GeneticsTier 1Medical Sciences concept

Thalassaemia inheritance and genotype-phenotype correlation (alpha/beta)

Core concept

Beta-thalassaemia: 2 beta-globin genes (one per chromosome 11) -- autosomal recessive-like phenotype severity scales with number of affected alleles (trait = 1 affected, major = 2 affected)
Alpha-thalassaemia: 4 alpha-globin genes (2 per chromosome 16) -- phenotype severity scales with number of genes deleted/non-functional (0-4), giving a graded spectrum rather than a simple recessive pattern
Genotype-phenotype correlation is the core exam skill: predict clinical severity and offspring risk from the stated genotype

Alpha-thal genotype	Genes affected	Phenotype
-a/aa (silent carrier)	1	Normal/near-normal
--/aa or -a/-a (trait)	2	Mild microcytic anaemia
--/-a (HbH disease)	3	Moderate-severe anaemia; HbH = beta4 tetramer (excess unpaired beta chains form a tetramer)
--/-- (Hb Barts hydrops fetalis)	4	Incompatible with life -- Hb Barts = gamma4 tetramer (excess gamma chains), severe intrauterine hypoxia

Electrophoresis in beta-thalassaemia trait: raised HbA2 (>3.5%) +/- mildly raised HbF -- the discriminating finding from iron deficiency (which does not raise HbA2)
Punnett square for alpha-thal: two trait carriers of the cis form (--/aa), common in South-East Asian populations, risk 1 in 4 offspring with Hb Barts hydrops (--/--) -- higher-risk combination than the trans form (-a/-a), common in African populations, where affected offspring can only inherit HbH disease (--/-a) at worst, not hydrops

Trap: microcytic anaemia with normal/low HbA2 is more likely iron deficiency or alpha-thalassaemia trait than beta-thalassaemia trait -- HbA2 is specifically raised in beta-thal trait
Ethnicity is directly relevant to alpha-thal risk counselling: cis deletions (South-East Asian) carry hydrops fetalis risk in carrier x carrier pairings; trans deletions (African, Mediterranean) do not -- same "2 genes affected" trait genotype, very different reproductive risk depending on deletion configuration
Beta-thalassaemia major (both alleles severely affected) presents in infancy with severe transfusion-dependent anaemia as HbF switches to HbA -- genotype (both alleles null vs one null/one reduced-function) predicts transfusion dependence vs intermedia phenotype

Same Hardy-Weinberg/carrier-frequency logic (separate note) applies to calculating population carrier rates and offspring risk once genotypes are known
HbH and Hb Barts are both abnormal tetramers formed from an excess of the globin chain not affected by the mutation -- same unifying mechanism, different chain (beta vs gamma) depending on which globin gene cluster is affected
Contrast with sickle cell disease (a single beta-globin point mutation, not a deletion/reduced-production defect) -- a qualitative rather than quantitative haemoglobinopathy

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