Genomic screen for linkage of May-Hegglin anomaly. J.F. Korczak1, W. Jawien2, A.Y. Lin3, K. Hoffmeister2, M.J. Kelley4. 1) Georgetown Univ Med Ctr, Washington, DC; 2) National Naval Med Ctr, Bethesda, MD; 3) Santa Clara Valley Med Ctr, Santa Clara, CA; 4) Duke Univ Med Ctr, Durham, NC.
May-Hegglin anomaly (MHA; MIM#155100), an autosomal dominant platelet disorder, is characterized by the triad thrombocytopenia, giant platelets, and inclusion bodies in the leukocytes. About 30% of affected individuals have mild to moderate hemorrhagic symptoms and are frequently misdiagnosed and subjected to inappropriate treatments. Although about 300 cases have been reported, the genetic defect for MHA has not been identified, nor have functional studies revealed its etiology.
We evaluated three families with multiple cases (9, 2, and 2) of MHA in several generations, with affected individuals evenly distributed across genders (7 males and 6 females), and performed a genomic screen for linkage to identify chromosomal region(s) to which the MHA locus may map. Sufficient power to detect linkage was demonstrated by the program SIMLINK. Based on 200 replicates, the estimated mean and maximum lod scores at a recombination fraction of 0.05 (for a 10 cM map) were 3.3 and 6.4, respectively, assuming a rare, autosomal dominant gene with complete penetrance. DNA from 34 individuals (12 of 13 with MHA) was genotyped for 386 markers spaced 10 cM apart of the CHLC version 9 set at the Center for Inherited Disease Research (CIDR). Nonparametric two-point sib-pair linkage methods (affected sib-pair (ASP) and Haseman-Elston regression (H-E)), implemented in the S.A.G.E. (3.1) program SIBPAL, were used to test for linkage. Possible regions containing the MHA gene were suggested on chromosomes 3, 10, and 22, based on nominal P-values £ 0.01 for two or more adjacent markers for the ASP and/or H-E tests.
We are performing two-point lod score analysis to corroborate our findings and genotyping additional markers in regions of interest for multipoint analysis. We have also ascertained additional multiplex families to fine-map the MHA gene prior to undertaking a positional candidate approach to identify it.