Nanopore long-read sequencing reveals a novel 3.4-kb HBB deletion causing β-thalassemia in prenatal diagnosis: a case report

A 36-year-old pregnant woman was referred to our hospital for routine thalassemia screening at 12 weeks of gestation. Her complete blood count revealed mild microcytic hypochromic anemia, with hemoglobin (Hb) of 101 g/L, mean corpuscular volume (MCV) of 67.3 fL, and mean corpuscular hemoglobin (MCH) of 22.3 pg. Hemoglobin electrophoresis showed abnormally elevated levels of Hb A2 (6%) and Hb F (5%), with a concomitant decrease in Hb A (89%). Serum ferritin levels were within the normal range, excluding the possibility of iron deficiency anemia. Based on these findings, a β-thalassemia trait was initially suspected. Genomic DNA was extracted from peripheral blood and subjected to next-generation sequencing (NGS) targeting the α- and β-globin gene clusters. However, no pathogenic variants were detected. To further investigate, the remaining sample was analysed using a new nanopore sequencing platform (CycloneSEQ-WT02, MGI Tech) according to previously reported protocols,1 which identified a heterozygous deletion of approximately 3.4 kb involving the HBB gene cluster. Sanger sequencing confirmed the variant as NC_000011.10: g.5224014_5227482del, a heterozygous deletion spanning the entire HBB gene (Figure 1). This alteration leads to loss of gene function, consistent with a β0-thalassemia–like pathogenic mechanism.