scholarly journals Noninvasive prenatal testing of α-thalassemia and β-thalassemia through population-based parental haplotyping

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chao Chen ◽  
Ru Li ◽  
Jun Sun ◽  
Yaping Zhu ◽  
Lu Jiang ◽  
...  
Keyword(s):  
Viterbi Algorithm ◽  
Hidden Markov ◽  
Prenatal Testing ◽  
Turnaround Time ◽  
Population Based ◽  
Carrier Screening ◽  
Noninvasive Prenatal Testing ◽  
Parental Haplotype ◽  
Monogenic Diseases ◽  
Family Based

Abstract Background Noninvasive prenatal testing (NIPT) of recessive monogenic diseases depends heavily on knowing the correct parental haplotypes. However, the currently used family-based haplotyping method requires pedigrees, and molecular haplotyping is highly challenging due to its high cost, long turnaround time, and complexity. Here, we proposed a new two-step approach, population-based haplotyping-NIPT (PBH-NIPT), using α-thalassemia and β-thalassemia as prototypes. Methods First, we deduced parental haplotypes with Beagle 4.0 with training on a large retrospective carrier screening dataset (4356 thalassemia carrier screening-positive cases). Second, we inferred fetal haplotypes using a parental haplotype-assisted hidden Markov model (HMM) and the Viterbi algorithm. Results With this approach, we enrolled 59 couples at risk of having a fetus with thalassemia and successfully inferred 94.1% (111/118) of fetal alleles. We confirmed these alleles by invasive prenatal diagnosis, with 99.1% (110/111) accuracy (95% CI, 95.1–100%). Conclusions These results demonstrate that PBH-NIPT is a sensitive, fast, and inexpensive strategy for NIPT of thalassemia.

scholarly journals Noninvasive Prenatal Testing for Wilson Disease by Use of Circulating Single-Molecule Amplification and Resequencing Technology (cSMART)

2015 ◽  
Vol 61 (1) ◽  
pp. 172-181 ◽  
Author(s):  
Weigang Lv ◽  
Xianda Wei ◽  
Ruolan Guo ◽  
Qin Liu ◽  
Yu Zheng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Single Molecule ◽  
Wilson Disease ◽  
Prenatal Testing ◽  
Maternal Plasma ◽  
Inverse Pcr ◽  
Noninvasive Prenatal Testing ◽  
Whole Exome ◽  
Monogenic Diseases

Abstract BACKGROUND Noninvasive prenatal testing (NIPT) for monogenic diseases by use of PCR-based strategies requires precise quantification of mutant fetal alleles circulating in the maternal plasma. The study describes the development and validation of a novel assay termed circulating single-molecule amplification and resequencing technology (cSMART) for counting single allelic molecules in plasma. Here we demonstrate the suitability of cSMART for NIPT, with Wilson Disease (WD) as proof of concept. METHODS We used Sanger and whole-exome sequencing to identify familial ATP7B (ATPase, Cu++ transporting, β polypeptide) gene mutations. For cSMART, single molecules were tagged with unique barcodes and circularized, and alleles were targeted and replicated by inverse PCR. The unique single allelic molecules were identified by sequencing and counted, and the percentage of mutant alleles in the original maternal plasma sample was used to determine fetal genotypes. RESULTS Four families with WD pedigrees consented to the study. Using Sanger and whole-exome sequencing, we mapped the pathogenic ATP7B mutations in each pedigree and confirmed the proband's original diagnosis of WD. After validation of cSMART with defined plasma models mimicking fetal inheritance of paternal, maternal, or both parental mutant alleles, we retrospectively showed in second pregnancies that the fetal genotypes assigned by invasive testing and NIPT were concordant. CONCLUSIONS We developed a reliable and accurate NIPT assay that correctly diagnosed the fetal genotypes in 4 pregnancies at risk for WD. This novel technology has potential as a universal strategy for NIPT of other monogenic disorders, since it requires only knowledge of the parental pathogenic mutations.

scholarly journals Expanded Noninvasive Prenatal Testing for Chromosomal aneuploidies and Copy Number Variants in a Cohort of 16128 Single Pregnancies

2021 ◽  
Author(s):  
Jing He ◽  
Xuan Feng ◽  
Xing Wang ◽  
Qinghua Zhang ◽  
Lei Zheng ◽  
...  
Keyword(s):  
Copy Number ◽  
Chromosomal Abnormalities ◽  
Copy Number Variants ◽  
Prenatal Testing ◽  
True Positive ◽  
Noninvasive Prenatal Testing ◽  
Cell Free Fetal Dna ◽  
Monogenic Diseases ◽  
Positive Rate ◽  
Chromosomal Aneuploidies

