Development of a comprehensive noninvasive prenatal test

Malcher, Carolina; Yamamoto, Guilherme Lopes; Burnham, Philip; Ezquina, Suzana; Lourenço, Naila Cristina Vilaça; Balkassmi, Sahilla; Antônio, David Santos Marco; Hsia, Gabriella Shih Ping; Gollop, Thomaz Rafael; Pavanello, Rita de Cássia M.; Lopes, Marco Antônio Borges; Bakker, Egbert; Zatz, Mayana; Bertola, Débora Romeo; Vlaminck, Iwijn De; Passos‐Bueno, Maria Rita

doi:10.1590/1678-4685-gmb-2017-0177

Cited by 8 publications

(13 citation statements)

References 52 publications

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“…One possible solution to overcome this challenge is to use the expected median FF of 10% [25]. In the case of the AR and RCAR models, we used informative polymorphic SNPs with heterozygous alleles in mother and/or fetus to infer the sample-specific FF ( S1 Fig ), similarly to previous studies [26–29]. Additionally, in the case of the AR and RCAR models, allelic count data at informative SNPs can be used to calculate allelic ratios, distinguishing maternally and paternally originated trisomies (see “Allelic ratio calculation” in Materials and Methods) according to their distinct allelic patterns ( S1 Table ).…”

Section: Resultsmentioning

confidence: 99%

Computational framework for targeted high-coverage sequencing based NIPT

et al. 2019

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Non-invasive prenatal testing (NIPT) enables accurate detection of fetal chromosomal trisomies. The majority of publicly available computational methods for sequencing-based NIPT analyses rely on low-coverage whole-genome sequencing (WGS) data and are not applicable for targeted high-coverage sequencing data from cell-free DNA samples. Here, we present a novel computational framework for a targeted high-coverage sequencing-based NIPT analysis. The developed framework uses a hidden Markov model (HMM) in conjunction with a supplemental machine learning model, such as decision tree (DT) or support vector machine (SVM), to detect fetal trisomy and parental origin of additional fetal chromosomes. These models were developed using simulated datasets covering a wide range of biologically relevant scenarios with various chromosomal quantities, parental origins of extra chromosomes, fetal DNA fractions, and sequencing read depths. Developed models were tested on simulated and experimental targeted sequencing datasets. Consequently, we determined the functional feasibility and limitations of each proposed approach and demonstrated that read count-based HMM achieved the best overall classification accuracy of 0.89 for detecting fetal euploidies and trisomies on simulated dataset. Furthermore, we show that by using the DT and SVM on the HMM classification results, it was possible to increase the final trisomy classification accuracy to 0.98 and 0.99, respectively. We demonstrate that read count and allelic ratio-based models can achieve a high accuracy (up to 0.98) for detecting fetal trisomy even if the fetal fraction is as low as 2%. Currently, existing commercial NIPT analysis requires at least 4% of fetal fraction, which can be possibly a challenge in case of early gestational age (<10 weeks) or high maternal body mass index (>35 kg/m 2 ). More accurate detection can be achieved at higher sequencing depth using HMM in conjunction with supplemental models, which significantly improve the trisomy detection especially in borderline scenarios (e.g., very low fetal fraction) and enables to perform NIPT even earlier than 10 weeks of pregnancy.

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Section: Resultsmentioning

confidence: 99%

Computational framework for targeted high-coverage sequencing based NIPT

et al. 2019

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“…Recently, three studies reported targeted capture NIPT to screen for chromosome aneuploidy, copy number variation, and monogenic disease. [32][33][34] such as early pregnancies or certain aneuploidies. 2,,35 A recent study has demonstrated the importance of prenatal screening for genetically dominant disorders caused by de novo mutations.…”

Section: Discussionmentioning

confidence: 99%

“…, 31 However, these methods require experiments that cannot cope with conventional NIPT method for chromosome analysis. Recently, three studies reported targeted capture NIPT to screen for chromosome aneuploidy, copy number variation, and monogenic disease 32–34 . However, their methods were time‐consuming due to 16–72 hours of hybridization capture after the preparation of cfDNA sequencing library.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous detection of fetal aneuploidy, de novoFGFR3 mutations and paternally derived β‐thalassemia by a novel method of noninvasive prenatal testing

