The Unravelling of the Genetic Architecture of Plasminogen Deficiency and its Relation to Thrombotic Disease

Martín-Fernández, Laura; Marco, Pascual; Corrales, Irene; Pérez, Raquel Yazmin López; Ramı́rez, Leonardo; López, Sònia; Vidal, Francisco; Soria, José Manuel Nieto

doi:10.1038/srep39255

Cited by 16 publications

(17 citation statements)

References 33 publications

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“…Overall, we did not observe an association between PLG p.Arg172Gly and risk of thrombotic disease. Similarly, mutations associated with congenital plasminogen deficiency do not appear to be a strong risk factor for VTE [ 36 – 38 ].…”

Section: Discussionmentioning

confidence: 99%

Rare coding variants pinpoint genes that control human hematological traits

Mousas¹,

Ntritsos²,

Chen³

et al. 2017

PLoS Genet

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The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45–0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39–0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.

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Section: Discussionmentioning

confidence: 99%

Rare coding variants pinpoint genes that control human hematological traits

Mousas¹,

Ntritsos²,

Chen³

et al. 2017

PLoS Genet

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“…Therefore, NGS‐targeted gene panels have changed the paradigm of routine molecular studies. In the face of the multiple genetic changes found in every patient, the critical challenge was discriminating disease‐associated variants from the broader background of variants present in all patients’ genomes …”

Section: Discussionmentioning

confidence: 99%

“…In the face of the multiple genetic changes found in every patient, the critical challenge was discriminating disease-associated variants from the broader background of variants present in all patients' genomes. [51][52][53][54][55] In conclusion, the study of these 77 TMA Portuguese patients contributes to the better understanding of the molecular genetics of ADAMTS13/complement gene-related phenotypes. Moreover, our study provides evidence of the usefulness of the NGS panel as an excellent advantageous technology that enables more rapid and economic diagnosis of TMA.…”

Section: Cfh-h3 Allelesmentioning

confidence: 92%

Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing

Fidalgo

Martinho

Pinto

et al. 2017

Research and Practice in Thrombosis and Haemostasis

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Essentials The differential diagnosis of acute thrombotic microangiopathy (TMA) is challenging.To the ADAMTS13 activity < or >10% was added a next‐generation sequencing (NGS) gene panel.The ADAMTS13 mutation p.Cys754Arg was frequent in hereditary thrombotic thrombocytopenic purpura.We identified novel complement gene mutations and this procedure improved our diagnostic strategy. BackgroundThe 2 main forms of thrombotic microangiopathy (TMA) are thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS). Deficiency of ADAMTS13 and dysregulation of the complement pathway result in TTP and aHUS, respectively; however, overlap of their clinical characteristics makes differential diagnosis challenging.Objectives and MethodsWe aimed to develop a TMA diagnosis workflow based on ADAMTS13 activity and screening of ADAMTS13 and complement genes using a custom next‐generation sequencing (NGS) gene panel.PatientsFor this, from a cohort of 154 Portuguese patients with acute TMA, the genotype‐phenotype correlations were analyzed in 7 hereditary TTP (ADAMTS13 activity <10%, no inhibitor), 36 acquired TTP (ADAMTS13 activity <10%, presence of an inhibitor), and in 34 presumable aHUS.ResultsIn total, 37 different rare variants, 8 of which novel (in ADAMTS13,CFH, and CD46), were identified across 7 genes. Thirteen TTP patients were homozygous (n=6), compound heterozygous (n=2), and heterozygous (n=5) for 11 ADAMTS13 variants (6 pathogenic mutations). Among the 34 aHUS patients, 17 were heterozygous for 23 variants in the different complement genes with distinct consequences, ranging from single pathogenic mutations associated with complete disease penetrance to benign variants that cause aHUS only when combined with other variants and/or CFH and CD46 risk haplotypes or CFHR1‐3 deletion.ConclusionsOur study provides evidence of the usefulness of the NGS panel as an excellent technology that enables more rapid diagnosis of TMA, and is a valuable asset in clinical practice to discriminate between TTP and aHUS.

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“…A previously reported variant c.782G > A (p.Arg261His) was identified in both cases and controls with multiple sclerosis 43 , but is novel for OM. A variant at the same amino acid position p.Arg261Cys was identified in a family with all heterozygous individuals having reduced PLG levels to 64-68% 44 . This might suggest that c.782G > A (p.Arg261His), and other rare variants in PLG, are likely to be functional or pathogenic.…”

Section: Discussionmentioning

confidence: 99%

Multi-omic studies on missense PLG variants in families with otitis media

Bootpetch

Hafrén

Elling

et al. 2020

Sci Rep

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Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.

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The Unravelling of the Genetic Architecture of Plasminogen Deficiency and its Relation to Thrombotic Disease

Cited by 16 publications

References 33 publications

Rare coding variants pinpoint genes that control human hematological traits

Rare coding variants pinpoint genes that control human hematological traits

Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing

Multi-omic studies on missense PLG variants in families with otitis media

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