Congenital Factor XI deficiency: Variant detection rate supports the importance of molecular genetic testing in diagnostics

Introduction Factor XI (FXI) deficiency is a rare autosomal recessive bleeding disorder characterized by a decrease in plasma FXI activity (FXI:C) and mild to moderate, mostly injury-related bleeding diathesis [ 1 ]. Hereditary FXI deficiency is associated with genetic defects in the F11 gene. It consists of 15 exons, located on the long arm of chromosome 4 (4q35) adjacent to the KLKB1 gene encoding prekallikrein [ 2 ]. We investigated the correlation between FXI activity level and variant detection rate (VDR) [ 3 ]. Method Over 14 years, 316 index patients (IPs) with FXI:C 1-70 IU/dl underwent molecular genetic analysis by Next Generation Sequencing and Sanger Sequencing of all exons and exon/intron boundaries. Detection of large deletions was performed by MLPA (Multiplex Ligation-dependent Probe Amplification) analysis (MRC Holland) and CNV (Copy Number Variant) analysis (SeqNext). Results Cohort Data: In 249 from 316 IPs genetic defects were identified (286 variants), with an overall VDR of 79%. In 40 families segregation was confirmed. 72 patients had severely reduced FXI:C (