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  • Correspondence
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Reply to Van Opstal D. & Faas B.H.W.

European Journal of Human Genetics volume 34, pages 5–7 (2026)Cite this article

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The Original Article was published on 07 November 2024

A Correspondence to this article was published on 07 November 2024

The Original Article was published on 16 July 2024

We appreciate the opportunity to address the concerns raised by our esteemed colleagues. However, we wish to underscore the importance of precision and context in assessing the methodology of our work, particularly within the field of prenatal diagnosis. We believe that the critique provided lacks the necessary nuance and overlooks several crucial aspects relevant to the scenario in question. In the following response, we aim to demonstrate the pertinence of the strategy we have chosen and to clarify the rationale behind our methodological approach.

Montpellier University Hospital’s cytogenetics laboratory is structured to prioritize prenatal molecular biology techniques, notably chromosomal microarray (CMA) and QF-PCR, using uncultured chorionic villus sampling (CVS). This choice reflects a balance between the inherent advantages and limitations of both uncultured CVS and cultured mesenchymal core (MC) analysis (Table 1). One significant advantage of uncultured CVS is the markedly reduced time-to-results, which is crucial in urgent clinical scenarios where waiting for MC cultures can delay critical decision-making. Additionally, although cultured MC analysis may more closely reflect the fetal genome, it lacks the sensitivity to detect cytotrophoblast (CTB)-restricted CPM (CPM type I), focusing instead on MC-related CPM (CPM type II and III). Hence, this limitation might result in the cultured MC-based analyses overlooking clinically relevant cases of CPM. Indeed, CPM can be associated with deleterious fetal outcomes such as intrauterine growth restriction (IUGR), fetal structural morphological anomalies, and preterm birth. Evidence shows CPM involving seven chromosomes (i.e. chromosomes 2, 3, 7, 13, 15, 16, 22) significantly correlates with a birthweight below the 3rd percentile, while 24.2% of cases are associated with fetal malformations [1]. This study reviewing 328 CPM cases further reports fifteen pregnancy terminations (4.6%) and nine premature postnatal deaths (2.7%), primarily due to severe IUGR [1]. Interestingly, a recent complementary study supervised by our esteemed colleague, Mrs. Van Opstal, whom we are privileged to address in this response, provides further insight into the IUGR risks associated with the different CPM subtypes. The study reports that CPM type I is associated with a 29.4% rate of IUGR (15/51), compared to 44.2% (19/41) for CPM type III and 7% (3/15) for CPM type II [2]. From our perspective, these findings directly align with our stance on the importance of screening for CTB-restricted CPM, as it allows for a closer and more tailored follow-up during pregnancy, ensuring optimal care for the affected couple. Moreover, detecting all kinds of CPM may help in uncovering fetal uniparental disomy (UPD), often arising from post-zygotic trisomy rescue, which might occur without any accompanying ultrasound abnormalities [3]. Identifying such UPDs is particularly critical when involving chromosomes associated with imprinting disorders (ID), such as chromosomes 7, 14, and 15 [4]. A striking example is the case reported by Grati et al., where a fetal maternal UPD14 was likely linked to CPM type I, as supported by the presence of a CTB-restricted trisomy 14 (47,XY, + 14 in 12/28 direct metaphases) and normal results from cultured MC analysis (46,XY in 8/8 metaphases) [5]. Maternal UPD14 is the primary genetic cause of Temple syndrome (MIM 616222), an autosomal dominant ID characterized by neurodevelopmental delay, short stature, craniofacial features, and hypotonia [6]. Notably, this case of fetal UPD14 would have been presumably missed if genetic testing had relied solely on cultured MC, underscoring the limitations of this approach in detecting certain fetal genomic events. Nevertheless, noteworthy it is to mention that the increasing adoption of noninvasive prenatal testing (NIPT) represents an aid in the detection of CPM type I and might support the use of cultured MC as the primary biological material for molecular analyses [7, 8]. However, crucial it is to outline that guidelines for NIPT use, as well as the scope of genetic variations it is designed to detect, highly differ from one country to another. As a matter of fact, to date, clinical French guidelines recommend NIPT exclusively for single pregnancies with a first-trimester risk of trisomy 21 between 1/51 and 1/1000, and in the absence of ultrasound abnormalities [9]. Of note, women pregnant with twins can also benefit from NIPT as a first line aneuploidy screening test [9]. Hence, in the presented scenario, NIPT was not appropriate in light of the French recommendations as the fetus exhibited increased nuchal translucency, justifying the need for a CVS.

Table 1 Comparison between uncultured chorionic villus sampling and cultured mesenchymal core.
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Fig. 1: Summary of possible scenario’s frameworks.

References

  1. Eggenhuizen GM, Go A, Koster MPH, Baart EB, Galjaard RJ. Confined placental mosaicism and the association with pregnancy outcome and fetal growth: a review of the literature. Hum Reprod Update. 2021;27:885–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Eggenhuizen GM, Go ATJI, Sauter Z, Hoffer MJV, Haak MC, Geeven G, et al. The role of confined placental mosaicism in fetal growth restriction: a retrospective cohort study. Prenat Diagn. 2024;44:289–96.

    Article  PubMed  Google Scholar 

  3. Eggermann T, Soellner L, Buiting K, Kotzot D. Mosaicism and uniparental disomy in prenatal diagnosis. Trends Mol Med. 2015;21:77–87.

