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Recent Trends in Prenatal Genetic Screening and Testing
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Recent Trends in Prenatal Genetic Screening and Testing

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Obstetrics & Gynecology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 11897

Special Issue Editors

Prof. Dr. Sabrina Giglio

E-Mail Website
Guest Editor
Medical Genetics Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
Interests: clinical genomics; precision medicine and omics science; pediatric rare diseases; genome and exome sequencing in oncology; exome and genome sequencing in prenatal diagnosis; cell free DNA
Dr. Aldesia Provenzano

E-Mail Website
Guest Editor
Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
Interests: pre-conceptional, post-conception genetic counseling; prenatal and post-natal genetic counseling; pediatric and adulthood genetic counseling; complex evaluations of clinical genetics in the pediatric field and adulthood diseases; multidisciplinary prenatal, pediatric and adult evaluations; interpretation of next generation sequencing data
Prof. Dr. Orsetta Zuffardi

E-Mail Website
Guest Editor
Department of Molecular Medicine, University of Pavia, Someraro, Italy
Interests: pre-conceptional, post-conception genetic counseling; prenatal and post-natal genetic counseling; pediatric and adulthood genetic counseling; complex evaluations of clinical genetics in the pediatric field and adulthood diseases; multidisciplinary prenatal, pediatric and adult evaluations; interpretation of next generation sequencing data

Special Issue Information

Dear Colleagues,

Noninvasive prenatal diagnosis (NIPD) has become routine test in the last years. It is achieved by studying cell-free DNA (cfDNA) in the maternal plasma, which contains fetal cfDNA (cffDNA) derived from the placenta. NIPD is frequently limited to the screening of chromosomal anomalies, fetal sex determination and Rhesus D genotyping.

Actually, about 25-30% of genomic rearrangements visible through molecular cytogenetics are underlying congenital anomalies and 10-20% of isolated or syndromic anomalies can be associated with monogenic diseases, whose diagnosis is often established based on a family history, clinical examination, and confirmed through genetic tests.

In our study, the challenge was to apply trio-Whole Exome Sequencing (trio-WES) strategy using cffDNA, in order to implement NIPD to cases of fetal ultrasound malformations.

This approach was able to evaluate the presence of genetic variants in a cohort of different fetuses with structural anomalies, after exclusion of aneuploidy and CNVs in those women that were undergoing invasive testing for increased nuchal translucency (> 4mm), structural anomalies in their fetus, or family history for genetic diseases.

Our primary endpoint, which was evaluated in all fetuses, was the identification of diagnostic genetic variants believed to be responsible for the fetal abnormality. The results were compared with those obtained from the invasive procedure, demonstrating the validity of our method that could also be used in routinely prenatal diagnosis.

Although WES on cffDNA requires technical and analytical challenges, we have highlighted that this approach has an excellent diagnostic yield and could be used also in the diagnostic prenatal setting for both recessive and dominant disorders. Therefore, WES on cffDNA could be regularly used in families negative for hereditary genetic conditions to identify new pathogenetic variants in the offspring avoiding the use of invasive tests.

Prof. Dr. Sabrina Giglio
Dr. Aldesia Provenzano
Prof. Dr. Orsetta Zuffardi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • noninvasive prenatal diagnosis
  • fetal cell-free DNA (cffDNA)
  • Whole Exome Sequencing (WES)
  • genetic variants, genomic rearrangements
  • prenatal genetic counselling
  • aneuploidy and CNVs

Published Papers (3 papers)

