Detection of overlooked rare thalassemia genotypes: A case series

Thalassemia is the most prevalent type of monogenic disorder, requiring multiple laboratory tests for diagnosis. The complex structure and mutations of hemoglobin (Hb) genes pose notable obstacles to genetic counselling and prenatal diagnosis. Consequently, detecting and confirming rare thalassemia genotypes that are easily overlooked holds considerable importance in these fields. The present study describes three cases of incidentally discovered rare thalassemia genotypes. It analyzes their detection and diagnostic pathways to investigate causes of misdiagnosis and missed diagnosis in rare thalassemia, with the aim of enhancing sensitivity in identifying rare thalassemia and improving diagnostic standards. The findings revealed that all subjects carried rare thalassemia genotypes: Case 1 exhibited a normal phenotype as an α‑thalassemia heterozygote (αα/αα^{3'UTR +71 G>C}, β^N/β^N); case 2 presented with a family history of hereditary diseases and a history of iron deficiency anemia, with a compound αβ‑thalassemia triple genotype [‑^{Southeast Asian}/αα^{Quong Sze} (HBA2: c.377T>C), β^{intron variant site (IVS)II‑672 A>C}/β^N]; and case 3 exhibited a normal phenotype and was a compound carrier of rare αβ‑double genotypes (αα/αα^{CD 27 GAG>AAG}, β^{IVSII‑180 T>C}/β^N). To the best of our knowledge, the αα/αα^{3'UTR +71 G>C} and β^{IVSII‑180 T>C}/β^N genotypes are reported for the first time in the Chinese population; case 2 is the first reported rare instance of a triple thalassemia gene carrier; and case 3 is the first documented case of a compound double rare thalassemia gene carrier. The present report on rare thalassemia genes, particularly the two cases of rare thalassemia gene combinations, enrich the spectrum of thalassemia gene mutations in the Chinese population. Moreover, the present study provides valuable molecular information and case studies for thalassemia diagnosis and counselling, and offers clinical experience for the identification and diagnosis of rare thalassemia gene cases that are often overlooked.