    Article  PubMed  Google Scholar 

  4. Benn P. Uniparental disomy: origin, frequency, and clinical significance. Prenat Diagn. 2021;41:564–72.

    Article  CAS  PubMed  Google Scholar 

  5. Grati FR, Grimi B, Frascoli G, Di Meco AM, Liuti R, Milani S, et al. Confirmation of mosaicism and uniparental disomy in amniocytes, after detection of mosaic chromosome abnormalities in chorionic villi. Eur J Hum Genet. 2006;14:282–8.

    Article  CAS  PubMed  Google Scholar 

  6. Prasasya R, Grotheer KV, Siracusa LD, Bartolomei MS. Temple syndrome and Kagami-Ogata syndrome: clinical presentations, genotypes, models and mechanisms. Hum Mol Genet. 2020;29:R107–16.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Brison N, Neofytou M, Dehaspe L, Bayindir B, Van Den Bogaert K, Dardour L, et al. Predicting fetoplacental chromosomal mosaicism during non-invasive prenatal testing. Prenat Diagn. 2018;38:258–66.

    Article  CAS  PubMed  Google Scholar 

  8. Mardy AH, Norton ME. Diagnostic testing after positive results on cell free DNA screening: CVS or Amnio? Prenat Diagn. 2021;41:1249–54.

    Article  CAS  PubMed  Google Scholar 

  9. Haute Autorité de Santé [Internet]. Place des tests ADN libre circulant dans le sang maternel dans le dépistage de la trisomie 21 foetale. Available from: https://www.has-sante.fr/jcms/c_2768510/fr/place-des-tests-adn-libre-circulant-dans-le-sang-maternel-dans-le-depistage-de-la-trisomie-21-foetale

  10. Coorens THH, Oliver TRW, Sanghvi R, Sovio U, Cook E, Vento-Tormo R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. 2021;592:80–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Grati FR. Chromosomal mosaicism in human feto-placental development: implications for prenatal diagnosis. J Clin Med. 2014;3:809–37.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Verebi C, Gravrand V, Bienvenu T, Leturcq F, Nectoux J. A retrospective cohort study and review of the literature about germline mosaicism in Duchenne/Becker muscular dystrophy prenatal counseling: How to estimate the recurrence risk in clinical settings? J Genet Couns. 2024;00:1–10.

    Google Scholar 

  13. Kubota A, Ishiura H, Porto KJL, Tanaka M, Mitsui J, Unuma A, et al. DMD exon 2 duplication due to a complex genomic rearrangement is associated with a somatic mosaicism. Neuromuscul Disord. 2022;32:263–9.

    Article  PubMed  Google Scholar 

  14. Zampatti S, Mela J, Peconi C, Pagliaroli G, Carboni S, Barrano G, et al. Identification of Duchenne/Becker muscular dystrophy mosaic carriers through a combined DNA/RNA analysis. Prenat Diagn. 2018;38:1096–102.

    Article  CAS  PubMed  Google Scholar 

  15. Kesari A, Neel R, Wagoner L, Harmon B, Spurney C, Hoffman EP. Somatic mosaicism for Duchenne dystrophy: evidence for genetic normalization mitigating muscle symptoms. Am J Med Genet A. 2009;149A:1499–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Juan-Mateu J, Paradas C, Olivé M, Verdura E, Rivas E, González-Quereda L, et al. Isolated cardiomyopathy caused by a DMD nonsense mutation in somatic mosaicism: genetic normalization in skeletal muscle. Clin Genet. 2012;82:574–8.

    Article  CAS  PubMed  Google Scholar 

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No specific funding was allocated to this study.

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Author notes

  1. These authors contributed equally: Mireille Cossée, Vincent Gatinois.

Authors and Affiliations

  1. Montpellier University, Centre de Référence « Anomalies du Développement et Syndromes Malformatifs », ERN-ITHACA, Department of Clinical Genetics, University Hospital of Montpellier, Montpellier, France

    Quentin Sabbagh & Christine Coubes

  2. Montpellier University, Molecular Diagnostic Laboratory, University Hospital of Montpellier, Montpellier, France

    Marion Larrieux, Corinne Theze, Marie-Claire Vincent, Michel Koenig & Mireille Cossée

  3. Montpellier University, Laboratory of Cytogenomics, University Hospital of Montpellier, Montpellier, France

    Anouck Schneider, Jacques Puechberty, Franck Pellestor & Vincent Gatinois

  4. Montpellier University, INSERM, CNRS, PhyMedExp, Montpellier, France

    Marie-Claire Vincent, Michel Koenig & Mireille Cossée

  5. Perpignan Hospital, Department of Obstetrics and Gynecology, Perpignan, France

    Sarah Renard

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Contributions

Conception and design of the reply: QS, JP, FP, MC, VG. Drafting the manuscript: QS. Revising the manuscript: QS, ML, AS, CT, MCV, CC, JP, SR, MK, FP, MC, VG. Approval of the version of the manuscript to be published: QS, ML, AS, CT, MCV, CC, JP, SR, MK, FP, MC, VG.

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Correspondence to Quentin Sabbagh.

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Sabbagh, Q., Larrieux, M., Schneider, A. et al. Reply to Van Opstal D. & Faas B.H.W.. Eur J Hum Genet 34, 5–7 (2026). https://doi.org/10.1038/s41431-024-01724-6

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