Localization of the Thiamine-Responsive Megaloblastic Anemia Syndrome Locus to a 1.4-cM Region of 1q23

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Abstract 791 Inborn Errors of Metabolism Platform, Monday, 5/3

Thiamine-responsive megaloblastic anemia (TRMA; MIM 249270) is a rare autosomal recessive syndrome characterized by megaloblastic anemia, deafness, and diabetes mellitus. Congenital heart defects and optic atrophy have also been reported in affected individuals. A genome scan previously established linkage of this disorder to 1q23 and haplotype analysis defined a 16-cM critical region ( Am. J. Hum. Genet. 61:1335, 1997). Four unrelated multiplex Iranian families with TRMA were recruited and studied in order to refine the TRMA critical region. Parents of all affected individuals were consanguineous and the families were of different ethnic origins. Genotyping was performed with genomic DNA samples from 43 individuals including 11 patients using 12 simple tandem repeat DNA markers (STRs) that spanned the 16-cM TRMA critical region. Multipoint linkage analysis was performed using the Mapmaker/Homoz software and revealed a maximal LOD score of 10.85 between D1S3464 and DS1619, confirming linkage of this disorder to 1q23. Using haplotype analysis, homozygosity-by-descent for some or all of the TRMA critical region was observed in all patients, consistent with genetic homogeneity. Two recombinant chromosomes were identified which permitted significant refinement of the TRMA critical region. One affected individual was heterozygous at STRs telomeric to D1S1619, confining the TRMA locus to the region centromeric to D1S3464. Another patient was heterozygous at STRs centromeric to D1S1619, confining the TRMA critical region telomeric of D1S3464. Thus, the TRMA was confined to the interval between D1S3464 and D1S1619, a 1.4-cM interval. Comparison of the putative ancestral haplotypes found in the four families revealed that two were identical at the four STRs flanking the critical region, while the other two differed, consistent with three independent mutational events. Review of the known genes and expressed sequence tags which have been mapped to or near the TRMA critical 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.

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