Dataset Information

Molecular Diagnosis of Hemophilia A and Pathogenesis of Novel F8 Variants in Shanxi, China.

ABSTRACT: The aim of this study was to perform a molecular diagnosis of hemophilia A (HA) among patients in the Shanxi Province of China. Fifty-two HA patients were tested, including IVS22 (31 samples), IVS1 (3 samples), missense (11 samples), nonsense (3 samples), and 4 cases of frameshift (2 cases of deletion, 1 case of insertion, 1 case of single-base duplication). With the exception of the single-base G duplication variant (p.Ile1213Asnfs*28), this was the hotspot variant reported by research groups at an early stage. The remaining variants were found, for the first time, in the region. The missense variants p.Cys172Ser, p.Tyr404Ser, p.Asp1903Gly, and p.Ser2284Asn, the deletion variant p.Leu2249fs*9, and the insertion variant p.Pro2319fs*97 were novel variants. The application of next-generation sequencing (NGS) molecular diagnosis enriched the variant spectrum of HA, which is greatly significant for individualized genetic counseling, clinical diagnosis, and treatment. NGS and a variety of bioinformatics prediction methods can further analyze the impact of genetic variation on protein structure or function and lay the foundation to reveal the molecular pathogenic mechanism of novel variants.

SUBMITTER: Zhang X

PROVIDER: S-EPMC10499503 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Molecular Diagnosis of Hemophilia A and Pathogenesis of Novel F8 Variants in Shanxi, China.

Zhang Xialin X Chen Kun K Bian Sicheng S Wang Gang G Qin Xiuyu X Zhang Ruijuan R Yang Linhua L

Global medical genetics 20230913 3

The aim of this study was to perform a molecular diagnosis of hemophilia A (HA) among patients in the Shanxi Province of China. Fifty-two HA patients were tested, including IVS22 (31 samples), IVS1 (3 samples), missense (11 samples), nonsense (3 samples), and 4 cases of frameshift (2 cases of deletion, 1 case of insertion, 1 case of single-base duplication). With the exception of the single-base G duplication variant (p.Ile1213Asnfs*28), this was the hotspot variant reported by research groups a ...[more]

PMID: 37711502

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Project description:Diverse DNA structural variations (SVs) in human cancers and several other diseases are well documented. For genomic inversions in particular, the disease causing mechanism may not be clear, especially if the inversion border does not cross a coding sequence. Understanding about the molecular processes of these inverted genomic sequences, in a mainly epigenetic context, may provide additional information regarding sequence-specific regulation of gene expression in human diseases. Herein, we study one such inversion hotspot at Xq28, which leads to the disruption of F8 gene and results in hemophilia A phenotype. To determine the epigenetic consequence of this rearrangement, we evaluated DNA methylation levels of 12 CpG rich regions with the coverage of 550 kb by using bisulfite-pyrosequencing and next-generation sequencing (NGS)-based bisulfite re-sequencing enrichment assay. Our results show that this inversion prone area harbors widespread methylation changes at the studied regions. However, only 5/12 regions showed significant methylation changes, specifically in case of intron 1 inversion (two regions), intron 22 inversion (two regions) and one common region in both inversions. Interestingly, these aberrant methylated regions were found to be overlapping with the inversion proximities. In addition, two CpG sites reached 100% sensitivity and specificity to discriminate wild type from intron 22 and intron 1 inversion samples. While we found age to be an influencing factor on methylation levels at some regions, covariate analysis still confirms the differential methylation induced by inversion, regardless of age. The hemophilia A methylation inversion "HAMI" assay provides an advantage over conventional PCR-based methods, which may not detect novel rare genomic rearrangements. Taken together, we showed that genomic inversions in the F8 (Xq28) region are associated with detectable changes in methylation levels and can be used as an epigenetic diagnostic marker.

Dataset Information

Molecular Diagnosis of Hemophilia A and Pathogenesis of Novel F8 Variants in Shanxi, China.

Publications

Molecular Diagnosis of Hemophilia A and Pathogenesis of Novel F8 Variants in Shanxi, China.

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