Prenatal diagnosis of 2q13 duplications: The crucial role of the family survey in genetic counseling on novel copy number variations

Abstract Background Noninvasive prenatal testing (NIPT) has been wildly used to screen for common aneuplodies. In recent years, the test has been expanded to detect rare autosomal aneuploidies (RATs) and copy number variations (CNVs). This study was performed to investigate the performance of expanded noninvasive prenatal testing (expanded NIPT) in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RATs), and copy number variations (CNVs) and parental willingness for invasive prenatal diagnosis in a Chinese prenatal diagnosis center. Methods A total of 24,702 pregnant women were retrospectively analyzed at the Women and Children’s Hospital from January 2013 to April 2019, among which expanded NIPT had been successfully conducted in 24,702 pregnant women. The high-risk expanded NIPT results were validated by karyotype analysis and chromosomal microarray analysis. All the tested pregnant women were followed up for pregnancy outcomes. Results Of the 24,702 cases, successful follow-up was conducted in 98.77% (401/446) of cases with common trisomies and SCAs, 91.95% (80/87) of RAT and CNV cases, and 76.25% (18,429/24,169) of cases with low-risk screening results. The sensitivity of expanded NIPT was 100% (95% confidence interval[CI], 97.38–100%), 96.67%(95%CI, 82.78–99.92%), and 100%(95%CI, 66.37–100.00%), and the specificity was 99.92%(95%CI, 99.87–99.96%), 99.96%(95%CI, 99.91–99.98%), and 99.88% (95%CI, 99.82–99.93%) for the detection of trisomies 21, 18, and 13, respectively. Expanded NIPT detected 45,X, 47,XXX, 47,XXY, XYY syndrome, RATs, and CNVs with positive predictive values of 25.49%, 75%, 94.12%, 76.19%, 6.45%, and 50%, respectively. The women carrying fetuses with Trisomy 21/Trisomy 18/Trisomy 13 underwent invasive prenatal diagnosis and terminated their pregnancies at higher rates than those at high risk for SCAs, RATs, and CNVs. Conclusions Our study demonstrates that the expanded NIPT detects fetal trisomies 21, 18, and 13 with high sensitivity and specificity. The accuracy of detecting SCAs, RATs, and CNVs is still relatively poor and needs to be improved. With a high-risk expanded NIPT result, the women at high risk for common trisomies are more likely to undergo invasive prenatal diagnosis procedures and terminate their pregnancies than those with unusual chromosome abnormalities.

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Prenatal Genetic Diagnosis for Pediatricians

PEDIATRICS ◽

10.1542/peds.93.6.1010 ◽

1994 ◽

Vol 93 (6) ◽

pp. 1010-1015

Author(s):

Keyword(s):

Decision Making ◽

Genetic Counseling ◽

Prenatal Diagnosis ◽

Diagnostic Tests ◽

Genetic Disorder ◽

Genetic Diagnosis ◽

Decision Making Process ◽

Know How ◽

Prenatal Genetic Diagnosis ◽

The Family

Pediatricians may be called upon to counsel a family in which prenatal diagnosis is being considered or in which there is a fetus with a genetic disorder. In some settings, the pediatrician may be the primary resource for counseling the family. More frequently, counseling may already have been provided by a clinical geneticist and/or obstetrician. However, because of a previous relationship with the family, the pediatrician may be called upon to review this information and to assist the family in the decision-making process. The pediatrician should be familiar with the principles of prenatal genetic diagnosis and know how to apply them to specific problems in genetic counseling, diagnosis, and management in clinical practice. At the same time, pediatricians should be familiar with resources available in their region for obtaining information about whether and how a specific disorder can be diagnosed and when and where to refer patients for prenatal genetic diagnosis. The technology of prenatal diagnosis is changing rapidly, and genetic consultants can assist pediatricians in the appropriate utilization and interpretation of the diagnostic tests that are available.

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Seduction and Surprise

10.4018/978-1-5225-0525-9.ch009 ◽

2017 ◽

pp. 188-205

Author(s):

Dina Mendonça

Keyword(s):

Lived Experience ◽

Crucial Role ◽

The Family ◽

Situated Approach ◽

The Way

The chapter explores the meaning of seduction from a situated approach to emotions by tracing the way surprise uncovers emotional traits that enable commitment. The adoption of a Situated Approach reveals how emotions are intrinsically tied to the situations from which they arise and the crucial role of surprise. The emotion of surprise is central for the value of experience because it amplifies other emotions as well as other traits, and details of the lived situations fixing the meaning of the lived experience. The examination of how various emotions belong to the family of surprise further explains the established differences between persuasion, manipulation and seduction. Ultimately the chapter shows that seduction asks for the recognition of various layers of emotional reality, and how they are made visible by the way in which seduction establishes commitments.

