GFI1B mutation causes a bleeding disorder with abnormal platelet function.

BACKGROUND: GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development but previously unknown to be associated with human disease. METHODS: A family with a novel bleeding disorder was identified and characterized. Genetic linkage analysis and massively parallel sequencing were used to localize the mutation causing the disease phenotype on chromosome 9. Functional studies were then performed in megakaryocytic cell lines to determine the biological effects of the mutant transcript. RESULTS: We have identified a family with an autosomal dominant bleeding disorder associated with macrothrombocytopenia, red cell anisopoikilocytosis, and platelet dysfunction. The severity of bleeding is variable with some affected individuals experiencing spontaneous bleeding while other family members exhibit only abnormal bleeding with surgery. A single nucleotide insertion was identified in GFI1B that predicts a frameshift mutation in the fifth zinc finger DNA-binding domain. This mutation alters the transcriptional activity of the protein, resulting in a reduction in platelet α-granule content and aberrant expression of key platelet proteins. CONCLUSIONS: GFI1B mutation represents a novel human bleeding disorder, and the described phenotype identifies GFI1B as a critical regulator of platelet shape, number, and function.

Variable hearing impairment in a DFNB2 family with a novel MYO7A missense mutation.

Myosin VIIA mutations have been associated with non-syndromic hearing loss (DFNB2; DFNA11) and Usher syndrome type 1B (USH1B). We report clinical and genetic analyses of a consanguineous Iranian family segregating autosomal recessive non-syndromic hearing loss (ARNSHL). The hearing impairment was mapped to the DFNB2 locus using Affymetrix 50K GeneChips; direct sequencing of the MYO7A gene was completed. The Iranian family (L-1419) was shown to segregate a novel homozygous missense mutation (c.1184G>A) that results in a p.R395H amino acid substitution in the motor domain of the myosin VIIA protein. As one affected family member had significantly less severe hearing loss, we used a candidate approach to search for a genetic modifier. This novel MYO7A mutation is the first reported to cause DFNB2 in the Iranian population and this DFNB2 family is the first to be associated with a potential modifier. The absence of vestibular and retinal defects, and less severe low frequency hearing loss, is consistent with the phenotype of a recently reported Pakistani DFNB2 family. Thus, we conclude this family has non-syndromic hearing loss (DFNB2) rather than USH1B, providing further evidence that these two diseases represent discrete disorders.

Generating linkage mapping files from Affymetrix SNP chip data.

SUMMARY: LINKDATAGEN is a perl tool that generates linkage mapping input files for five different linkage mapping tools using data from all 11 HAPMAP Phase III populations. It provides rudimentary error checks and is easily amended for personal linkage mapping preferences. AVAILABILITY AND IMPLEMENTATION: LINKDATAGEN is available from http://bioinf.wehi.edu.au/software/linkdatagen/ with accompanying annotation files, reference manual and test dataset.