Identification of mutations in SLC4A1, GP1BA and HFE in a family with venous thrombosis of unknown cause by next-generation sequencing

Abstract

Various risk factors, including high age, female gender, obesity and certain genetic defects have been linked to venous thrombosis. A Taiwanese family with venous thrombosis of unknown cause were enrolled in the present study. In this pedigree, two women without any specific underlying diseases suffered from venous thrombotic events at the same age. No specific risk factors or coagulation abnormalities were identified. The main proband's younger brother also had intestinal arterial thrombosis at 54 years of age. Therefore, it was hypothesized that familial genetic defects may be the cause of venous thrombosis within this family. Blood samples collected from certain members of this pedigree were subjected to whole-exome sequencing, and three genetic variants were identified, including a missense variant of solute carrier family 4 member 1 (SLC4A1) (c.388G>A), a deletion on glycoprotein Ib platelet α subunit (GP1BA) (c.1322_1344del23) and an insertion in the splice site of homeostatic iron regulator (HFE). To date, none of these three genetic variants have been reported to be associated with venous thrombosis, to the best of our knowledge. The present study suggests that these genetic variants of SLC4A1, GP1BA and HFE may be associated with venous thrombosis in an Asian pedigree.

Keywords: glycoprotein Ib platelet α subunit; homeostatic iron regulator; next-generation sequencing; solute carrier family 4 member 1; venous thrombosis; whole-exome sequencing.

Figure 1.

Pedigree chart and selection for whole-exome sequencing. Pedigree members are represented as squares (males) and circles (females). Filled and unfilled symbols indicate subjects with and without venous thrombosis, respectively. The mother (I-2) of the main proband (II-3) had a stroke. The younger brother (II-4) of the main proband had arterial thrombosis. The star symbols indicate pedigree members enrolled for next-generation sequencing in the present study. The ′X symbol indicates that the subject is deceased.

Figure 2.

Flowchart depicting the analytical strategy. Steps in the analysis of the whole-exome sequencing data are presented. GMAF, global minor allele frequency.

Figure 3.

Illustration of protein features and domains of GP1BA. The yellow star indicates the variant of GP1BA identified in the proband and the proband's sister. GP1BA, glycoprotein Ib platelet α subunit.

Figure 4.

Venn diagram for the genes with identical variants among the proband, the proband's sister and the proband's daughter. A total of 168 identical variants were observed between the proband and proband's sister, and 313 identical variants were observed among the proband, the proband's sister and the proband's daughter.

Figure 5.

Summary scheme. In the present study, mutations in GP1BA, SLC4A1 and HFE were identified in a female patient and two of her pedigree members with venous thrombosis of unknown cause via next-generation sequencing. GPIBA is associated with diseases of platelets, and SCL4A1 and HFE are associated with diseases involving red blood cells. BMI, body mass index; GP1BA, glycoprotein Ib platelet α subunit; SLC4A1, solute carrier family 4 member 1; HFE, homeostatic iron regulator.