Cytogenetic and molecular analysis of a ring (21) in a patient with partial trisomy 21 and megakaryocytic leukemia.

We describe a patient with an asymmetric double ring 21 in mosaic form, 45,XX, -21/46, XX, -21, +r(21), who has limited manifestations of Down syndrome and who developed acute myelofibrosis and megakaryocytic leukemia (AMKL), FAB M7, a hematologic disorder particularly common in Down syndrome patients. In situ hybridization studies, gene dosage, and DNA polymorphism analysis showed that the ring chromosome carries a duplicated region which extends from D21S406 on the centromeric side and includes marker D21S3 on the telomeric side. FISH studies indicate two sizes of ring 21 in the patient. The origin of the supernumerary chromosome 21 in the proband was paternal; furthermore, the r(21) probably was formed postzygotically. Included in the duplicated segment are the candidate genes for leukemia AML-1, ETS, and ERG. The potential significance of disomic homozygosity of loci on 21q in M7 megakaryocytic leukemia is discussed.

Isolation and characterization of a candidate gene for progressive myoclonus epilepsy on 21q22.3.

The Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1) and autoimmune polyglandular disease type I (APECED) have been mapped to human chromosome 21q22.3 by genetic linkage analysis and/or linkage disequilibrium studies. In order to isolate the genes for these disorders, we have constructed BAC contigs in this region and a 14 week trisomy 21 fetal brain cDNA library. A direct cDNA selection technique, modified to permit the recovery 5' and 3' ends of cDNA, was applied to gene identification using the BAC contigs. We have isolated and characterized a novel gene defined by three overlapping but distinct cDNAs of 5, 3, and 3 kb in size all named EHOC-1 (Epilepsy, HOloprosencephaly Candidate-1). This gene maps less than 45 kb centromeric of D21S25, and spans at least 56 kb of genomic DNA. Northern analysis of the 5 kb cDNA revealed that 8, 7.5 and 5.3 kb transcripts are ubiquitously expressed in adult tissues. DNA sequence analysis of the 5 kb cDNA showed a complete coding sequence of 3570 bp that has multiple putative transmembrane domains and has partial homologies to transmembrane proteins including sodium channel proteins. This gene (EHOC-1) is a good candidate for APECED, and particularly for EPM1 because of the location, size, structure and homologies.