Familial thrombotic risk based on the genetic background of Protein C Deficiency in a Portuguese Study

Fidalgo, Teresa; Martinho, Patrícia; Salvado, Ramón; Manco, Licínio; Oliveira, Ana Catarina Lima de; Pinto, Carla; Gonçalves, Elsa; Marques, Dalila; Sevivas, Teresa; Martins, Natália; Ribeiro, M. Letícia

doi:10.1111/ejh.12488

Cited by 7 publications

(6 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As we did not study PROC deep intronic regions, we cannot exclude that a few detrimental mutations were missed in our study. Concerning PROC promoter polymorphisms at positions 28 In a small family cohort of carriers of PROC detrimental mutations, retrospectively studied, Fidalgo et al reported a higher number of VTEs in CG homozygotes than in carriers of other PROC promoter genotypes; in our study, this was not observed either in the whole population or in the subgroup of subjects carrying the mutations previously studied by Fidalgo et al 45 Genome-wide association studies of PC have been conducted with aim of finding genetic determinants located outside the PROC locus. The GAIT study estimated that sequence variations in other genes than PROC could explain approximately half of the phenotypic variation in PC level.…”

Section: Discussioncontrasting

confidence: 49%

See 1 more Smart Citation

Genotype–Phenotype Relationships in a Large French Cohort of Subjects with Inherited Protein C Deficiency

et al. 2020

View full text Add to dashboard Cite

Inherited protein C (PC) deficiency caused by mutations in the PROC gene is a well-known risk factor for venous thromboembolism. Few studies have investigated the relationship between PROC genotype and plasma or clinical phenotypes. We addressed this issue in a large retrospective cohort of 1,115 heterozygous carriers of 226 PROC pathogenic or likely pathogenic mutations. Mutations were classified in three categories according to their observed or presumed association with type I, type IIa, or type IIb PC deficiency. The study population comprised 876 carriers of type I category mutations, 55 carriers of type IIa category mutations, and 184 carriers of type IIb category mutations. PC anticoagulant activity significantly influenced risk of first venous thrombosis (p trend < 10−4). No influence of mutation category on risk of whole or unprovoked thrombotic events was observed. Both PC anticoagulant activity and genotype significantly influenced risk of venous thrombosis. Effect of detrimental mutations on plasma phenotype was ambiguous in several carriers, whatever the mutation category. Altogether, our findings confirm that diagnosing PC inherited deficiency based on plasma measurement may be difficult but show that diagnosis can be improved by PROC genotyping.

show abstract

Section: Discussioncontrasting

confidence: 49%

“…47 Fidalgo et al reported that PROCR H3 carrying could explain differences in plasma PC levels among carriers of PROC mutations. 45 Interestingly, high and even sometimes very high PC (> 160%) levels have been observed in H3 homozygous carriers. 48 Unfortunately, genotyping for this haplotype could not be performed in our study.…”

Section: Discussionmentioning

confidence: 99%

Genotype–Phenotype Relationships in a Large French Cohort of Subjects with Inherited Protein C Deficiency

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Compared to healthy individuals, heterozygous individuals have PC levels that are approximately 50% of the standard value. Generally, no clinical symptoms or delayed venous thromboembolism occur [ 8 ]. Our patients had PC activities of 53%, 40%, and 45%.…”

Section: Discussionmentioning

confidence: 99%

Two cases of venous thromboembolism in siblings after splenectomy due to a novel PROC gene mutation

