The gene for May-Hegglin anomaly localizes to a <1-Mb region on chromosome 22q12.3-13.1 - PubMed (original) (raw)

. 2000 Apr;66(4):1449-54.

doi: 10.1086/302873. Epub 2000 Mar 17.

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The gene for May-Hegglin anomaly localizes to a <1-Mb region on chromosome 22q12.3-13.1

J A Martignetti et al. Am J Hum Genet. 2000 Apr.

Abstract

The May-Hegglin anomaly (MHA) is an autosomal dominant platelet disorder of unknown etiology. It is characterized by thrombocytopenia, giant platelets, and leukocyte inclusion bodies, and affected heterozygotes are predisposed to bleeding episodes. The MHA gene has recently been localized, by means of linkage analysis, to a 13.6-cM region on chromosome 22, and the complete chromosome 22 sequence has been reported. We recently performed a genome scan for the MHA gene in 29 members of a large, multigenerational Italian family, and we now confirm that the MHA locus is on chromosome 22q12. 3-13.1. The maximal two-point LOD score of 4.50 was achieved with the use of marker D22S283, at a recombination fraction of.05. Haplotype analysis narrowed the MHA critical region to 6.6 cM between markers D22S683 and D22S1177. It is of note that the chromosome 22 sequence allowed all markers to be ordered correctly, identified all the candidate genes and predicted genes, and specifically determined the physical size of the MHA region to be 0. 7 Mb. These results significantly narrow the region in which the MHA gene is located, and they represent the first use of chromosome 22 data to positionally clone a disease gene.

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Figures

Figure 1

Figure 1

Pedigree of the Italian kindred with MHA. This family was previously described elsewhere (Bizzaro 1997), and we have herein updated its members' disease status. Family members in the present study are numbered. Blackened symbols denote affected individuals; unblackened symbols denote unaffected individuals. Affected individual V.3 (gray-shaded circle) also has von Willebrand disease.

Figure 2

Figure 2

Haplotypes of the kindred with MHA. Twelve markers (D22S345, D22S277, D22S1142, D22S683, D22S283, D22S1177, IL2RB, D22S445, D22S272, D22S284, D22S423, and D22S444) from within and flanking the linkage region are shown. Family numbers and individual numbers are the same as those in figure 1. Affected individuals are underlined with a blackened bar; unaffected individuals are underlined with an unblackened bar. Spouses are shown to determine phase.

Figure 3

Figure 3

Chromosome 22 ideogram. The markers used in this study are shown with their relative locations and genetic distances, as previously defined (Broman et al. 1998), and with the actual physical distances based on chromosome 22 sequence data (Dunham et al. 1999).

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References

Electronic-Database Information

    1. Center for Medical Genetics, Marshfield Medical Research Foundation, http://www.marshmed.org/genetics/ (for the human genetic map)
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for MHA [MIM <155100>], Fechtner syndrome [MIM <153640>], and familial platelet disorder with associated myeloid malignancy [MIM <601399>])

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