DNA studies are necessary for accurate patient diagnosis in compound heterozygosity for Hb Adana (HBA2:c.179>A) with deletional or nondeletional α-thalassaemia

Abstract

Haemoglobin (Hb) Adana (HBA2:c.179>A) interacts with deletional and nondeletional α-thalassaemia mutations to produce HbH disorders with varying clinical manifestations from asymptomatic to severe anaemia with significant hepatosplenomegaly. Hb Adana carriers are generally asymptomatic and haemoglobin subtyping is unable to detect this highly unstable α-haemoglobin variant. This study identified 13 patients with compound heterozygosity for Hb Adana with either the 3.7 kb gene deletion (-α3.7), Hb Constant Spring (HbCS) (HBA2:c.427T>C) or Hb Paksé (HBA2:429A>T). Multiplex Amplification Refractory Mutation System was used for the detection of five deletional and six nondeletional α-thalassaemia mutations. Duplex-PCR was used to confirm Hb Paksé and HbCS. Results showed 84.6% of the Hb Adana patients were Malays. Using DNA studies, compound heterozygosity for Hb Adana and HbCS (αcodon 59α/αCSα) was confirmed in 11 patients. A novel point in this investigation was that DNA studies confirmed Hb Paksé for the first time in a Malaysian patient (αcodon 59α/αPakséα) after nine years of being misdiagnosis with Hb Adana and HbCS (αcodon 59α/αCSα). Thus, the reliance on haematology studies and Hb subtyping to detect Hb variants is inadequate in countries where thalassaemia is prevalent and caused by a wide spectrum of mutations.

The first report of hemoglobin E in combination with the highly unstable alpha‐globin variant Hb Adana: The importance of molecular confirmation

“…The complete blood count (CBC) (Horiba medical, ABX Micros 4 Especially when on the dominantly expressed alpha 2-globin gene, this mutation may even cause HbH hydrops fetalis in homozygosity or in combination with alpha 0-thalassemia. 2,5 Due to its unstable nature, heterozygosity for Hb Adana is not visible by routine biochemical assay such as HPLC and CE, 6 but the carrier does present with microcytic hypochromic parameters. As carriers of HbE may also present with mild microcytic hypochromic parameters, the co-inheritance of alpha-thalassemia defects could be easily overlooked unless the HbE percentage is taken into account, which is usually slightly decreased in those cases.…”

Hb Adana (HBA2 or HBA1: c.179G > A) and alpha thalassemia: Genotype–phenotype correlation

“…The remainder of Adana cases compounded with alpha globin deletions yielded varying phenotypes, ranging from mild anemia (−α 3.7 and −α 4.2 ) to severe HbH‐like disease (− − 20.5 and −α 4.2‐QT [Q‐Thailand]) . The cases of Adana alpha 2 mutations that combined with a single alpha 2 nondeletional mutation in general gave more severe HbH‐like presentations (α2 CS [Constant Spring], α2 Paksé , α2 IVS‐II‐142 , α2 IVS‐I‐1 , α2 codon24 , α2 codon22 , and rSNP 149709T > C) . The incidence of hydrops fetalis was generally associated with genotype and not ethnicity.…”

“…11,19,37,38 The cases of Adana alpha 2 mutations that combined with a single alpha 2 nondeletional mutation in general gave more severe HbH-like presentations ( 2 CS [Constant Spring], 2 Paksé , 2 IVS-II-142 , 2 IVS-I-1 , 2 codon24 , 2 codon22 , and rSNP 149709T > C). 15,17,22,35,36,39,40 The incidence of hydrops fetalis was generally associated with genotype and not ethnicity. Mild differences in clinical severity between patients of identical genotype were likely due to various unknown genetic factors implicated in HbH disease that require further study.…”

Non-deletional alpha thalassaemia: a review

“…2 ) [39,40] to a more critical HbH-like condition (− − 20.5 and -α 4.2-QT (Q-Thailand) [41]. Hb Adana HBA2 point mutations that are coinherited with a single α 1 non-deletional mutation generally have severe Hb H-like manifestations (such as α 2 CS [Constant Spring], α 2 Paksé , α 2 IVS-II-142 , α 2 IVS-II , α 2 codon24, α 2 codon22, and rSNP 149,709 T > C) [41].…”

“…2 ) [39,40] to a more critical HbH-like condition (− − 20.5 and -α 4.2-QT (Q-Thailand) [41]. Hb Adana HBA2 point mutations that are coinherited with a single α 1 non-deletional mutation generally have severe Hb H-like manifestations (such as α 2 CS [Constant Spring], α 2 Paksé , α 2 IVS-II-142 , α 2 IVS-II , α 2 codon24, α 2 codon22, and rSNP 149,709 T > C) [41]. The incidence of Hb Adana is found to be low in countries such as Turkey (0.5-0.6%) [39], Iran and Iraq (1-2.5%) [42,43], and China (1%) [43], while countries like Saudi Arabia (11.6%) [44], and Indonesia (16%) have a higher prevalence [40].…”