Noninvasive Prenatal Diagnosis of Monogenic Disorders

Allen, Stephanie; Young, Elizabeth; Gerrish, Amy

doi:10.1016/b978-0-12-814189-2.00009-8

Cited by 5 publications

(5 citation statements)

References 52 publications

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“…The analysis of fetus-derived cfDNA through a noninvasive prenatal diagnosis (NIPD) has recently been clinically implemented for several monogenetic disorders [ 63 ]. Using a combination of NGS techniques, depending on the family history, we developed NIPD for retinoblastoma [ 39 ] that offers significant advantages over both newborn and invasive prenatal testing.…”

Section: Diagnosis Of Retinoblastomamentioning

confidence: 99%

The Impact of Cell-Free DNA Analysis on the Management of Retinoblastoma

Gerrish

Jenkinson

Cole

2021

Cancers

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Retinoblastoma is a childhood eye cancer, mainly caused by mutations in the RB1 gene, which can be somatic or constitutional. Unlike many other cancers, tumour biopsies are not performed due to the risk of tumour dissemination. As a result, until recently, somatic genetic analysis was only possible if an affected eye was removed as part of a treatment. Several recent proof of principle studies have demonstrated that the analysis of tumour-derived cell-free DNA, either obtained from ocular fluid or blood plasma, has the potential to advance the diagnosis and influence the prognosis of retinoblastoma patients. It has been shown that a confirmed diagnosis is possible in retinoblastoma patients undergoing conservative treatment. In vivo genetic analysis of retinoblastoma tumours is also now possible, allowing the potential identification of secondary genetic events as prognostic biomarkers. In addition, noninvasive prenatal diagnosis in children at risk of inheriting retinoblastoma has been developed. Here, we review the current literature and discuss the potential impact of cell-free DNA analysis on both the diagnosis and treatment of retinoblastoma patients and their families.

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Section: Diagnosis Of Retinoblastomamentioning

confidence: 99%

The Impact of Cell-Free DNA Analysis on the Management of Retinoblastoma

Gerrish

Jenkinson

Cole

2021

Cancers

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“…Therefore, test results of both WGS‐ and SNP‐based NIPTs were affected by factors not characterized in the testing sample. Moreover, quantitative measures were used to detect aneuploidies and pCNVs for both NIPT methods, which were greatly affected by outliers 6,8,27 . For our method, each sequencing read was either assigned to an allele or discarded, and then relative counts between different alleles were analyzed.…”

Section: Discussionmentioning

confidence: 99%

“…NIPT shows high sensitivity and specificity for common fetal aneuploidies, such as trisomies 21, 18, and 13, but low sensitivity and specificity for detecting subchromosomal deletions and duplications, 6 especially when the genomic aberrations are small 7 . For monogenic disorders (MDs), different noninvasive approaches have been developed, 8 but the application of such methods in clinical practice has lagged behind aneuploidy testing due to high costs and technical challenges. Due to different test philosophies, current NIPT approaches cannot be extended to detect monogenetic disorders in a cost‐effective manner.…”

Section: Introductionmentioning

confidence: 99%

Noninvasive detection of fetal genetic variations through polymorphic site sequencing of maternal plasma DNA

Gao

2021

The Journal of Gene Medicine

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Background Noninvasive prenatal testing (NIPT) for common fetal aneuploidies has been widely adopted in clinical practice for its sensitivity and accuracy. However, detection of pathogenic copy number variations (pCNVs) or monogenic disorders (MDs) is inaccurate and not cost effective. Here we developed an assay, the noninvasive prenatal testing based on goodness‐of‐fit and graphical analysis of polymorphic sites (GGAP‐NIPT), to simultaneously detect fetal aneuploidies, pCNVs, and MDs. Methods Polymorphic sites were amplicon sequenced, followed by fetal fraction estimation using allelic reads counts and a robust linear regression model. The genotype of each polymorphic site or MD variant was then determined by allelic goodness‐of‐fit test or graphical analysis of its different alleles. Finally, aneuploidies and pCNVs were detected using collective goodness‐of‐fit test to select each best fit from all possible chromosomal models. Results Of the simulated 1,692 chromosomes and 1,895 pCNVs, all normals and variants were correctly identified (accuracy 100%, sensitivity 100%, specificity 100%). Of the 713,320 simulated MD variants, more than 90% of the genotypes were determined correctly (accuracy: 98.3 ± 1.0%; sensitivity: 98.7 ± 1.96%; specificity: 99.7 ± 0.6%). The detection accuracies of three public MD datasets were 95.70%, 93.43%, and 96.83%. For an MD validation dataset, 75% detection accuracy was observed when a site with sample replicates was analyzed individually, and 100% accuracy was achieved when analyzed collectively. Conclusions Fetal aneuploidies, pCNVs, and MDs could be detected simultaneously and with high accuracy through amplicon sequencing of polymorphic and target sites, which showed the potential of extending NIPT to an expanded panel of genetic disorders.

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“…The routine clinical diagnosis of thalassemia is to use invasive prenatal diagnostic techniques such as amniocentesis, chorionic villus sampling, or umbilical cord puncture to obtain fetal cells and perform thalassemia gene detection. It inevitably carries a risk of infection and a fetal loss rate of approximately 1% [21][22][23][24]. However, even in cases where both parents are carriers of the same recessive monogenic disorder, the probability that the child is homozygous is only one in four, meaning that 75 percent of diagnoses result in a healthy child or a carrier who does not require further treatment.…”

Section: Introductionmentioning

confidence: 99%

Integration of targeted sequencing and pseudo-tetraploid genotyping into clinically assisted decision support for β-thalassemia invasive prenatal diagnosis

et al. 2023

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Background The high prevalence of β-thalassemia indicates the severe medical burden in Guangxi province in China. Millions of thousands of prenatal women with healthy or thalassemia-carrying fetuses received an unnecessary prenatal diagnosis. We designed a prospective single-center proof-of-concept study to evaluate the utility of a noninvasive prenatal screening method in the stratification of beta-thalassemia patients before invasive procedures. Methods Next-generation and optimized pseudo-tetraploid genotyping-based methods were utilized in preceding invasive diagnosis stratification to predict the mater-fetus genotype combinations in cell-free DNA, which is from maternal peripheral blood. Populational linkage disequilibrium information with additional neighboring loci to infer the possible fetal genotype. The concordance of the pseudo-tetraploid genotyping with the gold standard invasive molecular diagnosis was used to evaluate the effectiveness of this method. Results 127 β-thalassemia carrier parents were consecutively recruited. The total genotype concordance rate is 95.71%. The Kappa value was 0.8248 for genotype combinations and 0.9118 for individual alleles. Conclusion This study offers a new approach to picking out the health or carrier fetus before invasive procedures. It provides valuable novel insight into patient stratification management on β-thalassemia prenatal diagnosis.

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Noninvasive Prenatal Diagnosis of Monogenic Disorders

Cited by 5 publications

References 52 publications

The Impact of Cell-Free DNA Analysis on the Management of Retinoblastoma

The Impact of Cell-Free DNA Analysis on the Management of Retinoblastoma

Noninvasive detection of fetal genetic variations through polymorphic site sequencing of maternal plasma DNA

Integration of targeted sequencing and pseudo-tetraploid genotyping into clinically assisted decision support for β-thalassemia invasive prenatal diagnosis

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