Abstract Background: Noninvasive prenatal testing (NIPT) is based on second-generation genomic sequencing technology to scan cell-free fetal DNA originating from the placenta in maternal plasma. As the depth of sequencing increases, it can be used to focus on chromosomal aneuploidies, copy number variants (CNVs), and monogenic diseases. It can significantly improve the accuracy of prenatal screening and reduces the number of invasive testing.Methods: In this study, we retrospectively analyzed 16128 naturally conceived singleton pregnancies who underwent expanded NIPT to calculate the true positive rate (TPR) of chromosomal aneuploidies and CNVs, and analyzed the potential influence of maternal sex chromosome abnormalities (SCAs) and maternal CNVs on expanded NIPT results.Results: After invasive prenatal diagnosis and follow-up, 103 pregnancies were found to be true-positive, including 73 cases of chromosomal abnormalities and 30 cases of CNVs. The TPR of T21 was 84.62%, T18 was 50.00%, T13 was 22.22%, SCA was 34.06%, and CNVs was 40.28%. In addition, we found that the positive rate of aneuploidies increased with maternal age and that maternal SCAs accounted for 13.33% of the 60 false positive cases of SCAs.Conclusion: Expanded NIPT showed high sensitivity and specificity in detecting diseases of chromosomal abnormalities. It also shows good performance in detecting CNVs, but maternal SCAs and CNVs confused some NIPT results, indicating it is still necessary to study the potential maternal influence on expanded NIPT results and to report related clinical validation studies.

scholarly journals Noninvasive Prenatal Testing of Methylmalonic Acidemia cblC Type Using the cSMART Assay for MMACHC Gene Mutations

2022 ◽  
Vol 12 ◽  
Author(s):  
Weigang Lv ◽  
Lili Liang ◽  
Xin Chen ◽  
Zhuo Li ◽  
Desheng Liang ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Sensitivity And Specificity ◽  
Single Molecule ◽  
Gene Mutations ◽  
Prenatal Testing ◽  
Maternal Plasma ◽  
Methylmalonic Acidemia ◽  
Plasma Dna ◽  
Noninvasive Prenatal Testing ◽  
Monogenic Diseases

Noninvasive prenatal testing (NIPT) for monogenic disorders has been developed in recent years; however, there are still significant technical and analytical challenges for clinical use. The clinical feasibility of NIPT for methylmalonic acidemia cblC type (cblC type MMA) was investigated using our circulating single-molecule amplification and re-sequencing technology (cSMART). Trios molecular diagnosis was performed in 29 cblC type MMA-affected children and their parents by traditional Sanger sequencing. In the second pregnancy, invasive prenatal diagnosis (IPD) of the pathogenic MMACHC gene was used to determine fetal genotypes, and NIPT was performed using a novel MMACHC gene–specific cSMART assay. Maternal–fetal genotypes were deduced based on the mutation ratio in maternal plasma DNA. Concordance of fetal genotypes between IPD and NIPT, and the sensitivity and specificity of NIPT were determined. After removing two cases with a low P value or reads, the concordance ratio for NIPT and IPD was 100.00% (27/27), and the sensitivity and specificity were 100.00% (54.07–100.00%) and 100.00% (83.89–100.00%), respectively. This study demonstrates that NIPT using the cSMART assay for cblC type MMA was accurate in detecting fetal genotypes. cSMART has a potential clinical application as a prenatal diagnosis and screening tool for carrier and low-risk genotypes of cblC type MMA and other monogenic diseases.

Hidden Markov Processes

2014 ◽  
Author(s):  
M. Vidyasagar
Keyword(s):  
Hidden Markov Models ◽  
Markov Processes ◽  
Viterbi Algorithm ◽  
Markov Models ◽  
Hidden Markov ◽  
Local Alignment ◽  
Biological Applications ◽  
Standard Material ◽  
Hidden Markov Processes ◽  
Genomics And Proteomics

This book explores important aspects of Markov and hidden Markov processes and the applications of these ideas to various problems in computational biology. It starts from first principles, so that no previous knowledge of probability is necessary. However, the work is rigorous and mathematical, making it useful to engineers and mathematicians, even those not interested in biological applications. A range of exercises is provided, including drills to familiarize the reader with concepts and more advanced problems that require deep thinking about the theory. Biological applications are taken from post-genomic biology, especially genomics and proteomics. The topics examined include standard material such as the Perron–Frobenius theorem, transient and recurrent states, hitting probabilities and hitting times, maximum likelihood estimation, the Viterbi algorithm, and the Baum–Welch algorithm. The book contains discussions of extremely useful topics not usually seen at the basic level, such as ergodicity of Markov processes, Markov Chain Monte Carlo (MCMC), information theory, and large deviation theory for both i.i.d and Markov processes. It also presents state-of-the-art realization theory for hidden Markov models. Among biological applications, it offers an in-depth look at the BLAST (Basic Local Alignment Search Technique) algorithm, including a comprehensive explanation of the underlying theory. Other applications such as profile hidden Markov models are also explored.

