Heterogeneous lengths of copy number mutations in human coagulopathy revealed by genome-wide high-density SNP array

Kim, Hee‐Jin; Kim, Duk Kyung; Yoo, Kyung Yeon; You, Chur Woo; Yoo, Jongha; Lee, Ki-O; Park, In-Ae; Choung, H.-S.; Kim, Heejung; Song, Mee; Kim, Sun‐Hee

doi:10.3324/haematol.2011.052324

Cited by 7 publications

(6 citation statements)

References 23 publications

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“…For PS and AT deficiency, we additionally performed MLPA experiments when no point mutations were detected on direct sequencing analyses, considering the significant occurrence of large dosage mutations in PROS1 and SERPINC1. 11 The figures we obtained are, therefore, conservative estimations of population frequencies of natural anticoagulant deficiency. A recent study from China adopted the same strategy as in our study (below 1 st percentile of coagulation tests followed by molecular confirmation) on 3,493 individuals from the general population, and found that the frequency of natural anticoagulant deficiency was 0.43% (PC deficiency 0.29%, AT deficiency 0.086%, and PS deficiency 0.057%) without any prevalent mutations (Table 3).…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 87%

“…Multiplex ligationdependent probe amplification (MLPA) experiments were additionally performed to detect large dosage mutations when no point mutations had been detected (SALSA MLPA kit P112 PROS1 and P227 SERPINC1; MRC Holland, Amsterdam, the Netherlands), as previously described. 11 Mutations identified are described following the recommendations from the Human Genome Variation Society (http://www.hgvs.org/mutnomen/), along with the conventional numbering. For validation of novel mutations, population frequencies were obtained by targeted sequencing involving 100 control chromosomes of Korean descent.…”

Section: Molecular Genetic Analysesmentioning

confidence: 99%

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Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o nIn this regard, we investigated the molecular genetic defects of natural anticoagulant deficiencies (PC, PS, and AT) in a large number of consecutive VTE patients and in the general population in Korea screened by coagulation tests. The results revealed unique frequencies and mutation spectrums of natural anticoagulant deficiencies in the group of VTE patients and in the general population. These frequencies and the mutation spectrums in Korea were not only distinct from those in Caucasian populations but also from those in other Asian countries. Methods Patients and populationThe group of patients consisted of consecutive VTE patients screened for thrombophilia including PC, PS, and AT deficiencies at Samsung Medical Center, Seoul, Korea, from January 2005 to December 2012. For the population group, at least 3,000 individuals visiting the institution for routine check-ups were screened from September 2005 to January 2006 using the same coagulation tests for natural anticoagulant deficiency as those used in the patients. In each group, those suspected of having a natural anticoagulant deficiency underwent molecular genetic tests to confirm the deficiency. In both groups, we excluded those with low levels of multiple (2 or more) natural anticoagulants, especially in association with underlying liver disease or other extrinsic factors. Written informed consent was obtained from the patients in the study, which was approved by the Institutional Review Board of the Samsung Medical Center, Seoul, Korea. Coagulation testsThe thrombophilia profile tests for VTE patients included screening for genetic thrombophilia: PC activity (Stachrom ® Protein C, Diagnostica Stago, Asnieres-Sur-Seine, France), PS free antigen (Liatest ® Free Protein S, Diagnostica Stago), and AT activity (Stachrom ® ATIII, Diagnostica Stago). All coagulation tests were performed on the STA ® coagulation analyzer (Diagnostica Stago). The local reference intervals were determined according to the guidelines from the Clinical and Laboratory Standards Institute (http://www.clsi.org/) as the 2.5-97.5 percentiles (PC activity, PS free antigen,.2% for males and 56.0-132.6% for females; and AT activity, 81.5-119.3%). 10 Tests for PC antigen, PS total antigen and activity, and AT antigen were additionally performed when indicated. Natural anticoagulant deficiency was suspected in VTE patients when the result was below the lower limit of the reference interval (2.5 percentile). Screening for natural anticoagulant deficiency in the population group was performed using the same coagulation tests as those used in the VTE patients. Individuals with levels of PC, PS, or AT below the 1 st percentile were selected for molecular genetic tests. Molecular genetic analysesGenomic DNA was extracted from peripheral blood leukocytes using the Wizard Genomic DNA Purification kit following the standard protocols (Promega, Madison, WI, USA). Molecular genetic diagnosis of natural anticoagulant deficiency was performed by...

