Abstract Number: PB2195
Meeting: ISTH 2020 Congress
Theme: Venous Thromboembolism and Cardioembolism » Genetic Risk Factors of Thrombosis
Background: Genetic variations, generated by different mechanisms, are responsible of diversity but they are also involved in diseases. There is no a systematic analysis of de novo variants in antithrombin deficiency, the first and so far, strongest congenital thrombophilia.
Aims: To identify and characterize de novo variants in SERPINC1 associated with antithrombin deficiency.
Methods: The study included 370 unrelated patients with antithrombin deficiency. SERPINC1 was studied by sequencing (Sanger, NGS and/or nanopore) and MLPA. Comparative genome hybridization was performed in some cases. Paternity was determined by genotyping 16 Short Tandem Repeats (PowerPlex® 16). Mosaicism was evaluated by deep sequencing (Ion Torrent). The origin of the mutated allele was determined by haplotyping long-range PCRs of the whole SERPINC1 gene and nanopore sequencing.
Results: After selecting patients with SERPINC1 defects (N=244) and those with available parental samples (N=145), we identified 7 cases with severe thrombosis and type I deficiency, who had de novo mutations. Paternity was proved in all cases. Five cases had SNVs (no one was CpG), and 2 showed gross gene defects: one with a 2Mb deletion (22 genes) and the second with a 19KB deletion affecting exon 1 and the neighboring gene. In both cases nanopore sequencing revealed repetitive elements (LINEs and ALUs) flanking the deletions. Anticoagulant activity and deep sequencing (>6000 reads) of the mutated amplicon supported a germline variant and discarded paternal mosaicism in all cases. Haplotype analysis revealed the origin of the mutated allele in 5 cases.
| Case | Sample | Age (years) | Thrombosis (age 1st event, years) | Anti-FXa (%) | Variant | Procedence mutated alelle |
| P1 | Proband Mother Father |
54 — — |
DVT(–) No No |
52 112 111 |
c.1201C>T;p.His401Tyr No No |
Father |
| P2 | Proband Father Mother |
26 56 53 |
DVT(15) No No |
26 86 83 |
c.335C>T;p.Pro112Leu No No |
Father |
| P3 | Proband Father Mother |
28 — — |
DVT&PE(14) No No |
59 101 99 |
c.1141T>C;p.Ser381Pro No No |
Mother |
| P4 | Proband Father Mother |
33 — 63 |
DVT(19) No No |
39 130 114 |
c.1315C>A;p.Pro439Thr No No |
Unknown |
| P5 | Proband Father Mother |
24 63 59 |
DVT,PE&CT(13) No No |
60 91 101 |
Deletion2MB No No |
Father |
| P6 | Proband Father Mother |
54 — — |
DVT(36) No No |
50 98 97 |
c.817A>G;p.Lys273Glu No No |
Unknown |
| P7 | Proband Father Mother |
1 38 35 |
DVT(3 w) No No |
30 92 72 |
Deletion19Kb&p.Val30Glu p.Val30Glu No |
Mother |
[Cases with SERPINC1 de novo variants.DVT:DVT:Deep venous thrombosis;PE:Pulmonary embolism;CT:Cerebral thrombosis;w:weeks]
Conclusions: The rate of de novo variants underlying antithrombin deficiency (4.8%) supports their analysis even in cases with no affected parents. Incidence of de novo gross gene rearrangements is remarkable (28%) probably because repetitive elements are abundant in this gene. Mosaicism was discarded, and in most cases variations were probably originated during paternal gametogenesis. PI18/00598 (ISCIII y FEDER); and 19873/GERM/15 (Fundación Séneca).
To cite this abstract in AMA style:
de la Morena-Barrio ME, de la Morena-Barrio B, Miñano A, Teruel-Montoya R, Padill J, Bravo-Perez C, Cifuentes R, Gonzalez-Porras JR, Rodriguez-Alen A, López-Fernández MF, Velasco F, Blanco-Bañares MJ, Vicente V, Corral J. De Novo Variants in Antithrombin Deficiency: Incidence and Heterogeneous Mechanisms [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/de-novo-variants-in-antithrombin-deficiency-incidence-and-heterogeneous-mechanisms/. Accessed November 29, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/de-novo-variants-in-antithrombin-deficiency-incidence-and-heterogeneous-mechanisms/