Prenatal Counseling Conundrum: Unexpectedly Mild Phenotype in a Pregnant Woman with Homozygous CD41/42(-TTCT) β-Thalassemia.

We describe a pregnant woman with a genotype consistent with β-thalassemia major but a phenotype suggestive of the β-thalassemia trait. Routine genetic testing revealed a homozygous CD41/42(-TTCT) (HBB:c.126_129delCTTT) mutation in the β-globin gene. Hemoglobin electrophoresis showed an Hb F level of 98.9% and an Hb A2 level of 1.1%, while the complete blood count indicated an Hb concentration of 98 g/L. Pedigree analysis confirmed that both parents were heterozygous CD41/42(-TTCT) carriers, consistent with their mild clinical presentations. Further investigations using multiplex ligation-dependent probe amplification excluded copy number variations in the α- and β-globin gene clusters, and third-generation sequencing ruled out potential cis-acting mutations. Sanger sequencing confirmed that the proband harbored two mutations in the γ-globin chain (Gγ-158 C > T and Aγ + 25 G > A). Because her husband was also a heterozygous carrier of the same mutation, prenatal diagnosis was performed and indicated a homozygous CD41/42(-TTCT) genotype in the fetus. This marked genotype-phenotype discordance in the pregnant woman posed a significant challenge for prenatal genetic counseling. Ultimately, given the current limitations in understanding such phenotypic variations, the couple decided to terminate the pregnancy.