HBA2 – Hb Bart's Hydrops Fetalis

HBA2‐related α‐thalassemia is inherited in an autosomal recessive manner, where biallelic loss‐of‐function HBA2 alleles in trans with α^0‐thalassemia deletions lead to complete absence of α‐globin production and lethal fetal hydrops (Hb Bart’s) ([PMID:25500521]).

Multiple unrelated cases (n=5) of Hb Bart’s hydrops fetalis have been reported in fetuses compound heterozygous for HBA2 nondeletional mutations (e.g., c.178G>C (p.Gly60Arg)) and Southeast Asian (--SEA) or other large 0‐thalassemia deletions ([PMID:27686733]; [PMID:29493331]; [PMID:39286901]; [PMID:39526114]). Affected fetuses uniformly present with hydrops and cardiomegaly (HP:0001640) without any α‐globin production. Carrier parents are asymptomatic with typical red cell indices.

Segregation analysis confirms that heterozygous carriers of single α‐globin gene deletions or HBA2 point mutations are clinically silent, while trans inheritance of two null alleles results in the hydrops phenotype. Variant spectrum includes large gene deletions (--SEA, --GX, --SA, -α^3.7) and nondeletional alleles such as missense (c.178G>C (p.Gly60Arg)) and novel deletions, with the SEA deletion recurrent in Southeast Asia.

Functional studies demonstrate that splicing mutations (HBA2:c.95+1G>A) activate cryptic splice sites leading to nonsense‐mediated decay ([PMID:21967524]; [PMID:24274170]), promoter variants (c.-59C>T, c.-91G>A) significantly reduce transcriptional activity ([PMID:24300714]), and frameshift deletions generate truncated, unstable α‐chains ([PMID:25791745]). These concordant cellular assays corroborate the loss‐of‐function mechanism.

Routine prenatal screening limited to common deletions can miss rare HBA2 alleles, resulting in diagnostic errors. Comprehensive approaches including MLPA, SMRT sequencing and PCR‐SSCP have been shown to identify both common and novel nondeletional HBA2 variants, improving diagnostic accuracy and enabling timely genetic counseling ([PMID:26892340]; [PMID:39526114]; [PMID:39286901]).

In summary, biallelic HBA2 null and nondeletional mutations definitively cause Hb Bart’s hydrops fetalis. Early and comprehensive HBA2 genotyping in at‐risk pregnancies is critical for accurate prenatal diagnosis and informed clinical management.

References

• The Malaysian Journal of Pathology • 2014 • α-Thalassemia with Haemoglobin Adana mutation: prenatal diagnosis; PMID:25500521
• Hemoglobin • 2016 • Hydrops Fetalis Associated with Compound Heterozygosity for Hb Zurich-Albisrieden (HBA2: c.178G>C) and the Southeast Asian (--SEA) Deletion. PMID:27686733
• Hemoglobin • 2018 • Characterization of Hb Bart's Hydrops Fetalis Caused by --SEA and a Large Novel α0-Thalassemia Deletion. PMID:29493331
• Diagnosis (Berlin, Germany) • 2024 • Prenatal diagnostic errors in hemoglobin Bart's hydrops fetalis caused by rare genetic interactions of α-thalassemia. PMID:39286901
• Practical Laboratory Medicine • 2024 • A novel case of Hb Bart's hydrops fetalis following prenatal diagnosis: Case report from Huizhou, China. PMID:39526114
• Blood • 1990 • Molecular basis for alpha-thalassemia associated with the structural mutant hemoglobin Suan-Dok (alpha 2 109leu----arg). PMID:2265255
• Hemoglobin • 2012 • In vitro characterization of the α-thalassemia point mutation HBA2:c.95+1>A [IVS-I-1(G>A) (α2)]; PMID:21967524
• Pathology • 2014 • Molecular and cellular analysis of three novel alpha2-globin gene promoter mutations [HBA2:c.-59C>T], [HBA2:c.-81C>A] and [HBA2:c.-91G>A] reveal varying patterns of transcriptional and translational activities. PMID:24300714
• Hemoglobin • 2015 • Molecular characterization of Hb Hamilton Hill (HBA2:c.388delC), a novel HBA2 variant generating a premature termination codon and truncated HBA2 chain. PMID:25791745
• Journal of Clinical Laboratory Analysis • 2016 • Scanning for α-Hemoglobin Variants by High-Resolution Melting Analysis; PMID:26892340

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