants, two of which alter the same residue, p.W161. This report adds further evidence that de novo variants in WASF1 cause an autosomal dominant NDD.

scholarly journals Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes

2019 ◽  
Vol 105 (4) ◽  
pp. 384-389 ◽  
Author(s):  
Adam Jackson ◽  
Heather Ward ◽  
Rebecca Louise Bromley ◽  
Charulata Deshpande ◽  
Pradeep Vasudevan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Copy Number ◽  
Developmental Disorders ◽  
Drug Exposure ◽  
Genetic Disorders ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
In Utero ◽  
Developmental Problems ◽  
Number Of Children

IntroductionFetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.MethodsWe reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.ResultsSeven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10).ConclusionsThis study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.

scholarly journals Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations

2015 ◽  
Vol 172 (6) ◽  
pp. 803-811 ◽  
Author(s):  
Maya B Lodish ◽  
Bo Yuan ◽  
Isaac Levy ◽  
Glenn D Braunstein ◽  
Charalampos Lyssikatos ◽  
...  
Keyword(s):  
Copy Number ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Genetic Defect ◽  
Molecular Cytogenetics ◽  
Case Series ◽  
Sporadic Case ◽  
Genomic Rearrangements ◽  
Clinical Presentations ◽  
Depth Analysis

ObjectiveWe have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype–phenotype correlation of theirPRKACAamplification.DesignThis study is a case series.MethodsMolecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS.ResultsReinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entirePRKACAgene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient,PRKACAtriplication was associated with a more severe phenotype.ConclusionsConstitutional chromosomalPRKACAgene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occurde novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication.PRKACAamplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.

scholarly journals An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Leandro de Araújo Lima ◽  
Ana Cecília Feio-dos-Santos ◽  
Sintia Iole Belangero ◽  
Ary Gadelha ◽  
Rodrigo Affonseca Bressan ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Integrative Approach ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Hyperactivity Disorder ◽  
New Genes

Abstract Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

scholarly journals Detection and characterization of copy number variants based on whole-genome sequencing by DNBSEQ platforms

2019 ◽  
Author(s):  
Junhua Rao ◽  
Lihua Peng ◽  
Fang Chen ◽  
Hui Jiang ◽  
Chunyu Geng ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
Whole Genome ◽  
Genome Wide ◽  
Wide Range ◽  
Distribution Sensitivity ◽  
Cnv Detection

AbstractBackgroundNext-generation sequence (NGS) has rapidly developed in past years which makes whole-genome sequencing (WGS) becoming a more cost- and time-efficient choice in wide range of biological researches. We usually focus on some variant detection via WGS data, such as detection of single nucleotide polymorphism (SNP), insertion and deletion (Indel) and copy number variant (CNV), which playing an important role in many human diseases. However, the feasibility of CNV detection based on WGS by DNBSEQ™ platforms was unclear. We systematically analysed the genome-wide CNV detection power of DNBSEQ™ platforms and Illumina platforms on NA12878 with five commonly used tools, respectively.ResultsDNBSEQ™ platforms showed stable ability to detect slighter more CNVs on genome-wide (average 1.24-fold than Illumina platforms). Then, CNVs based on DNBSEQ™ platforms and Illumina platforms were evaluated with two public benchmarks of NA12878, respectively. DNBSEQ™ and Illumina platforms showed similar sensitivities and precisions on both two benchmarks. Further, the difference between tools for CNV detection was analyzed, and indicated the selection of tool for CNV detection could affected the CNV performance, such as count, distribution, sensitivity and precision.ConclusionThe major contribution of this paper is providing a comprehensive guide for CNV detection based on WGS by DNBSEQ™ platforms for the first time.

scholarly journals HandyCNV: Standardized Summary, Annotation, Comparison, and Visualization of Copy Number Variant, Copy Number Variation Region, and Runs of Homozygosity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinghang Zhou ◽  
Liyuan Liu ◽  
Thomas J. Lopdell ◽  
Dorian J. Garrick ◽  
Yuangang Shi
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
R Package ◽  
Copy Number Variation Region ◽  
Runs Of Homozygosity ◽  
Number Variation ◽  
Genomic Studies ◽  
Computing Platforms ◽  
Analysis System

Detection of CNVs (copy number variants) and ROH (runs of homozygosity) from SNP (single nucleotide polymorphism) genotyping data is often required in genomic studies. The post-analysis of CNV and ROH generally involves many steps, potentially across multiple computing platforms, which requires the researchers to be familiar with many different tools. In order to get around this problem and improve research efficiency, we present an R package that integrates the summarization, annotation, map conversion, comparison and visualization functions involved in studies of CNV and ROH. This one-stop post-analysis system is standardized, comprehensive, reproducible, timesaving, and user-friendly for researchers in humans and most diploid livestock species.

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