Digenic Inheritance of PROC and SERPINC1 Mutations Contributes to Multiple Sites Venous Thrombosis

Abstract

Venous thromboembolism (VTE) represents a worldwide health challenge, impacting millions of people each year. The genesis of venous thrombosis is influenced in part by genetic components. Hereditary thrombosis is described as a genetically determined susceptibility to VTE. In the present study, a male patient was referred to our department presenting with multiple venous thrombosis events in different locations. Given a lack of identifiable risk factors, we aimed to investigate the possible genetic factor underlying venous thrombosis. Whole-exome sequencing was employed to examine genes linked to inherited thrombophilia in the proband. Putative variants were subsequently confirmed through Sanger sequencing within the family. The proband was identified as carrying two genetic mutations. One is the novel c.400G > C (p.E134Q) mutation affecting the final nucleotide of exon 5 in the PROC gene, potentially impacting splicing. The other is a previously reported heterozygous nonsense variant c.1016G > A (p.W339X) in the SERPINC1 gene. The proband inherited the former from her mother and the latter from her father. The presence of digenic inheritance in the patient reflects the complex phenotype of venous thrombosis and demonstrates the significance of an unbiased approach to detect pathogenic variants, especially in patients with a high risk of hereditary thrombosis.

Keywords

digenic inheritance - inherited thrombophilia - PROC gene - SERPINC1 gene - whole-exome sequencing

Ethics Approval and Consent to Participate

Ethical approval was obtained from the Institutional Review Board, The Second Affiliated Hospital of Nanchang University. After explanation of the possible consequences of the study, written informed consent was obtained from all study participants.

Consent for Publication

The patient provided informed consent for the publication of this study.

Availability of Data and Materials

All data generated or analyzed during this study are included in this published article

Authors' Contributions

Recruited and phenotyped the participants: X.G.L., W.W.Z. Performed molecular genetic experiments: X.G.L., W.W.Z. Analyzed the data: X.G.L., JBZ, W.W.Z. Wrote the manuscript: X.G.L., J.B.Z. Revised: F.Z.L., W.Q.M., W.M.Z. All authors read and approved the final manuscript.

Web links and URLs

1. Public single nucleotide polymorphism databases: dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/); 1000G (http://www.1000genomes.org/); ESP(http://evs.gs.washington.edu/EVS); ExAC (http://exac.broadinstitute.org). Accessed September 15, 2022.

2. A toolkit that offers various utilities for working with high-throughput sequencing (HTS) data in the BAM format: Picard MarkDuplicates (http://sourceforge.net/projects/picard/). Accessed September 15, 2022.

3. Computational algorithms designed to predict the functional impact of amino acid substitutions on proteins: The PolyPhen2 (http://genetics.bwh.harvard.edu/pph2/) and SIFT (http://sift.bii.a-star.edu.sg/) algorithm. Accessed September 15, 2022.

4. The Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/all.php). Accessed September 15, 2021.

5. A unique database focused on digenic diseases: The Digenic Diseases Database (DIDA: http://dida.ibsquare.be) database. Accessed September 15, 2022.

6. A computational tool designed to predict splice sites and splicing regulatory sequences in human genes: Human Splice Finder (HSF: https://hsf.genomnis.com/home). Accessed September 15, 2023.

^† X.L. and J.Z. should be considered joint first authors.

Publication History

Received: 19 June 2023

Accepted: 16 November 2023

Article published online:
15 January 2024

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