Clinical and molecular genetic analysis of a family with macrothrombocytopenia and early onset sensorineural hearing loss

A kindred with inherited macrothrombocytopenia (MTCP) and sensorineural hearing loss (SNHL) from Ghent, Belgium was identified. Currently, joint expression of MTCP and hearing loss are linked to mutations within MYH9 only. Thus, we tested the hypothesis that a mutation within MYH9 is responsible for the autosomal dominant inheritance of MTCP and hearing loss in the Ghent family. A mutation screen of MYH9 coding region including its intron–exon junctions, as well as common hearing loss genes GJB2, GJB3, and GJB6, was performed. However, no pathogenic sequence alteration was identified. Patients' leukocytes were determined to be normal for NMMHC-A distribution via immunofluorescence analysis and free of Döhle body-like inclusions, identified as aggregates of mutant NMHC-IIA in MYH9 disorders. Also, western blot analysis with anti-NMHC-IIA antibody identified a single 220 kDa immunoreactive band with normal expression level of NMHC-IIA within the platelets and leukocytes of the affected family members. The immunoblot analysis eliminates the possibility of a large deletion within MYH9 that can escape detection by direct sequencing. Collectively, these results suggest that molecular genetic etiology of the Ghent family disorder may be due to as yet unidentified gene whose mutation(s) yields a phenocopy of the MYH9-related disease.