Parenting the Child With Down Syndrome: Understanding—but Going Beyond—the “Down Syndrome Advantage”

2020 ◽  
Author(s):  
Robert M. Hodapp ◽  
Ellen G. Casale
Keyword(s):  
Socioeconomic Status ◽  
Down Syndrome ◽  
Behavior Problems ◽  
Prenatal Testing ◽  
Children With Autism ◽  
Facial Features ◽  
Cultural Resources ◽  
Noninvasive Prenatal Testing ◽  
Birth Parents ◽  
Children With Down Syndrome

Compared to parents of children with other types of intellectual disabilities, parents of children with Down syndrome experience less stress and more rewards, although this “Down syndrome advantage” mostly occurs compared to parents of children with autism and before groups are equated. Behaviorally, children with Down syndrome display more sociable interactional styles and baby-faced facial features, along with fewer instances of severe behavior problems. Demographically, parents of children with (versus without) Down syndrome average 5 years older when giving birth; parents are more often well educated, married, of higher socioeconomic status, and they likely provide these children greater financial and cultural resources. In most industrialized societies, rates of Down syndrome seem steady, with easily available, noninvasive prenatal testing counteracted by increasing numbers of women giving birth at older ages. Parenting children with Down syndrome relates to characteristics of children, their parents, and society, all of which intersect in important, underexplored ways.

Jacobsen Syndrome Detected by Noninvasive Prenatal Testing

2015 ◽  
Vol 125 (2) ◽  
pp. 387-389 ◽  
Author(s):  
Jamie O. Lo ◽  
Cori D. Feist ◽  
Jason Hashima ◽  
Brian L. Shaffer
Keyword(s):  
Prenatal Testing ◽  
Noninvasive Prenatal Testing ◽  
Jacobsen Syndrome

scholarly journals Case–Parent Trio Studies in Cleft Lip and Palate

2020 ◽  
Vol 07 (03) ◽  
pp. 075-079
Author(s):  
Mahamad Irfanulla Khan ◽  
Prashanth CS
Keyword(s):  
Genetic Variants ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Association Studies ◽  
Geographical Location ◽  
Genetic Association Studies ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Family Based ◽  
Study Designs

AbstractCleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations in humans involving various genetic and environmental risk factors. The prevalence of CL/P varies according to geographical location, ethnicity, race, gender, and socioeconomic status, affecting approximately 1 in 800 live births worldwide. Genetic studies aim to understand the mechanisms contributory to a phenotype by measuring the association between genetic variants and also between genetic variants and phenotype population. Genome-wide association studies are standard tools used to discover genetic loci related to a trait of interest. Genetic association studies are generally divided into two main design types: population-based studies and family-based studies. The epidemiological population-based studies comprise unrelated individuals that directly compare the frequency of genetic variants between (usually independent) cases and controls. The alternative to population-based studies (case–control designs) includes various family-based study designs that comprise related individuals. An example of such a study is a case–parent trio design study, which is commonly employed in genetics to identify the variants underlying complex human disease where transmission of alleles from parents to offspring is studied. This article describes the fundamentals of case–parent trio study, trio design and its significances, statistical methods, and limitations of the trio studies.

scholarly journals Expanded noninvasive prenatal testing for fetal aneuploidy and copy number variations and parental willingness for invasive diagnosis in a cohort of 18,516 cases

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yunsheng Ge ◽  
Jia Li ◽  
Jianlong Zhuang ◽  
Jian Zhang ◽  
Yanru Huang ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
High Risk ◽  
Pregnant Women ◽  
Copy Number ◽  
Prenatal Testing ◽  
Copy Number Variations ◽  
Trisomy 13 ◽  
Noninvasive Prenatal Testing ◽  
Predictive Values ◽  
Parental Willingness

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.

Prenatal Genetic Screening, Epistemic Justice, and Reproductive Autonomy

Hypatia ◽  
2021 ◽  
Vol 36 (1) ◽  
pp. 1-21
Author(s):  
Amber Knight ◽  
Joshua Miller
Keyword(s):  
Prenatal Testing ◽  
Relevant Information ◽  
Medical Professionals ◽  
Reproductive Decisions ◽  
Reproductive Autonomy ◽  
Noninvasive Prenatal Testing ◽  
Epistemic Justice ◽  
Reproductive Decision Making ◽  
Testimonial Injustice ◽  
And Control

AbstractNoninvasive prenatal testing (NIPT) promises to enhance women's reproductive autonomy by providing genetic information about the fetus, especially in the detection of genetic impairments like Down syndrome (DS). In practice, however, NIPT provides opportunities for intensified manipulation and control over women's reproductive decisions. Applying Miranda Fricker's concept of epistemic injustice to prenatal screening, this article analyzes how medical professionals impair reproductive decision-making by perpetuating testimonial injustice. They do so by discrediting positive parental testimony about what it is like to raise a child with DS. We argue that this testimonial injustice constitutes a twofold harm: (1) people with DS and their family members who claim that parenting a child with DS may be a rewarding and joyous experience are harmed when they are systematically silenced, disbelieved, and/or denied epistemic credibility by medical professionals, and (2) pregnant women are harmed since they might make poorly informed choices without access to all relevant information. The broader implication of the analysis is that epistemic justice is a precondition of reproductive autonomy. We conclude by calling for federal oversight of the acquisition and dissemination of information that prospective parents receive following a positive diagnosis of DS to ensure that it is comprehensive and up to date.

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