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• W2080997911 abstract "MYH9 disorders, such as May–Hegglin anomaly, are characterized by macrothrombocytopenia and leukocyte inclusion bodies that result from mutations in MYH9, the gene for non-muscle myosin heavy chain-IIA (NMMHC-IIA) (Heath et al, 2001; Kunishima et al, 2001a; Seri et al, 2003; Dong et al, 2005). To date, more than 200 families with MYH9 disorders have been studied, in which about 30 different MYH9 mutations have been identified. Most MYH9 mutations cluster in a limited region of the gene, especially exons 1, 16, 26, 30, 38 and 40. MYH9 disorders are inherited in an autosomal dominant manner, although more than 20% of cases occur in sporadic de novo form. This indicates recurrent mutational events at specific sites. We previously reported somatic mosaicism in the father of a child affected with sporadic May–Hegglin anomaly (Kunishima et al, 2005). We here report the first demonstration of germinal mosaicism in a family with two affected siblings of normal parents. The proband was a 15-year-old girl who was referred for the evaluation of thrombocytopenia. Peripheral blood smears showed that platelets were markedly large, as large as erythrocytes. Cytoplasmic inclusion bodies were observed in most granulocytes. Blood chemistry and urinalysis were normal. Cataracts and hearing disability were absent. Further investigation in the family showed that the younger brother was also affected. However, the parents had normal platelet counts and size. Granulocyte inclusion bodies were absent. Immunofluorescence analysis of neutrophil NMMHC-IIA in the affected siblings showed the type I localization containing one or two large, intensely stained, oval- to spindle-shaped cytoplasmic NMMHC-IIA-positive granules (Kunishima et al, 2001b, 2003). As type I NMMHC-IIA localization is mostly associated with MYH9 exon 38 and exon 40 mutations, these two exons were amplified with polymerase chain reaction (PCR) and sequenced. A heterozygous E1841K mutation was found in both patients. However, this mutation was not detected in the parents. The ethical committees of Kumamoto Medical Centre and Nagoya Medical Centre approved this study. Peripheral blood samples were obtained after the patients and the parents gave informed consent for the study. To investigate the presence of germinal mosaicism in either parent, further genetic analysis was conducted. Paternity was confirmed using a combination of three highly polymorphic microsatellite markers (D1S80, vWA and D17S5) (Kunishima et al, 1997). Genotyping of a total of 13 MYH9 intragenetic polymorphic sites in all the family members revealed that the affected siblings shared the same alleles for MYH9: they inherited the same MYH9 haplotypes from the father and mother (Fig 1). Next, we determined which allele (paternal or maternal) harbored the E1841K mutation. By cloning and sequencing the PCR products of the region spanning the mutation and rs2071732, which is located 194 bp 5′ to the mutation site, it was possible to distinguish the paternal and maternal alleles. This analysis revealed that both patients had the maternal rs2071732 A allele containing E1841K mutation and the paternal rs2071732 G allele containing wild-type E1841. Thus, these results led us to conclude that the family represents the first germinal mosaicism in MYH9 disorders. Close observation of the peripheral blood smears showed that the parents had normal-sized platelets: no large-sized populations were observed. Granulocyte inclusion bodies and abnormal NMMHC-IIA localization were absent. Thus somatic mosaicism even at the low rate in either parent could be excluded. Pedigree of the family, with haplotypes for MYH9. Squares and circles symbolize males and females, respectively, and black symbols denote affected patients. The maternal haplotype, which contains E1841K mutation, is shown in bold. Genotypes for the MYH9 mutation and 13 intragenetic polymorphic sites, from centromere to telomere on chromosome 22q, E1841K-rs2071732-rs2071733-rs5995276-rs16996643-rs2071734-rs5756130-rs2269529-rs2269530-rs2071730-rs4821478-rs3752462-rs3833922-rs3752463, are shown. W, wild-type; M, mutant. We show germinal as well as somatic mosaicism accounts for some apparently de novo mutations in families with MYH9 disorders. Patients with an MYH9 mutation in motor domain, especially those at R702, have a considerably higher risk of developing Alport manifestations (Kunishima et al, 2007; Pecci et al, 2008). Furthermore, R702 mutation is associated with high rate of de novo mutation. In terms of genetic counselling, detecting mosaicism in apparently normal parents with a sporadic case is important. There is no conflict of interest. This work was supported by grants to SK from the Japan Society for the Promotion of Science (18591094 and 20591161), the Ministry of Health, Labor and Welfare (Grant for Child Health and Development 19C-2), Charitable Trust Laboratory Medicine Foundation of Japan and National Hospital Organization Research Fund." @default.
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• W2080997911 date "2009-03-26" @default.
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• W2080997911 title "Germinal mosaicism in<i>MYH9</i>disorders: a family with two affected siblings of normal parents" @default.
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• W2080997911 doi "https://doi.org/10.1111/j.1365-2141.2009.07584.x" @default.
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