Diagnosis of a patient with severe sensorineural hearing loss as the initial symptom caused by novel compound heterozygous variant in SLC19A2 gene

This is the authors' abstract. We don't add key points for this paper.

OBJECTIVE: Thiamine-Responsive Megaloblastic Anemia (TRMA) syndrome, caused by biallelic variants in the SLC19A2 gene, typically presents with a triad of megaloblastic anemia, diabetes mellitus, and sensorineural hearing loss. This study aims to determine the genetic etiology and clinical phenotype of a patient who presented with severe sensorineural hearing loss as the initial symptom, and to expand our understanding of the SLC19A2 variant spectrum. METHODS: Proband-only whole-exome sequencing was performed to screen the candidate variants, which were subsequently validated by Sanger sequencing within the family. cDNA sequencing based on RT-PCR and TA cloning analysis was used to determine the effect of splicing variants on mRNA processing of SLC19A2 gene. Detailed clinical features were evaluated by a diagnostic hearing test, laboratory and imaging examination. RESULTS: A 2-year-5-month-old Chinese girl was diagnosed with diabetes mellitus and severe sensorineural hearing loss, without abnormal hemoglobin. DNA sequencing revealed a novel compound heterozygous variant of c.808-1G > A and c.1228C > T (p.Gln410*) in the SLC19A2 gene. Both variants were previously unreported. The c.808-1G > A splicing variant is located in intron 2 of SLC19A2, and is predicted to cause exon 3 skipping. The cDNA experiment confirmed this biological event, further indicating that the splicing variant can cause amino acid frameshift alteration (p.Glu270Valfs*10) in SLC19A2. CONCLUSION: We report a patient with TRMA syndrome (without anemia) caused by a novel compound heterozygous variant in SLC19A2 gene. This study suggests that the possibility of TRMA syndrome should be considered when encountering patients with early-onset severe sensorineural hearing loss in clinical practice. LEVEL OF EVIDENCE: Level 4.