# Unraveling thalassemia intermedia: Novel insights of a hemoglobin Jax [HBA2:c.44G>C] and deletional α0-thalassemia interaction phenotype

## TL;DR

A new α-globin variant called hemoglobin Jax interacts with α0-thalassemia to cause a hemoglobinopathy, requiring DNA analysis for accurate diagnosis.

## Contribution

Identifies a novel α2-globin mutation (HBA2:c.44G>C) and its interaction with deletional α0-thalassemia, revealing a new hemoglobinopathy phenotype.

## Key findings

- Hemoglobin Jax mutation is unstable and associated with a specific α-globin haplotype [+ - S + - + -].
- The mutation is asymptomatic in heterozygotes but causes a hemoglobin H-like phenotype when combined with α0-thalassemia.
- Accurate diagnosis requires DNA-level analysis due to the variant's anomalous HPLC and electrophoretic behavior.

## Abstract

To elucidate the molecular basis, hematological features, and electrophoretic and chromatographic mobility behavior of an unstable α2-globin chain variant, and to describe the diagnostic approach.

A Thai patient with unexplained chronic anemia and her daughter were investigated. Hematological data were analyzed using a standard automated cell counter. Hemoglobin was analyzed using high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE). Mutational analysis was performed using appropriate polymerase chain reaction (PCR) techniques and direct sequencing. Additionally, α-globin haplotype analysis was conducted. Simple and rapid diagnostic methods were developed.

Hemoglobin analysis in the patient revealed anomalous peaks separated from normal hemoglobin visible using the HPLC technique. These peaks were virtually absent in the daughter. DNA analysis identified a G to C mutation at codon 14 of the α2-globin gene responsible for hemoglobin Jax in trans to the α0-thalassemia gene in the patient. Heterozygosity of this mutation was identified in her daughter. Hematological analysis showed mild thalassemia-like changes in simple heterozygotes and exhibited a hemoglobin H-like phenotype when combined with α0-thalassemia. Isopropanol stability testing and bioinformatic software indicated that the variant was unstable and potentially damaging. This mutation was confirmed using allele-specific PCR. Hemoglobin Jax was strongly associated with the haplotype [+ - S + - + -].

Hemoglobin Jax, a pathological α-globin variant, is asymptomatic in simple heterozygotes and demonstrates more pronounced clinical effects when associated with deletional α-thalassemia. This knowledge can help develop strategies to prevent hemoglobinopathies in regions of high prevalence. Accurate identification requires DNA level analysis.