Transcobalamin II deficiency is a rare autosomal recessive disorder classified as an inborn error of immunity. Transcobalamin II is a plasma protein essential for the absorption, transport, and cellular utilization of vitamin B12. Its deficiency leads to diverse clinical manifestations, including gastrointestinal disturbances, failure to thrive, megaloblastic anemia, pancytopenia, agammaglobulinemia, neurological impairments, metabolic abnormalities, and recurrent infections. According to Orphanet and PubMed, fewer than 50 cases have been reported globally, suggesting a prevalence of less than 1 in 1,000,000.
Genomic DNA was extracted from peripheral blood leukocytes using phenol-chloroform extraction. Whole-exome sequencing was performed on a DNBSEQ-G50 (MGI, China) using the Exome Capture V5 Probe Set (MGI, China). Secondary data processing of FASTQ files was performed using ZLIMS (MGI, China), and tertiary analysis involved the Annovar software, followed by variant filtering. Detected variants were evaluated using the Varsome software. Clinically significant variants were confirmed by Sanger sequencing on a 3500 Genetic Analyzer (Thermo Scientific, USA).
Two novel heterozygous variants in the TCN2 gene (NM_000355.3) were identified, neither reported in the gnomAD Exomes database. These included a splice-site variant c.1223-2 A>G (VarSome classification: likely pathogenic) and a coding region variant c.154C>T, p.Pro52Ser (VarSome classification: uncertain significance). The compound heterozygous genotype was consistent with the patient’s clinical presentation.
The patient was first admitted at age five with an acute anemic crisis (hemoglobin 49 g/L), required erythrocyte transfusion. Subsequent evaluations revealed persistent megaloblastic anemia, hyperbilirubinemia, and mild splenomegaly. Bone marrow analyses excluded myelodysplastic syndrome and hematologic malignancies. Iron and folate therapies were ineffective; however, cyanocobalamin normalized hemoglobin levels (130 g/L) and reduced splenomegaly. Mild intellectual impairment was noted during follow-up.
Transcobalamin II deficiency typically manifests in early childhood with symptoms such as developmental delays, hypotonia, diarrhea, pallor, anemia, pancytopenia, and agammaglobulinemia. This case contributes to the understanding of the condition, expands the allelic spectrum of TCN2, and supports the optimization of treatment strategies for this rare condition.
