Thiamine Responsive Megaloblastic Anemia via the SLC19A2 Gene

Thiamine Responsive Megaloblastic Anemia (TRMA), also known as Roger’s syndrome, is characterized by a phenotypic triad of megaloblastic anemia, non-type I diabetes mellitus, and sensorineural deafness. To date, less than 100 cases have been described worldwide. TRMA onset occurs between infancy and adolescence, however all key features are not initially present (Bergmann et al. 2009). Megaloblastic anemia results in loss of appetite, headache, pallor, lethargy, and paresthesia in hands and feet. In some cases retinal dystrophy, optic nerve atrophy, short stature, congenital heart defects, seizures, and strokes have been reported. Treatment of TRMA includes daily thiamine to alleviate anemia; however, thiamine is unable to improve sensorineural deafness. Genetic testing is helpful in the differential diagnosis of TRMA from Wolfram syndrome, mitochondrial disorders, acquired forms of megaloblastic anemia, myelodysplastic syndromes, and juvenile forms of diabetes (Oishi et al. 1993).

TRMA is inherited in an autosomal recessive manner through pathogenic variants in the SLC19A2 gene. SLC19A2 encodes a thiamine transporter and is the sole transporter in bone marrow, pancreatic beta cells, and a subset of cochlear cells (Diaz et al. 1999; Fleming et al. 1999). Truncating variants are most common with nonsense, frameshift, and splice site alterations accounting for the majority of TRMA cases (Bergmann et al. 2009; Raz et al. 2000). Missense variants have also been reported in TRMA patients and are predicted to result in impair protein function or intracellular trafficking (Bergmann et al. 2009). Gross deletions have only been reported in one case (Oishi et al. 1993) There is no clear genotype-phenotype presentation, but TRMA is fully penetrant (Oishi et al. 1993). Pathogenic variants are largely private and have been reported throughout the entire SLC19A2 gene (Bergmann et al. 2009).

Clinical sensitivity cannot be estimated due to the limited number of patients being reported. To date, the SLC19A2 gene is the only known cause of TRMA. Analytical sensitivity is estimated at >95% as gross deletions have only been reported in one case (Oishi et al. 1993).

This test provides full coverage of all coding exons of the SLC19A2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).