期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 24, 期 18, 页码 -出版社
MDPI
DOI: 10.3390/ijms241813809
关键词
venous thromboembolism; WES analysis; family studies; low-frequency variants; protein interaction pattern; CRP; F2; SERPINA1; THBS1; VWF
Whole-exome sequencing in families with unexplained venous thromboembolism can detect low-frequency variants in genes related to hemostasis, providing insights into disease susceptibility.
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.
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