Dataset Information

Molecular analysis of 76 Chinese hemophilia B pedigrees and the identification of 10 novel mutations.

ABSTRACT: BACKGROUND:Hemophilia B (HB) is an X-linked recessive inherited bleeding disorder caused by mutations in the F9 gene that lead to plasma factor IX deficiency. To identify the causative mutations in HB, a molecular analysis of HB pedigrees in China was performed. METHODS:Using next-generation sequencing (NGS) and an in-house bioinformatics pipeline, 76 unrelated HB pedigrees were analyzed. The mutations identified were validated by comparison with the results of Sanger sequencing or Multiplex Ligation-dependent Probe Amplification assays. The pathogenicity of the causative mutations was classified following the American College of Medical Genetics and Genomics guidelines. RESULTS:The mutation detection rate was 94.74% (72/76) using NGS. Of the 76 HB pedigrees analyzed, 59 causative variants were found in 72 pedigrees, with 38 (64.41%) missense mutations, 9 (15.25%) nonsense mutations, 2 (3.39%) splicing mutations, 5 (8.47%) small deletions, 4 (6.78%) large deletions, and 1 intronic mutation (1.69%). Of the 59 different F9 mutations, 10 were novel: c.190T>G, c.199G>T, c.290G>C, c.322T>A, c.350_351insACAATAATTCCTA, c.391+5delG, c.416G>T, c.618_627delAGCTGAAACC, c.863delA, and c.1024_1027delACGA. Of these 10 novel mutations, a mosaic mutation, c.199G>T(p.Glu67Ter), was identified in a sporadic HB pedigree. Using in-silico analysis, these novel variants were predicted to be disease-causing. However, no potentially causative mutations were found in the F9 coding sequences of the four remaining HB pedigrees. In addition, two HB pedigrees carrying additional F8/F9 mutations were discovered. CONCLUSION:The identification of these mutations enriches the spectrum of F9 mutations and provides further insights into the pathogenesis of HB in the Chinese population.

SUBMITTER: Huang L

PROVIDER: S-EPMC7667291 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Molecular analysis of 76 Chinese hemophilia B pedigrees and the identification of 10 novel mutations.

Huang Limin L Li Liyan L Lin Sheng S Chen Juanjuan J Li Kun K Fan Dongmei D Jin Wangjie W Li Yihong Y Yang Xu X Xiong Yufeng Y Li Fenxia F Yang Xuexi X Li Ming M Li Qiang Q

Molecular genetics & genomic medicine 20200901 11

<h4>Background</h4>Hemophilia B (HB) is an X-linked recessive inherited bleeding disorder caused by mutations in the F9 gene that lead to plasma factor IX deficiency. To identify the causative mutations in HB, a molecular analysis of HB pedigrees in China was performed.<h4>Methods</h4>Using next-generation sequencing (NGS) and an in-house bioinformatics pipeline, 76 unrelated HB pedigrees were analyzed. The mutations identified were validated by comparison with the results of Sanger sequencing o ...[more]

PMID: 32875744

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Project description:PurposeAutosomal dominant nanophthalmos is an inherited eye disorder characterized by a structurally normal but smaller eye. Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications. In this study, the clinical features and the genetic basis of nanophthalmos were investigated in two large autosomal dominant nanophthalmos pedigrees.MethodsFourteen members of a Caucasian pedigree from the United States and 15 members of a pedigree from the Mariana Islands enrolled in a genetic study of nanophthalmos and contributed DNA samples. Twenty of 29 family members underwent eye examinations that included measurement of axial eye length and/or refractive error. The genetic basis of nanophthalmos in the pedigrees was studied with linkage analysis, whole exome sequencing, and candidate gene (i.e., TMEM98) sequencing to identify the nanophthalmos-causing gene.ResultsNine members of the pedigree from the United States and 11 members of the pedigree from the Mariana Islands were diagnosed with nanophthalmos that is transmitted as an autosomal dominant trait. The patients with nanophthalmos had abnormally short axial eye lengths, which ranged from 15.9 to 18.4 mm. Linkage analysis of the nanophthalmos pedigree from the United States identified nine large regions of the genome (greater than 10 Mbp) that were coinherited with disease in this family. Genes within these "linked regions" were examined for disease-causing mutations using exome sequencing, and a His196Pro mutation was detected in the TMEM98 gene, which was recently reported to be a nanophthalmos gene. Sanger sequencing subsequently showed that all other members of this pedigree with nanophthalmos also carry the His196Pro TMEM98 mutation. Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members. Neither TMEM98 mutation was detected in public exome sequence databases.ConclusionsA recent report identified a single TMEM98 missense mutation in a nanophthalmos pedigree. Our discovery of two additional TMEM98 mutations confirms the important role of the gene in the pathogenesis of autosomal dominant nanophthalmos.

Dataset Information

Molecular analysis of 76 Chinese hemophilia B pedigrees and the identification of 10 novel mutations.

Publications

Molecular analysis of 76 Chinese hemophilia B pedigrees and the identification of 10 novel mutations.

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