Deep intronic F8 c.5999-27A>G variant causes exon 19 skipping and leads to moderate hemophilia A.

摘要: : Hemophilia A, an X-linked recessive bleeding disorder, is caused by mutations of F8 gene. In about 2% hemophilia A patients, no exonic mutation gene was found. We aimed to identify deep intronic reanalyzed the next-generation sequencing data six patients with negative variant in either coding region or splice site. Deep c.5999-27A>G (NM_000132.3) found two unrelated moderate from different region, and one patient's mother mild patient. Splice site prediction algorithms showed impact this on mRNA splicing exon 19, including Human Splicing Finder 3.1, NNSPLICE 0.9, NetGene2, Transcript-inferred Pathogenicity score. Exonic enhancer predicted ESEfinder, difference between wild type mutant sequence. The branch point SVM-BPfinder suggested that may disrupt intron 18 affect acceptor 19. Sanger cDNA peripheral blood mononuclear cells confirmed 19 skipping proband his mother. Skewed X chromosome inactivation another mother, combined trans. conclusion, our study suggests be responsible for lead A. Systematic reanalysis could promote diagnostic yields.