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Research

23 pages, 1198 KiB  
Article
A Critical Evaluation of Validation and Clinical Experience Studies in Non-Invasive Prenatal Testing for Trisomies 21, 18, and 13 and Monosomy X
by Zachary Demko, Brittany Prigmore and Peter Benn
J. Clin. Med. 2022, 11(16), 4760; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11164760 - 15 Aug 2022
Cited by 9 | Viewed by 2194
Abstract
Non-invasive prenatal testing (NIPT) for trisomies 21, 18, 13 and monosomy X is widely utilized with massively parallel shotgun sequencing (MPSS), digital analysis of selected regions (DANSR), and single nucleotide polymorphism (SNP) analyses being the most widely reported methods. We searched the literature [...] Read more.
Non-invasive prenatal testing (NIPT) for trisomies 21, 18, 13 and monosomy X is widely utilized with massively parallel shotgun sequencing (MPSS), digital analysis of selected regions (DANSR), and single nucleotide polymorphism (SNP) analyses being the most widely reported methods. We searched the literature to find all NIPT clinical validation and clinical experience studies between January 2011 and January 2022. Meta-analyses were performed using bivariate random-effects and univariate regression models for estimating summary performance measures across studies. Bivariate meta-regression was performed to explore the influence of testing method and study design. Subgroup and sensitivity analyses evaluated factors that may have led to heterogeneity. Based on 55 validation studies, the detection rate (DR) was significantly higher for retrospective studies, while the false positive rate (FPR) was significantly lower for prospective studies. Comparing the performance of NIPT methods for trisomies 21, 18, and 13 combined, the SNP method had a higher DR and lower FPR than other methods, significantly so for MPSS, though not for DANSR. The performance of the different methods in the 84 clinical experience studies was consistent with validation studies. Clinical positive predictive values of all NIPT methods improved over the last decade. We conclude that all NIPT methods are highly effective for fetal aneuploidy screening, with performance differences across methodologies. Full article
(This article belongs to the Special Issue Recent Trends in Prenatal Genetic Screening and Testing)
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10 pages, 1888 KiB  
Article
Non-Invasive Detection of a De Novo Frameshift Variant of STAG2 in a Female Fetus: Escape Genes Influence the Manifestation of X-Linked Diseases in Females
by Aldesia Provenzano, Andrea La Barbera, Francesco Lai, Andrea Perra, Antonio Farina, Ettore Cariati, Orsetta Zuffardi and Sabrina Giglio
J. Clin. Med. 2022, 11(14), 4182; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11144182 - 19 Jul 2022
Cited by 2 | Viewed by 1689
Abstract
Background: We report on a 20-week-old female fetus with a diaphragmatic hernia and other malformations, all of which appeared after the first-trimester ultrasound. Methods and Results: Whole trio exome sequencing (WES) on cell-free fetal DNA (cff-DNA) revealed a de novo frameshift variant of [...] Read more.
Background: We report on a 20-week-old female fetus with a diaphragmatic hernia and other malformations, all of which appeared after the first-trimester ultrasound. Methods and Results: Whole trio exome sequencing (WES) on cell-free fetal DNA (cff-DNA) revealed a de novo frameshift variant of the X-linked STAG2 gene. Loss-of-function (LoF) STAG2 variants cause either holoprosencephaly (HPE) or Mullegama–Klein–Martinez syndrome (MKMS), are de novo, and only affect females, indicating male lethality. In contrast, missense mutations associate with milder forms of MKMS and follow the classic X-linked recessive inheritance transmitted from healthy mothers to male offspring. STAG2 has been reported to escape X-inactivation, suggesting that disease onset in LoF females is dependent on inadequate dosing for at least some of the transcripts, as is the case with a part of the autosomal dominant diseases. Missense STAG2 variants produce a quantity of transcripts, which, while resulting in a different protein, leads to disease only in hemizygous males. Similar inheritance patterns are described for other escapee genes. Conclusions: This study confirms the advantage of WES on cff-DNA and emphasizes the role of the type of the variant in X-linked disorders. Full article
(This article belongs to the Special Issue Recent Trends in Prenatal Genetic Screening and Testing)
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13 pages, 1495 KiB  
Article
Fetal Nasal Bone Hypoplasia in the Second Trimester as a Marker of Multiple Genetic Syndromes
by Hanna Moczulska, Marcin Serafin, Katarzyna Wojda, Maciej Borowiec and Piotr Sieroszewski
J. Clin. Med. 2022, 11(6), 1513; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11061513 - 10 Mar 2022
Cited by 5 | Viewed by 11238
Abstract
Nasal bone hypoplasia is associated with a trisomy of chromosome 21, 18 or 13. Nasal bone hypoplasia can also be seen in other, rarer genetic syndromes. The aim of the study was to evaluate the potential of nasal bone hypoplasia, in the second [...] Read more.
Nasal bone hypoplasia is associated with a trisomy of chromosome 21, 18 or 13. Nasal bone hypoplasia can also be seen in other, rarer genetic syndromes. The aim of the study was to evaluate the potential of nasal bone hypoplasia, in the second trimester of pregnancy, as a marker of fetal facial dysmorphism, associated with pathogenic copy number variation (CNV). This retrospective analysis of the invasive tests results in fetuses with nasal bone hypoplasia, after excluding those with trisomy 21, 18 and 13. In total, 60 cases with nasal bone hypoplasia were analyzed. Chromosomal aberrations were found in 7.1% of cases of isolated nasal bone hypoplasia, and in 57% of cases of nasal bone hypoplasia with additional malformations. Additionally, in four of nine cases with non-isolated nasal bone hypoplasia but normal CMA results, a monogenic disease was diagnosed. Non-isolated hypoplastic nasal bone appears to be an effective objective marker of fetal facial dysmorphism, associated with pathogenic CNVs or monogenic diseases. In isolated cases, chromosomal microarray testing can be of additional value if invasive testing is performed, e.g., for aneuploidy testing after appropriate counseling. Full article
(This article belongs to the Special Issue Recent Trends in Prenatal Genetic Screening and Testing)
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