Characterization of a novel α-thalassemia deletion (Dongxing deletion; --DX) by CNV-seq in a Chinese female with Hb H disease: a case report.

Abstract

Objective: This study was initiated to resolve a discrepancy between conventional genetic findings and clinical presentation in a proband with α-thalassemia. The initial genotype (-α^4.2/-α^4.2) was inconsistent with the Hb H disease phenotype, suggesting the presence of an undetected pathogenic variant.

Methods: To characterize the underlying genetic defect, we employed a multi-technique approach. The proband's DNA was analyzed using multiplex ligation-dependent probe amplification (MLPA), third-generation sequencing (TGS), and copy number variation sequencing (CNV-seq). Prenatal diagnosis was performed because the husband carried the --^SEA/αα genotype.

Results: Investigations revealed a novel, large deletion on the α-globin gene cluster. Unlike MLPA and TGS, which indicated a deletion but could not precisely define its breakpoints due to its telomeric location, CNV-seq successfully mapped the deletion to chr16:97840-230167. This represents a 132,327 bp (132 kb) deletion, which we designated the 'Dongxing' (--^DX) deletion. The proband's corrected genotype was confirmed as --^DX/-α^4.2. Prenatal diagnosis revealed the fetus had Hb H disease (--^SEA/-α^4.2).

Conclusions: We identified and characterized a novel α-thalassemia deletion (Dongxing deletion) using CNV-seq. This case highlights the limitations of conventional genotyping and underscores the importance of comprehensive genetic analysis in cases of genotype-phenotype discrepancy.