Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan;29(1):248-255.
doi: 10.1111/hae.14666. Epub 2022 Oct 4.

Reinvestigation of unidentified causative variants in FXI-deficient patients: Focus on gene segment deletions

Philippe De Mazancourt  1   2 , Annie Harroche  3 , Katia Pouymayou  4 , Marianne Sigaud  5 , Céline Falaise  6 , Natalie Stieltjes  7 , Sabine-Marie Castet  8 , Brigitte Tardy  9 , Christophe Zawadzki  10 , Jenny Goudemand  10 , Yesim Dargaud  11
Affiliations

Reinvestigation of unidentified causative variants in FXI-deficient patients: Focus on gene segment deletions

Philippe De Mazancourt et al. Haemophilia. 2023 Jan.

Abstract

Introduction: Data on failure to identify the molecular mechanism underlying FXI deficiency by Sanger analysis and the contribution of gene segment deletions are almost inexistent.

Aims and methods: Prospective and retrospective analysis was conducted on FXI-deficient patients' DNA via Next Generation Sequencing (NGS), or Sanger sequencing and Multiplex Probe Ligation-dependent Assay (MLPA) to detect cryptic causative gene variants or gene segment deletions.

Results: Sanger analysis or NGS enabled us to identify six severe and one partial (median activity 41 IU/dl) FXI deficient index cases with deletions encompassing exons 11-15, the whole gene, or both. After Sanger sequencing, retrospective evaluation using MLPA detected seven additional deletion cases in apparently homozygous cases in non-consanguineous families, or in previously unsolved FXI-deficiency cases. Among the 504 index cases with a complete genetic investigation (Sanger/MLPA, or NGS), 23 remained unsolved (no abnormality found [n = 14] or rare intronic variants currently under investigation, [n = 9]). In the 481 solved cases (95% efficiency), we identified F11 gene-deleted patients (14 cases; 2.9%). Among these, whole gene deletion accounted for four heterozygous cases, exons 11-15 deletion for five heterozygous and three homozygous ones, while compound heterozygous deletion and isolated exon 12 deletion accounted for one case each.

Conclusion: Given the high incidence of deletions in our population (2.9%), MLPA (or NGS with a reliable bioinformatic pipeline) should be systematically performed for unsolved FXI deficiencies or apparently homozygous cases in non-consanguineous families.

Keywords: F11 gene deletion; FXI deficiency; MLPA; causative gene variant identification failure.

PubMed Disclaimer

References

REFERENCES

    1. Peyvandi F, Palla R, Menegatti M, et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European network of rare bleeding disorders. J Thromb Haemost. 2012;10(4):615-621.
    1. Peyvandi F, Di Michele D, Bolton-Maggs PHB, et al. Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity. J Thromb Haemost. 2012;10(9):1938-1943.
    1. Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia. 2008;14(6):1183-1189.
    1. Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost. 2013;39(6):621-631.
    1. Asakai R, Chung DW, Davie EW, et al. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med. 2010;325(3):153-158.

LinkOut - more resources