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Background: Hemophilia A (HEMA) is an X-linked bleeding disorder caused by reduced/absent coagulation factor VIII expression, as a result of pathogenic variants in the F8 gene. Preimplantation prevention of HEMA should ideally include direct pathogenic F8 variant detection, complemented by linkage analysis of flanking markers to identify the high-risk F8 allele. Linkage analysis is particularly indispensable when the pathogenic variant cannot be detected directly or identified. This study evaluated the suitability of a panel of F8 intragenic and extragenic short tandem repeat markers for standalone linkage-based preimplantation genetic testing for monogenic disorder (PGT-M) of the Inv22 pathogenic variant, an almost 600 kb paracentric inversion responsible for almost half of all severe HEMA globally, for which direct detection is challenging.

Methods: Thirteen markers spanning 1 Mb and encompassing both F8 and the Inv22 inversion interval were genotyped in 153 unrelated females of Viet Kinh ethnicity.

Results: All individuals were heterozygous for ≥ 1 marker, ~ 90% were heterozygous for ≥ 1 of the five F8 intragenic markers, and almost 98% were heterozygous for ≥ 1 upstream (telomeric) and ≥ 1 downstream (centromeric) markers. A prospective PGT-M couple at risk of transmitting F8 Inv22 were fully informative at four marker loci (2 intra-inversion, 1 centromeric, 1 telomeric) and partially informative at another five (2 intra-inversion, 3 centromeric), allowing robust phasing of low- and high-risk haplotypes. In vitro fertilization produced three embryos, all of which clearly inherited the low-risk maternal allele, enabling reliable unaffected diagnoses. A single embryo transfer produced a clinical pregnancy, which was confirmed as unaffected by amniocentesis and long-range PCR, and a healthy baby girl was delivered at term.

Conclusion: Robust and reliable PGT-M of HEMA, including the common F8 Inv22 pathogenic variant, can be achieved with sufficient informative intragenic and flanking markers.

Titel:	Robust preimplantation genetic testing of the common F8 Inv22 pathogenic variant of severe hemophilia A using a highly polymorphic multi-marker panel encompassing the paracentric inversion.
Autor/in / Beteiligte Person:	Nguyen, MT ; Nguyen, TT ; Nguyen, DB ; Nguyen, TM ; Nguyen, KN ; Ngo, VNM ; Nguyen, VD ; Tran, NA ; Lian, M ; Tan, ASC ; Chong, SS ; Dang, TT
Link:	Zum Volltext
Zeitschrift:	Thrombosis journal, Jg. 21 (2023-10-20), Heft 1, S. 108
Veröffentlichung:	[London] : BioMed Central, 2003-, 2023
Medientyp:	academicJournal
ISSN:	1477-9560 (print)
DOI:	10.1186/s12959-023-00552-w
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Thromb J] 2023 Oct 20; Vol. 21 (1), pp. 108. <i>Date of Electronic Publication: </i>2023 Oct 20. References: Konkle BA, Nakaya Fletcher S. Hemophilia A. Seattle: University of Washington, Seattle. 2000 [updated 2022 Oct 27]. https://www.ncbi.nlm.nih.gov/books/NBK1404/ . Accessed 30 Mar 2023. ; Stonebraker JS, Bolton-Maggs PH, Soucie JM, Walker I, Brooker M. A study of variations in the reported haemophilia A prevalence around the world. Haemophilia. 2010;16(1):20–32. (PMID: 10.1111/j.1365-2516.2009.02127.x19845775) ; Gouw SC, van den Berg HM, Oldenburg J, Astermark J, de Groot PG, Margaglione M, et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood. 2012;119(12):2922–34. (PMID: 10.1182/blood-2011-09-37945322282501) ; McVey JH, Rallapalli PM, Kemball-Cook G, Hampshire DJ, Giansily-Blaizot M, Gomez K, et al. The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases: Important resources for haemostasis clinicians and researchers. Haemophilia. 2020;26(2):306–13. (PMID: 10.1111/hae.1394732166871) ; Zhao M, Chen M, Tan ASC, Cheah FSH, Mathew J, Wong PC, et al. Single-tube tetradecaplex panel of highly polymorphic microsatellite markers < 1 Mb from F8 for simplified preimplantation genetic diagnosis of hemophilia A. J Thromb Haemost. 2017;15(7):1473–83. (PMID: 10.1111/jth.1368528345288) ; Kessler L, Adams R, Mighion L, Walther S, Ganguly A. Prenatal diagnosis in haemophilia A: experience of the genetic diagnostic laboratory. Haemophilia. 2014;20(6):e384–91. (PMID: 10.1111/hae.1251725196590) ; Harton GL, De Rycke M, Fiorentino F, Moutou C, SenGupta S, Traeger-Synodinos J, et al. ESHRE PGD consortium best practice guidelines for amplification-based PGD. Hum Reprod. 2011;26(1):33–40. (PMID: 10.1093/humrep/deq23120966462) ; Liu Q, Nozari G, Sommer SS. Single-tube polymerase chain reaction for rapid diagnosis of the inversion hotspot of mutation in hemophilia A. Blood. 1998;92(4):1458–9. (PMID: 10.1182/blood.V92.4.14589694739) ; Rossetti LC, Radic CP, Larripa IB, De Brasi CD. Genotyping the hemophilia inversion hotspot by use of inverse PCR. Clin Chem. 2005;51(7):1154–8. (PMID: 10.1373/clinchem.2004.04649015860568) ; Chen J, Wang J, Lin XY, Xu YW, He ZH, Li HY, et al. Genetic diagnosis in Hemophilia A from southern China: five novel mutations and one preimplantation genetic analysis. Int J Lab Hematol. 2017;39(2):191–201. (PMID: 10.1111/ijlh.1260227868395) ; Chen M, Chan JK, Nadarajah S, Tan AS, Chan ML, Mathew J, et al. Single-tube nonaplex microsatellite PCR panel for preimplantation genetic diagnosis of Hb Bart’s hydrops fetalis syndrome. Prenat Diagn. 2015;35(6):534–43. (PMID: 10.1002/pd.456825641621) ; Bui TMP, Tran VK, Nguyen TTH, Le TP, Nguyen TM, Tran HA, et al. Preimplantation genetic testing (PGT) for hemophilia A: experience from one center. Taiwan J Obstet Gynecol. 2022;61(6):1009–14. (PMID: 10.1016/j.tjog.2021.12.00736427965) ; UK Haemophilia Centre Doctors’ Organisation. Practice guidelines for the molecular diagnosis of haemophilia A. 2010. http://www.ukhcdo.org/docs/Haemophilia%20A%20BPG%20revision%20Sept%202011%20APPROVED.pdf . Accessed 30 Mar 2023. Grant Information: NUHSRO/2019/VMMU/01 National University Health System; NUHSRO/2019/VMMU/01 National University Health System Contributed Indexing: Keywords: F8 gene; Hemophilia A (HEMA); Microsatellite markers; Preimplantation genetic testing for monogenic disorders (PGT-M); Short tandem repeats (STRs) Entry Date(s): Date Created: 20231020 Latest Revision: 20231118 Update Code: 20240514 PubMed Central ID: PMC10588207

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Robust preimplantation genetic testing of the common F8 Inv22 pathogenic variant of severe hemophilia A using a highly polymorphic multi-marker panel encompassing the paracentric inversion.