Sickle cell disease

SCD is inherited in an autosomal recessive manner. When both parents are heterozygous carriers, each child has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither variant. Carrier testing of at-risk relatives and reproductive partners is informative once the familial variants are known. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Diagnosis usually starts with a haemoglobin assay (electrophoresis or HPLC) that detects HbS, with or without a second abnormal beta-globin variant. HbS as the only adult beta chain indicates Hb S/S or Hb S/β⁰-thalassaemia, which are then distinguished by molecular genetic testing. Alternatively, the diagnosis is confirmed by identifying biallelic HBB pathogenic variants, including at least one sickle allele.

Main differential diagnoses include:

• Other haemolytic anaemias: distinguished by the absence of HbS on the haemoglobin assay; causes include red-cell enzymopathies and membrane defects; multiple genes (e.g., G6PD, PKLR, SPTB, ANK1).
• Anaemia of other aetiology: distinguished by the absence of HbS; includes iron-deficiency, anaemia of chronic disease, and marrow-failure anaemias; multifactorial or non-syndromic basis.
• Osteomyelitis: mimics a vaso-occlusive bone crisis (and may also complicate SCD); distinguished by microbiological and imaging evidence of bone infection; non-genetic (infectious).

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variants, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive and carrier testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

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• GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Haematology. 2023;10(8):e585-e599. doi: 10.1016/S2352-3026(23)00118-7. PMID: .