Molecular dissection of structural variations involved in antithrombin deficiency.
生物
遗传学
外显子
节段重复
基因复制
结构变异
多重连接依赖探针扩增
基因
后转座子
作者
Belén de la Morena-Barrio,Christelle Orlando,Alba Sanchis-Juan,Juan Luis García,José Padilla,María Eugenia 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 María Hernández-Rivas,Willem Ouwehand,K. Jochmans,Javier Corral
Inherited antithrombin deficiency, the most severe 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 structural variants but two had repetitive elements and/or microhomologies involved 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 the most appropriate method to identify and characterize all structural variants at nucleotide level, independently of their size or type.