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    Inherited antithrombin deficiency, the most severe form of thrombophilia, is predominantly caused by variants in SERPINC1. Few causal structural variants have been described, usually detected by multiplex ligation-dependent probe amplification or cytogenetic arrays, which only define the gain or loss and the approximate size and location. This study has done a complete dissection of the structural variants affecting SERPINC1 of 39 unrelated patients with antithrombin deficiency using multiplex ligation-dependent probe amplification, comparative genome hybridization array, long-range PCR, and whole genome nanopore sequencing. Structural variants, in all cases only affecting one allele, were deleterious and caused a severe type I deficiency. Most defects were deletions affecting exons of SERPINC1 (82.1%), but the whole cohort was heterogeneous, as tandem duplications, deletion of introns, or retrotransposon insertions were also detected. Their size was also variable, ranging from 193 bp to 8 Mb, and in 54% of the cases involved neighboring genes. All but two structural variants had repetitive elements and/or microhomologies in their breakpoints, suggesting a common mechanism of formation. This study also suggested regions recurrently involved in structural variants causing antithrombin deficiency and found three structural variants with a founder effect: the insertion of a retrotransposon, duplication of exon 6, and a 20-gene deletion. Finally, nanopore sequencing was determined to be the most appropriate method to identify and characterize all structural variants at nucleotide level, independently of their size or type. Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.


    Belén de la Morena-Barrio, Christelle Orlando, Alba Sanchis-Juan, Juan L García, José Padilla, María E de la Morena-Barrio, Marija Puruunen, Katrien Stouffs, Rosa Cifuentes, Nina Borràs, Carlos Bravo-Pérez, Rocio Benito, Javier Cuenca-Guardiola, Vicente Vicente, Francisco Vidal, Jesús M Hernández-Rivas, Willem Ouwehand, Kristin Jochmans, Javier Corral. Molecular Dissection of Structural Variations Involved in Antithrombin Deficiency. The Journal of molecular diagnostics : JMD. 2022 May;24(5):462-475

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    PMID: 35218943

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