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Abdul Mannan: A Negative PCR Does Not Exclude β-Thalassaemia

Abdul Mannan/LinkedIn

Oct 30, 2026, 14:00

Abdul Mannan: A Negative PCR Does Not Exclude β-Thalassaemia

Abdul Mannan, Consultant Haematologist, Director Haemophilia Centre, Haematology Lab Lead at Betsi Cadwaladr University Health Board, shared a post on LinkedIn:

“The patient has β-thalassaemia major. The PCR says Negative.

Would you rule out the diagnosis?

I wouldn’t.

Imagine a child with severe microcytic anaemia, hepatosplenomegaly, growth failure, markedly raised HbF and transfusion dependence.
Clinically, everything points towards β-thalassaemia major.
But the molecular report states: ‘No β-thalassaemia mutation detected.’

Here is where the diagnostic trap lies.

A negative targeted PCR screen does not mean a normal HBB gene.
The test may simply not have looked for the causative variant.

What could have been missed?

A rare HBB variant absent from the mutation panel.
A large deletion involving the β-globin gene cluster.
A promoter, splice-site or regulatory variant.
Compound heterozygosity with an undetected second variant.
Allele dropout or another technical limitation.
And sometimes, the answer is a different globin disorder producing a similar phenotype.

So what should we do?

First, examine the original molecular report. Was this a targeted mutation panel or full HBB sequence analysis?
Review the pre-transfusion haemoglobin fractions.
Proceed to HBB sequencing and deletion/duplication analysis, including MLPA where appropriate.
If those investigations are unrevealing, reconsider the diagnosis and extend molecular testing.

The teaching point: