Refinement of the locus for thiamine-responsive megaloblastic anemia syndrome

Thiamine-responsive megaloblastic anemia (TRMA; MIM 249270) is a rare autosomal recessive syndrome with features that include megaloblastic anemia, deafness, and diabetes mellitus. A genome scan performed previously by Neufeld and co-workers (Am. J. Hum. Genet. 61:1335, 1997) established linkage of this trait to 1q23 and defined a 16-cM critical region. In the present study, two unrelated multiplex Iranian families inheriting TRMA were recruited and studied. Parents of affected individuals were consanguineous and the two families were of different ethnic origins. Genotyping was performed on 24 individuals including 6 patients using eight simple tandem repeat DNA markers (STRs) that spanned the TRMA critical region. Haplotype analysis revealed that all affected individuals were homozygous for some or all of these STRs and overlapping portions of the haplotypes were shared within the extended families, consistent with inheritance of defects at the TRMA locus on 1q23 by homozygosity-by-descent. Comparison of the putative ancestral haplotypes identified in the two families revealed identical alleles at only a single marker, suggesting separate founders for these ethnically diverse kindreds. Two recombinant chromosomes were identified which permitted refinement of the critical region. One affected individual was heterozygous at STRs telomeric to D1S2799, confining the TRMA locus to the region centromeric to D1S2851. Another patient was heterozygous at the STRs centromeric to D1S2851, confining the TRMA critical region telomeric of D1S2799. Thus, the TRMA was refined to the interval between D1S2799 and D1S2851, a 5.6-cM interval. Review of known genes which have been mapped to this region failed to reveal an obvious candidate gene. Future efforts to identify the TRMA disease gene will depend on further refinement of the critical region as well as identification and evaluation of positional candidate genes.