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Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Challenges in Parkinson's Disease ◽

10.5772/62881 ◽

2016 ◽

Cited By ~ 2

Author(s):

Valentina La Cognata ◽

Velia D'Agata ◽

Francesca Cavalcanti ◽

Sebastiano Cavallaro

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Copy Number ◽

Copy Number Variations

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Two Novel Distinct Subtypes of Myeloid Neoplasms Molecularly Associated with Histone H3K36 Methylations

Blood ◽

10.1182/blood.v126.23.2841.2841 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2841-2841 ◽

Cited By ~ 1

Author(s):

Yosaku Watatani ◽

Yasunobu Nagata ◽

Vera Grossmann ◽

Yusuke Okuno ◽

Tetsuichi Yoshizato ◽

...

Keyword(s):

Gene Expression ◽

Copy Number ◽

Copy Number Variations ◽

Healthy Controls ◽

Employment Equity ◽

Gene Deletions ◽

Myeloid Neoplasms ◽

Frequent Mutations ◽

Equity Ownership

Abstract Myelodysplastic syndromes (MDS) and related disorders are a heterogeneous group of chronic myeloid neoplasms with a high propensity to acute myeloid leukemia. A cardinal feature of MDS, as revealed by the recent genetic studies, is a high frequency of mutations and copy number variations (CNVs) affecting epigenetic regulators, such as TET2, IDH1/2, DNMT3A, ASXL1, EZH2, and other genes, underscoring a major role of deregulated epigenetic regulation in MDS pathogenesis. Meanwhile, these mutations/deletions have different impacts on the phenotype and the clinical outcome of MDS, suggesting that it should be important to understand the underlying mechanism for abnormal epigenetic regulation for better classification and management of MDS. SETD2 and ASH1L are structurally related proteins that belong to the histone methyltransferase family of proteins commonly engaged in methylation of histone H3K36. Both genes have been reported to undergo frequent somatic mutations and copy number alterations, and also show abnormal gene expression in a variety of non-hematological cancers. Moreover, germline mutation of SETD2 has been implicated in overgrowth syndromes susceptible to various cancers. However, the role of alterations in these genes has not been examined in hematological malignancies including myelodysplasia. In this study, we interrogated somatic mutations and copy number variations, among a total of 1116 cases with MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), who had been analyzed by target deep sequencing (n=944), and single nucleotide polymorphism-array karyotyping (SNP-A) (n=222). Gene expression was analyzed in MDS cases and healthy controls, using publically available gene expression datasets. SETD2 mutations were found in 6 cases, including 2 with nonsense and 4 with missense mutations, and an additional 10 cases had gene deletions spanning 1.8-176 Mb regions commonly affecting the SETD2 locus in chromosome 3p21.31, where SETD2 represented the most frequently deleted gene within the commonly deleted region. SETD2 deletion significantly correlated with reduced SETD2 expression. Moreover, MDS cases showed a significantly higher SETD2 expression than healthy controls. In total, 16 cases had either mutations or deletions of the SETD2 gene, of which 70% (7 out of 10 cases with detailed diagnostic information) were RAEB-1/2 cases. SETD2 -mutated/deleted cases had frequent mutations in TP53 (n=4), SRSF2 (n=3), and ASXL1 (n=3) and showed a significantly poor prognosis compared to those without mutations/deletions (HR=3.82, 95%CI; 1.42-10.32, P=0.004). ASH1L, on the other hand, was mutated and amplified in 7 and 13 cases, respectively, of which a single case carried both mutation and amplification with the mutated allele being selectively amplified. All the mutations were missense variants, of which 3 were clustered between S1201 and S1209. MDS cases showed significantly higher expression of ASH1L compared to healthy controls, suggesting the role of ASH1L overexpression in MDS development. Frequent mutations in TET2 (n=8) and SF3B1 (n=6) were noted among the 19 cases with ASH1L lesions. RAEB-1/2 cases were less frequent (n=11) compared to SETD2-mutated/deleted cases. ASH1L mutations did not significantly affect overall survival compared to ASH1L-intact cases. Gene Set Expression Analysis (Broad Institute) on suppressed SETD2 and accelerated ASH1L demonstrated 2 distinct expression signatures most likely due to the differentially methylated H3K36. We described recurrent mutations and CNVs affecting two histone methyltransferase genes, which are thought to represent novel driver genes in MDS involved in epigenetic regulations. Given that SETD2 overexpression and reduced ASH1L expression are found in as many as 89% of MDS cases, deregulation of both genes might play a more role than expected from the incidence of mutations and CNVs alone. Although commonly involved in histone H3K36 methylation, both methyltransferases have distinct impacts on the pathogenesis and clinical outcome of MDS in terms of the mode of genetic alterations and their functional consequences: SETD2 was frequently affected by truncating mutations and gene deletions, whereas ASH1L underwent gene amplification without no truncating mutations, suggesting different gene targets for both methyltransferases, which should be further clarified through functional studies. Disclosures Alpermann: MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Shih:Novartis: Research Funding.