Yang

et al. 2021

Prenatal Diagnosis

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Objective: The aim is to develop a novel noninvasive prenatal testing (NIPT) method that simultaneously performs fetal aneuploidy screening and the detection of de novo and paternally derived mutations. Methods: A total of 68 pregnancies, including 26 normal pregnancies, 7 cases with fetal aneuploidies, 7 cases with fetal achondroplasia or thanatophoric dysplasia, 18 cases with fetal skeletal abnormalities, and 10 cases with β-thalassemia high risk were recruited. Plasma cell-free DNA was amplified by Targeted And Genome-wide simultaneous sequencing (TAGs-seq) to generate around 99% of total reads covering the whole-genome region and around 1% covering the target genes. The reads on the whole-genome region were analyzed for fetal aneuploidy using a binary hypothesis T-score and the reads on target genes were analyzed for point mutations by calculating the minor allelic frequency of loci on FGFR3 and HBB. TAGs-seq results were compared with conventional NIPT and diagnostic results. Results: In each sample, TAGs-seq generated 44.7-54 million sequencing reads covering the whole-genome region of 0.1-3� and the target genes of >1000�depth. All cases of fetal aneuploidy and de novo mutations of achondroplasia/thanatophoric dysplasia were identified with high sensitivities and specificities except for one false-negative paternal mutation of β-thalassemia. Conclusions: TAGs-seq is a novel NIPT method that combines the fetal aneuploidy screening and the detection of de novo FGFR3 mutations and paternal HBB mutations. Lin Yang and Yujing Wu joint first authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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“…Several studies have sought to design an NIPD approach for the detection of common dominant skeletal dysplasias, including OI, and several cases have been successfully diagnosed using these methods [ 66 , 67 , 69 , 70 ]. All previous OI cases detected using NIPD harboured COL1A1 and COL1A2 variants, making these genes an essential part of the NIPD panel [ 67 , 69 , 70 , 71 ]. However, owing to the heterogeneity of OI, diagnosis may be inaccurate if other genes led to OI.…”

Section: Diagnosismentioning

confidence: 99%

Current Overview of Osteogenesis Imperfecta

et al. 2021

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Osteogenesis imperfecta (OI), or brittle bone disease, is a heterogeneous disorder characterised by bone fragility, multiple fractures, bone deformity, and short stature. OI is a heterogeneous disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. Severe OI is perinatally lethal, while mild OI can sometimes not be recognised until adulthood. Severe or lethal OI can usually be diagnosed using antenatal ultrasound and confirmed by various imaging modalities and genetic testing. The combination of imaging parameters obtained by ultrasound, computed tomography (CT), and magnetic resource imaging (MRI) can not only detect OI accurately but also predict lethality before birth. Moreover, genetic testing, either noninvasive or invasive, can further confirm the diagnosis prenatally. Early and precise diagnoses provide parents with more time to decide on reproductive options. The currently available postnatal treatments for OI are not curative, and individuals with severe OI suffer multiple fractures and bone deformities throughout their lives. In utero mesenchymal stem cell transplantation has been drawing attention as a promising therapy for severe OI, and a clinical trial to assess the safety and efficacy of cell therapy is currently ongoing. In the future, early diagnosis followed by in utero stem cell transplantation should be adopted as a new therapeutic option for severe OI.

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Development of a comprehensive noninvasive prenatal test

Cited by 8 publications

References 52 publications

Computational framework for targeted high-coverage sequencing based NIPT

Computational framework for targeted high-coverage sequencing based NIPT

Simultaneous detection of fetal aneuploidy, de novoFGFR3 mutations and paternally derived β‐thalassemia by a novel method of noninvasive prenatal testing

Current Overview of Osteogenesis Imperfecta

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