Your browser doesn't support javascript.
loading
Whole-Exome Sequencing in a Family with an Unexplained Tendency for Venous Thromboembolism: Multicomponent Prediction of Low-Frequency Variant Deleteriousness and of Individual Protein Interaction.
Lunghi, Barbara; Ziliotto, Nicole; Balestra, Dario; Rossi, Lucrezia; Della Valle, Patrizia; Pignatelli, Pasquale; Pinotti, Mirko; D'Angelo, Armando; Marchetti, Giovanna; Bernardi, Francesco.
Afiliación
  • Lunghi B; Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
  • Ziliotto N; Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
  • Balestra D; Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
  • Rossi L; Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
  • Della Valle P; Unit of Coagulation Service and Thrombosis Research, IRCCS San Raffaele Hospital, 20132 Milan, Italy.
  • Pignatelli P; Department of Clinical Internal, Anesthesiological, and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy.
  • Pinotti M; Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
  • D'Angelo A; Unit of Coagulation Service and Thrombosis Research, IRCCS San Raffaele Hospital, 20132 Milan, Italy.
  • Marchetti G; Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy.
  • Bernardi F; Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
Int J Mol Sci ; 24(18)2023 Sep 07.
Article en En | MEDLINE | ID: mdl-37762110
ABSTRACT
Whole-exome sequencing (WES) in families with an unexplained tendency for venous thromboembolism (VTE) may favor detection of low-frequency variants in genes with known contribution to hemostasis or associated with VTE-related phenotypes. WES analysis in six family members, three of whom affected by documented VTE, filtered for MAF < 0.04 in 192 candidate genes, revealed 22 heterozygous (16 missense and six synonymous) variants in patients. Functional prediction by multi-component bioinformatics tools, implemented by a database/literature search, including ClinVar annotation and QTL analysis, prioritized 12 missense variants, three of which (CRP Leu61Pro, F2 Asn514Lys and NQO1 Arg139Trp) were present in all patients, and the frequent functional variants FGB Arg478Lys and IL1A Ala114Ser. Combinations of prioritized variants in each patient were used to infer functional protein interactions. Different interaction patterns, supported by high-quality evidence, included eight proteins intertwined in the "acute phase" (CRP, F2, SERPINA1 and IL1A) and/or in the "fibrinogen complex" (CRP, F2, PLAT, THBS1, VWF and FGB) significantly enriched terms. In a wide group of candidate genes, this approach highlighted six low-frequency variants (CRP Leu61Pro, F2 Asn514Lys, SERPINA1 Arg63Cys, THBS1 Asp901Glu, VWF Arg1399His and PLAT Arg164Trp), five of which were top ranked for predicted deleteriousness, which in different combinations may contribute to disease susceptibility in members of this family.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tromboembolia Venosa Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Italia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tromboembolia Venosa Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Italia