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Role of Copy Number Variations in ADHD

10.5772/intechopen.94383 ◽

2020 ◽

Author(s):

Danijela Krgović

Keyword(s):

Autism Spectrum Disorder ◽

Attention Deficit ◽

Neurodevelopmental Disorders ◽

Copy Number ◽

Autism Spectrum ◽

Copy Number Variations ◽

Spectrum Disorder ◽

Genetic Diagnostics ◽

Healthy Controls

Copy number variations (CNV) have an important role in etiology of neurodevelopmental disorders (NDD). Among them, individuals with attention-deficit and hyperactivity disorders (ADHD) have 1.33 times higher overall rate of CNVs larger than 100 kb compared to healthy controls. These CNVs are often shared with other NDDs and neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD), although duplications of 15q13.3 and 16p13.11 have been found enriched in ADHD cohorts. CNVs provide new opportunities for studying and management of psychiatric disorders including ADHD. Therefore this chapter provides a brief overview of the literature on this topic and presents the benefits of CNV genetic diagnostics in ADHD patients.

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

Frontiers in Genetics ◽

10.3389/fgene.2021.665589 ◽

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 > 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.

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Analysis of Genomic Copy Number Variation in Miscarriages During Early and Middle Pregnancy

Frontiers in Genetics ◽

10.3389/fgene.2021.732419 ◽

2021 ◽

Vol 12 ◽

Author(s):

Heming Wu ◽

Qingyan Huang ◽

Xia Zhang ◽

Zhikang Yu ◽

Zhixiong Zhong

Keyword(s):

Prenatal Diagnosis ◽

Old Age ◽

Chromosomal Abnormality ◽

Copy Number ◽

Chromosomal Abnormalities ◽

Copy Number Variations ◽

Variants Of Unknown Significance ◽

Number Variation ◽

Structural Chromosomal Abnormality ◽

Numerical Chromosomal Abnormality

The purpose of this study was to explore the copy number variations (CNVs) associated with miscarriage during early and middle pregnancy and provide useful genetic guidance for pregnancy and prenatal diagnosis. A total of 505 fetal specimens were collected and CNV sequencing (CNV-seq) analysis was performed to determine the types and clinical significance of CNVs, and relevant medical records were collected. The chromosomal abnormality rate was 54.3% (274/505), among which the numerical chromosomal abnormality rate was 40.0% (202/505) and structural chromosomal abnormality rate was 14.3% (72/505). Chromosomal monosomy mainly occurred on sex chromosomes, and chromosomal trisomy mainly occurred on chromosomes 16, 22, 21, 15, 13, and 9. The incidence of numerical chromosomal abnormalities in ≥35 year-old age pregnant women was significantly higher than <35 year-old age group. The highest incidence of pathogenic CNV (pCNV) was found in fetuses at ≤6 weeks of pregnancy (5.26%), and the incidence of variants of unknown significance (VOUS) CNVs decreased gradually with the increase of gestational age. The rate of chromosomal abnormalities of fetuses in early pregnancy (59.5%) was higher than that of fetuses in middle pregnancy (27.2%) (p < 0.001). There were 168 genes in VOUS + pCNV regions. 41 functions and 12 pathways (p < 0.05) were enriched of these genes by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Some meaningful genetic etiology information such as genes and pathways has been obtained, it may provide useful genetic guidance for pregnancy and prenatal diagnosis.

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