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De Novo Variants in Antithrombin Deficiency: Incidence and Heterogeneous Mechanisms

M.E. de la Morena-Barrio1, B. de la Morena-Barrio1, A. Miñano1, R. Teruel-Montoya1, J. Padill1, C. Bravo-Perez1, R. Cifuentes1, J.R. Gonzalez-Porras2, A. Rodriguez-Alen3, M.F. López-Fernández4, F. Velasco5, M.J. Blanco-Bañares6, V. Vicente1, J. Corral1

1Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER, Murcia, Spain, 2Department of Hematology, University Hospital of Salamanca, Salamanca, Spain, 3Servicio de Hematología, Hospital Virgen de la Salud, Toledo, Spain, 4Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain, 5Hospital Universitario Reina Sofia, Cordoba, Spain, 6Haematology Department, La Paz University Hospital, IdiPAZ, Madrid, Spain

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.

CaseSampleAge (years)Thrombosis (age 1st event, years)Anti-FXa (%)VariantProcedence mutated alelle
P1Proband
Mother
Father
54
—
—
DVT(–)
No
No
52
112
111
c.1201C>T;p.His401Tyr
No
No
Father
P2Proband
Father
Mother
26
56
53
DVT(15)
No
No
26
86
83
c.335C>T;p.Pro112Leu
No
No
Father
P3Proband
Father
Mother
28
—
—
DVT&PE(14)
No
No
59
101
99
c.1141T>C;p.Ser381Pro
No
No
Mother
P4Proband
Father
Mother
33
—
63
DVT(19)
No
No
39
130
114
c.1315C>A;p.Pro439Thr
No
No
Unknown
P5Proband
Father
Mother
24
63
59
DVT,PE&CT(13)
No
No
60
91
101
Deletion2MB
No
No
Father
P6Proband
Father
Mother
54
—
—
DVT(36)
No
No
50
98
97
c.817A>G;p.Lys273Glu
No
No
Unknown
P7Proband
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 January 26, 2021.
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