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Essentials    Intronic variants of the factor VIII gene ( F8 ) causing hemophilia A have been reported.  We established an analysis method for whole  F8  and investigated the variants within its introns.  Rare variants located within introns of  F8  in patients with hemophilia A are not uncommon.  The c.6429+14194T>C variant was characteristically detected in patients with inversion.Background  No genetic defects are found in the coagulation factor  VIII  gene ( F8 ) of approximately 2% of patients with hemophilia A. Recently, genomic variants causative of hemophilia A that were located deep within introns have been reported.    Objectives  We aimed to establish a comprehensive method of analysis of  F8  using next‐generation sequencing ( NGS ) and investigate the variants located deep within the introns of  F8 .    Patients/Methods  Forty‐five male patients with hemophilia A, including 31 with previously identified causative mutations, were investigated.    Results  Our  NGS  analysis allowed for the identification of genetic variants in roughly 99% of  F8 . We confirmed that our  NGS  analysis can detect the single nucleotide variants and small deletions with high accuracy. After filtering, a total of 27 rare and unique individual variants from 16 patients remained. Three of these variants, c.144‐10810T>C, c.1010‐365A>G, and c.5219+9065A>G, were predicted as deleterious with high expected accuracy by Predict SNP 2 analysis. We also predicted the impact on splicing by in silico analysis using three different algorithms. Two patients with unknown causative mutations carried unique individual variants, c.144‐10810T>C and c.6723+193G>A. We inferred that the c.144‐10810T>C variant likely causes hemophilia, while the effect of the c.6723+193G>A variant remains unclear. Our analysis showed that the c.6429+14194T>C variant was significantly detected in patients carrying the intron 22 inversion.    Conclusions  Rare and unique individual variants located deep within the  F8  introns in patients with hemophilia A are not uncommon. Future studies are necessary to determine the function and effect of these variants on  F8  expression.

Identification of deep intronic individual variants in patients with hemophilia A by next‐generation sequencing of the whole factor VIII gene