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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:

  • A molecular test can be technically correct yet diagnostically incomplete.
  • Before allowing a negative result to exclude a diagnosis, ask one question:

‘What exactly was this test designed to detect?’

That question can change the entire diagnostic pathway.

Have you encountered a patient whose clinical phenotype and molecular findings did not agree?”

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

Find more posts featuring Abdul Mannan on Hemostasis Today.

Abdul Mannan Health Hematology Hemostasis Hemostasis News Hemostasis Today Medicine β-thalassaemia
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