An Endemic Region of Thiamine-Responsive Megaloblastic Anemia Caused by an SLC19A2 c.1223+1G>A Founder Mutation

Thiamine-responsive megaloblastic anemia (TRMA) is a rare autosomal recessive disorder caused by biallelic loss of function variants in the SLC19A2 gene. It typically presents with a triad of megaloblastic anemia, diabetes mellitus, and sensorineural deafness. In this work, we analyzed ten children with suspected TRMA: nine exhibited the full triad and one, a younger sibling of a patient with full triad, did not develop hearing loss by the age of 18 months. All patients became transfusion-independent on high-dose thiamine therapy. Whole-genome sequencing identified homozygosity for the canonical splice variant SLC19A2 c.1223+1G>A in eight patients. One patient was homozygous for a known SLC19A2 c.196G>T variant, and the other was compound heterozygous for two novel variants, c.120C>G and c.584T>C. All patients with the SLC19A2 c.1223+1G>A variant were ethnic Ingush. In the reference Ingush cohort, 9/328 unrelated adults were c.1223+1G>A carriers (heterozygous carrier frequency 2.7%; carrier frequency ≈ 1/36), and shared a 2.3 Mb ATP1B1-FMO2 haplotype on chromosome 1, demonstrating a strong founder effect. These findings identify Ingushetia as a new TRMA-endemic region and support targeted SLC19A2 screening and early thiamine therapy in patients with macrocytic anemia and diabetes of unclear origin in this population.