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 87%

Section: Molecular Genetic Analysesmentioning

confidence: 99%

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

et al. 2013

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“…PROS1 deficiencies can occur because of germline mutations (132–143) (Figure 4). These deficiencies are classified based on the concentration and anticoagulant function of PROS1 in the blood.…”

Section: Tams In Diseasesmentioning

confidence: 99%

TAM Receptor Signaling in Immune Homeostasis

Rothlin¹,

Silva²,

Bosurgi³

et al. 2015

Annu. Rev. Immunol.

389

407

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The TAM receptor tyrosine kinases (RTKs)—TYRO3, AXL, and MERTK—together with their cognate agonists GAS6 and PROS1 play an essential role in the resolution of inflammation. Deficiencies in TAM signaling have been associated with chronic inflammatory and autoimmune diseases. Three processes regulated by TAM signaling may contribute, either independently or collectively, to immune homeostasis: the negative regulation of the innate immune response, the phagocytosis of apoptotic cells, and the restoration of vascular integrity. Recent studies have also revealed the function of TAMs in infectious diseases and cancer. Here, we review the important milestones in the discovery of these RTKs and their ligands and the studies that underscore the functional importance of this signaling pathway in physiological immune settings and disease.

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“…Recent dosage analysis by SNP microarray that included AT and PS (SERPINC1 and PROS1) analysis demonstrated that some large deletions extend considerably further than a single gene. 45 Once mutation(s) have been identified in an index case, its presence can be sought in family members by analysis of the exon/intron containing the mutation or by dosage analysis as appropriate.…”

Section: Genetic Analysis Of At Pc and Psmentioning

confidence: 99%

Quality in Molecular Biology Testing for Inherited Thrombophilia Disorders

Cooper

Goodeve

Beauchamp

2012

Semin Thromb Hemost

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As the understanding of the genetic basis of the inherited thrombophilias has increased over recent years, their routine diagnostic genetic analysis has also matured. This review considers methods used to test for the factor V (F5) Leiden mutation and prothrombin 20210A (F2 c.*97G>A) allele, and analysis of the SERPINC1, PROC, and PROS1 genes in cases of antithrombin, protein C (PC), and protein S (PS) deficiency, respectively. Issues relating to quality are explored, highlighting where analytical and sample handling errors may occur. Detection of the factor V Leiden mutation and the prothrombin c.*97G>A allele are best performed using real-time polymerase chain reaction analysis as this relatively simple technique allows their discrimination from rare variants of neighboring nucleotides; not possible using the more time-consuming restriction digestion assays. With the advent of low-cost and high-throughput sequence analysis, direct sequencing has become the first-line method to provide a definitive diagnosis of inherited, rather than acquired, deficiencies. Large cohort studies have shown that antithrombin and PC mutations are identified in between 61 and 87% of patients, whereas the detection rate in PS deficiency is substantially lower in around 40% of patients. Large gene deletions make up between 7 and 10% of PS and antithrombin mutations and only 1% of PC mutations, but it is suggested that dosage analysis techniques such as multiplex ligation-dependent probe amplification should be used for all three genes as part of routine analysis to ensure mutations are not missed. Best practice guidelines are available from EuroGentest covering a wide variety of the issues raised in this review and all laboratories should participate in appropriate external quality assurance schemes to ensure they continue to offer high quality service.

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Heterogeneous lengths of copy number mutations in human coagulopathy revealed by genome-wide high-density SNP array

Cited by 7 publications

References 23 publications

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

TAM Receptor Signaling in Immune Homeostasis

Quality in Molecular Biology Testing for Inherited Thrombophilia Disorders

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