The molecular basis of β thalassaemia in Punjabi and Maharashtran Indians includes a multilocus aetiology involving triplicated α‐globin loci

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Abstract
Summary We have analysed 201 β-thalassaemia (β-thal) genes from natives of the Punjab (156) and Maharashtra states of India and found the causative mutation in 200 of them. The most common β-globin gene mutations differed significantly between these two groups and between these groups and Indian immigrants in the U.S.A. and the U.K. In the Punjabi Indians the IVS-1, nt 1 (G–T) mutation accounted for nearly one-quarter of β-thal genes, whereas it was 5% or less in the other groups. Likewise, the cap+ 1 mutation was much more prevalent in the Punjabis, whereas the nonsense codon 15 allele had a higher frequency in the Maharashtrans of the Bombay region. The common IVS-1, nt5 allele had a frequency of 60% of β-thal genes in the Maharastrans, 35% in North American immigrants, and only 23% in the Punjabis. Two-thirds of all β-thal genes in Punjab were found in the merchant caste (Khatri-Arora), whereas the menial caste (Shudra) was highly represented among those with β-thal genes in Maharashtra. Two novel β-globin alleles were each found once; a frameshift codon 55 (+ A) in Maharashtrans and a frameshift codons 47–48 (+ ATCT) in Punjabis. Of three Punjabi patients with β-thal intermedia in whom only a single severe β-globin gene mutation was found, two had six α-globin genes (homozygosity for a triplicated α-globin locus) instead of the normal α-globin gene number of four. Thus, these two individuals had a multilocus aetiology of β-thal and their parents have the unusual recurrence risk of 1 in 8 for conceiving a third with β-thal intermedia. Since 15% of 126 α-globin clusters studied in Punjabis contained either single (10%) or triplicated (5%) α-globin genes, the α-globin gene number is a frequent modifier of the phenotype of β-thal in this ethnic group.