Zhang,

Wang,

Bai

et al. 2024

Thrombosis J

View full text Add to dashboard Cite

Background Venous thromboembolism(VTE)is a common multifactorial disease. Anticoagulant protein deficiency is the most usual hereditary thrombophilia in the Chinese people, which includes protein C(PC), protein S and antithrombin deficiencies. Case presentation A retrospective analysis was conducted on clinical manifestations, laboratory tests, genetic information, and other relevant data of siblings diagnosed with VTE in 2020 at the Department of Pediatrics of Shenzhen Second People’s Hospital. The proband, a 12-year-old female, was admitted to the hospital in December 2020 with a complaint of pain in the left lower limb for four days. The examination found that the PC activity was 53%, and B-ultrasound showed bilateral thrombosis of the great saphenous vein in the thigh segment. The proband’s younger brother, a 10-year-old male, was admitted to the hospital in January 2021 due to right lower limb pain for two weeks. PC activity is 40%. B-ultrasound showed superficial venous thrombosis in the left lower limb and upper limb. Both siblings suffered from thalassemia and underwent splenectomy before recurrent thrombosis occurred. The proband’s mother was asymptomatic, and her PC activity was 45%. Both cases were treated with warfarin anticoagulation, and their symptoms improved. The proband’s mother was found to have a heterozygous mutation at this locus through Sanger sequencing. Conclusion Protein C deficiency should be considered for venous thromboembolism in childhood. The heterozygous mutation 1204 A > G in PROC exon 9 in this family is reported for the first time.

show abstract

“…These papers were not exactly focused on MDR in cases of AT, PC, and PS deficiency. More specific results have mainly been provided in studies where molecular diagnostics was provided by Sanger sequencing [10,11,[22][23][24][25][26][27][28][29][30][31][32][33][34][35].…”

Section: Discussionmentioning

confidence: 99%

“…Missense mutations c.1301T > C (p.Val434Ala), c.1019C > T (p.Thr340Met), and c.1106C > T (p.Pro369Leu) were identified in exon 9. They have been previously identified in probands with DVT or a positive family history of thrombosis [10,30,33]. The stop-loss variant c.1384T > C (p.Ter462Gln) found in female probands has been previously described [23].…”

Section: Protein C Deficiencymentioning

confidence: 98%

Detection of Unknown and Rare Pathogenic Variants in Antithrombin, Protein C and Protein S Deficiency Using High-Throughput Targeted Sequencing

et al. 2022

View full text Add to dashboard Cite

The deficiency of natural anticoagulants—antithrombin (AT), protein C (PC), and protein S (PS)—is a highly predisposing factor for thrombosis, which is still underdiagnosed at the genetic level. We aimed to establish and evaluate an optimal diagnostic approach based on a high-throughput sequencing platform suitable for testing a small number of genes. A fast, flexible, and efficient method involving automated amplicon library preparation and target sequencing on the Ion Torrent platform was optimized. The cohort consisted of a group of 31 unrelated patients selected for sequencing due to repeatedly low levels of one of the anticoagulant proteins (11 AT-deficient, 13 PC-deficient, and 7 PS-deficient patients). The overall mutation detection rate was 67.7%, highest in PC deficiency (76.9%), and six variants were newly detected—SERPINC1 c.398A > T (p.Gln133Leu), PROC c.450C > A (p.Tyr150Ter), c.715G > C (p.Gly239Arg) and c.866C > G (p.Pro289Arg), and PROS1 c.1468delA (p.Ile490fs) and c.1931T > A (p.Ile644Asn). Our data are consistent with those of previous studies, which mostly used time-consuming Sanger sequencing for genotyping, and the indication criteria for molecular genetic testing were adapted to this process in the past. Our promising results allow for a wider application of the described methodology in clinical practice, which will enable a suitable expansion of the group of indicated patients to include individuals with severe clinical findings of thrombosis at a young age. Moreover, this approach is flexible and applicable to other oligogenic panels.

show abstract

Familial thrombotic risk based on the genetic background of Protein C Deficiency in a Portuguese Study

Cited by 7 publications

References 43 publications

Genotype–Phenotype Relationships in a Large French Cohort of Subjects with Inherited Protein C Deficiency

Genotype–Phenotype Relationships in a Large French Cohort of Subjects with Inherited Protein C Deficiency

Two cases of venous thromboembolism in siblings after splenectomy due to a novel PROC gene mutation

Detection of Unknown and Rare Pathogenic Variants in Antithrombin, Protein C and Protein S Deficiency Using High-Throughput Targeted Sequencing

Contact Info

Product

Resources

About