PB0316 - De novo and recurrent SERPINC1 variants in antithrombin deficiency: origin, expansion and clinical implications.

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

Pedro Garrido-Rodríguez

PhD student
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain

Co-Author(s)

EN

Esther Navarro

Post-doc
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain

Co-Author(s)

Belén de la Morena-Barrio, PhD

Post-doc
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
EW

Ewa Wypasek

MD
The John Paul II Hospital
Krakov, Malopolskie, Poland
RC

Rosa Cifuentes-Riquelme

Predoctoral student
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
CB

Carlos Bravo-Pérez

PhD MD
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
JP

José Padilla

Tech
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
ML

María Llamas-López

PhD student
Servicio de Hematología, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
RT

Raúl Teruel

Doctor
REGIONAL CENTER OF HEMODONATION, DEPARTMENT OF HEMATOLOGY AND MEDICAL ONCOLOGY, UNIVERSITY GENERAL HOSPITAL MORALES MESEGUER, UNIVERSITY OF MURCIA, IMIB-PASCUAL PARRILLA, 30003, MURCIA, SPAIN.
Murcia, Murcia, Spain
AR

Agustín Rodríguez-Alen

Hematologist
Servicio de Hematología, Hospital Universitario de Toledo, Toledo, Spain
Toledo, Castilla-La Mancha, Spain
FV

Francisco Velasco

PhD MD
Department of Medicine. University of Cordoba (UCO). Maimonides Biomedical Research Institute of Córdoba (IMIBIC).
Córdoba, Andalucia, Spain
MB

María J Blanco

MD
Departamento de Hematología, Hospital Universitario La Paz
Madrid, Madrid, Spain
ML

María F. López-Fernández

PhD MD
Servicio de Hematología, Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
La Coruña, Galicia, Spain
Bf

Beatriz fernández-Pérez

MD
Servicio de Hematología Hospital Francesc de Borja
Valencia, Comunidad Valenciana, Spain
SA

Susana Asenjo

PhD MD
Servicio de Hematología, Hospital Clínico San Carlos,
Madrid, Madrid, Spain
JG

José R. González-Porras

PhD MD
Departamento de Hematología, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca (USAL),
Salamanca, Castilla y Leon, Spain
VV

Vicente Vicente

Senior Researcher
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
ML

María Luisa Lozano

Hematologist
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
María Eugenia de la Morena-Barrio, PhD

PhD
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain

Presenting Author(s)

Javier Corral

Professor
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain

Background: Antithrombin deficiency (ATD) is a rare thrombophilia mainly caused by genetic variants in SERPINC1. Identification and characterization of de novo and recurrent mutations (DNMs&RMs) help to understand the molecular mechanisms involved the susceptibility of SERPINC1 to suffer new mutations, and their spreading. Only 8 DNMs and 4 RMs have been described so far.

Aims: Systematic study of DNMs&RMs in ATD.

Methods: 433 unrelated patients with ATD were recruited. SERPINC1 (13Kb) was sequenced. Structural variants (SVs) were identified by MLPA and characterized by long-read nanopore sequencing. This method also allowed haplotype resolution. DNMs were evaluated in 210/433 cases having parents available. RMs were selected when present in ≥10 patients.

Results: The screening of 210 patient-parental trios revealed 11 (5.2%) with DNMs (8 had type I, and 3 type II pleiotropic ATD), ten of which exhibited severe clinical manifestations (early idiopathic thrombosis). DNMs included 7 SNVs (one shared by two cases), one small insertion, and 2 SVs. Antithrombin activity and deep sequencing supported a germline DNM in probands and ruled out mosaicism in parents. Paternal origin of the mutated allele was proved in 60% of cases (Table-1).
Seven RMs were identified in 145/433 (33.5%) cases. The more prevalent RMs caused type II or transient deficiency, had mild clinical phenotype and a founder effect. However, 2 RMs caused type I deficiency, one founder missense restricted to a population, and one severe nonsense with four different haplotypes (Table-2).

Conclusion(s): About 5.2% of ATD cases are attributed to DNMs, although underestimation of milder forms may occur. DNMs in SERPINC1 primarily consist of germline SNVs potentially occurring during male or female gametogenesis. Notably, 18% of DNMs are caused by SVs involving repetitive elements. Mutations causing milder ATD are recognized as more likely to spread as RMs, constituting over 33% of cases with ATD.

Funding: PI21/00174&PMP21/00052 (ISCIII&NextGeneration UE); 21886/PI/22 (Fundación Séneca)