Haplotype‐based non‐invasive prenatal diagnosis of recessive dystrophic epidermolysis bullosa via targeted capture sequencing of maternal plasma

Wang, Jianbo; Gao, Pengfei; Cao, Qiaoyu; Chen, Fuying; Song, Jinghui; Wang, Chen; Dou, Jinfa; Wu, Yiming; Niu, Qiaona; Li, Jianguo; Li, Ming; Lu, Daru

doi:10.1111/1346-8138.16760

Cited by 3 publications

(3 citation statements)

References 14 publications

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“…At the same time, it provides hope for those highrisk couples without pregnancy and birth history identi ed by carrier screening. According to the existing successful research like DMD, PKU, and SMA, appropriate novel probes were designed for different diseases when clinically necessary (33). Besides, population haplotype construction that does not depend on the trio family is also in the process of continuous development (34).…”

Section: Discussionmentioning

confidence: 99%

The promise of carrier screening: noninvasive prenatal diagnoses without proband for spinal muscular atrophy in early gestation age

Li,

Zhao

et al. 2024

Preprint

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The feasibility of traditional noninvasive prenatal diagnosis (NIPD) relying on proband-based relative haplotype dose analysis has been demonstrated. However, the prognosis of type I spinal muscular atrophy (SMA) is poor, and the proband sample is hard to collect during the second pregnancy. We investigate the feasibility of NIPD for SMA via haplotype construction without the need for a proband. Six samples were collected from both the paternal and maternal families in 36 families at risk of SMA. By enriching the SMN1/2 gene and its upstream and downstream informative SNPs, the family haplotype was constructed, and the Bayes factor was used to infer the fetal genotype by the dose changes of informational SNPs in cell-free DNA. All samples underwent MLPA testing after chorion villus sampling or amniocentesis. The MLPA results showed 100% consistency with NIPD. The earliest gestational week for successful NIPD was 7+ 3 weeks, with a minimum fetal fraction of 1.9%. Haplotype construction based on both paternal and maternal families demonstrated significant reliability and feasibility for families without a proband. Additionally, this approach provides a safer, and earlier prenatal diagnosis option for couples identified as at-risk through SMA carrier screening.

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Section: Discussionmentioning

confidence: 99%

The promise of carrier screening: noninvasive prenatal diagnoses without proband for spinal muscular atrophy in early gestation age

Li,

Zhao

et al. 2024

Preprint

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“…According to the existing successful research like DMD, PKU, and SMA, we believe that the application of NIPD for autosomal recessive genetic diseases is relatively mature. In addition, we can design appropriate probes for different diseases and perform haplotype analysis when clinically necessary [30]. Except for the design of new probes, population haplotype construction that does not depend on the trio family is also in the process of continuous development [31].…”

Section: Discussionmentioning

confidence: 99%

Haplotype-based noninvasive prenatal diagnoses of 36 fetuses with spinal muscular atrophy in the real clinical environment at early gestation age

Li²,

Zhao

et al. 2023

Preprint

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Objective To explore the feasibility of noninvasive prenatal diagnoses (NIPD) based on haplotype construction and Bayes factor (BF) for spinal muscular atrophy (SMA) in clinical application. Methods 36 singleton families with pregnancy risk of SMA were recruited and all the recruited members were conducted MLPA to validate the copy number of exons 7 and 8 in SMN1 and SMN2 genes. The designed capture panel covered the entire SMN1/2 genes, including all exon and intron regions of the two genes. To ensure the NIPD accuracy, four quality control standards were set: sequencing depth, the number of informative SNPs, cell-free DNA fetal fraction, and the recombination event assessment. By enriching targeting genes and informative SNP sites in adjacent regions, the family haplotype was constructed and the fetal genotype was determined based on the dose change of the informative SNPs in cfDNA combined with BF algorithm. All NIPD results were verified by chorionic villus sampling (CVS), amniocentesis, or apoblema testing. Results In the 36 recruited SMA families, 34 (94.4%) families were successfully tested for NIPD, and 2 (5.56%) families could not be determined exactly because of the recombination event near the pathogenic mutations. In successful families, the earliest gestational week for NIPD was 7+ 3 weeks, and the lowest free fetal DNA fraction was 1.9%. A total of 8 affected fetuses, 6 paternal carriers, 8 maternal carriers, and 12 unaffected fetuses were detected. The consistency between NIPD results and invasive MLPA diagnosis was 100%. Four (11.1%) of the families obtained accurate results after redrawing blood samples due to low fetal fraction or insufficiency of informative SNPs. Follow-up results showed that all families with affected NIPD results underwent abortions, and the families with carrier and normal results chose to deliver the fetus. Conclusion NIPD is a noninvasive, high-accuracy, early pregnancy detection and cost-controllable technical method. The haplotype construction and BF analysis have considerable reliability and feasibility and could be used in the detection of other recessive monogenic diseases.

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“…This was done as described (Wang et al 2023). Ten ml of maternal blood were centrifuged at 1600×g for 10 min, followed by 16000×g for 10 min for rapid separation of plasma from whole blood.…”

Section: Sample Processing and Next-generation Sequencingmentioning

confidence: 99%

A Feasibility Study of Non-Invasive Prenatal Testing of Thalassemia by Haplotype Analysis Based on Next Generation Sequencing and Long-Read Sequencing

Wang,

Huang,

et al. 2023

Preprint

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To investigate the feasibility of constructing parental haplotypes based on short-read next-generation (NGS) and long-read third-generation sequencing (TGS) for non-invasive prenatal testing (NIPT) of thalassemia.Families at risk of having children with moderate to severe thalassemia were recruited for this study. Genomic DNA from both couples and sibling or grandparents of the fetus was first applied to construct haplotypes in couples using targeted NGS. For families where parental haplotypes could not be built using NGS, directly using TGS. NGS was performed on cell-free DNA in maternal peripheral blood to obtain information on fetal allele depth distribution, fetal fraction, etc. Haplotypes and thalassemia genotypes of fetuses were then deduced using the Viterbi decoding algorithm based on a hidden Markov model. Finally, the NIPT results were verified by invasive prenatal diagnosis (IPD). As a result, pedigree-based NGS successfully deduced the thalassemia genotype of the fetus in 93.3%(28/30). However, 2 families had failed because both sibling or grandparents of the fetus and couples were heterozygous for point mutations in the same thalassemia gene. In these 2 families, TGS directly inferred parental haplotypes and deduced fetuses genotypes. This combined strategy resulted in the prediction of fetal genotypes in all 30 families, and its coincidence rate with IPD results reached 100%. In brief, Pedigree-based NGS is enough to construct haplotype and decuce genotypes in most fetuses. TGS is helpful in certain families in which NGS failed. Therefore, comprehensive application of haplotype analysis based on NGS and TGS data is an effective strategy for NIPT in thalassemia.

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Haplotype‐based non‐invasive prenatal diagnosis of recessive dystrophic epidermolysis bullosa via targeted capture sequencing of maternal plasma

Cited by 3 publications

References 14 publications

The promise of carrier screening: noninvasive prenatal diagnoses without proband for spinal muscular atrophy in early gestation age

The promise of carrier screening: noninvasive prenatal diagnoses without proband for spinal muscular atrophy in early gestation age

Haplotype-based noninvasive prenatal diagnoses of 36 fetuses with spinal muscular atrophy in the real clinical environment at early gestation age

A Feasibility Study of Non-Invasive Prenatal Testing of Thalassemia by Haplotype Analysis Based on Next Generation Sequencing and Long-Read Sequencing

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