Systematic Review of Non-Coding Genomic Variants in Globin and Non-Globin Clusters and Their Impact on Phenotypic Severity in Thalassemia and Sickle Cell Disease

<b>Background:</b> Haemoglobinopathies such as beta-thalassemia (β-thal), alpha-thalassemia (α-thal) and sickle cell disease (SCD) are characterised by pathogenic gene variations (mutations) in the globin genes. Patients with haemoglobinopathies have the same disease-causing coding variations with very different disease phenotypes, from requiring blood transfusions to being non-symptomatic. The gap between the expected clinical outcomes based on primary coding mutations (the genotype) and the actual observed symptoms (the phenotype) often remains unexplained. We refer to the contribution of secondary genetic modifiers-specifically, non-coding variants of the genome that alter globin gene expression and pathophysiology-as the "missing heritability" of the clinical presentation [Primary Mutation + Missing Heritability (Non-Coding Variants) = Actual Clinical Phenotype]. <b>Objectives:</b> This systematic review aims to find evidence connecting genetic differences outside of the protein-coding region, as in promoters, enhancers or untranslated regions (UTRs), to the clinical severity (phenotype) of beta-thalassemia, alpha-thalassaemia and SCD. We summarise the molecular basis of phenotypic variation among haemoglobinopathy patients with identical variations to reveal their missing heritability and to enhance our understanding of prognostic strategies. <b>Methods:</b> This systematic review was performed in accordance with the PRISMA 2020 guidelines. We used search terms related to haemoglobinopathies, non-coding variation, SNP, promoters, enhancers and clinical severity to search major databases (PubMed and Google Scholar) as of October 2025. A total of 527 (out of 572) abstracts were fit for initial screening to identify the eligible reports. Due to heterogeneity in study designs and reported outcomes, findings were synthesised descriptively and grouped by variant mechanism (<i>cis</i>-acting and <i>trans</i>-acting). The final analysis included 89 articles that demonstrated a direct association between a non-coding genomic variant and a quantitative measure of clinical severity. <b>Results:</b> Two main groups of non-coding variants (NCVs) that modulate foetal haemoglobin (HbF) induction were identified. The first major group comprises <i>cis</i>-acting variants within globin gene clusters (<i>HBG2</i> promoter <i>XmnI</i> polymorphism, <i>HBB</i> promoter mutations and α-globin enhancer variants), while the second major group comprises <i>trans</i>-acting quantitative trait loci (QTLs) (<i>BCL11A</i> and <i>HBS1L-MYB</i> loci). Non-globin NCVs in the UGT1A1 promoter were also found to influence the severity measures in β-thal and SCD. NCVs primarily alter the binding of transcription factors and the looping dynamics of chromatin, modulating the α/β chain balance ratio and γ-globin repression. The <i>XmnI</i> polymorphism is the most prominent cis-acting modifier associated with β-thal intermedia. The promoter polymorphisms in <i>TNF-α</i> and <i>VCAM1</i> are associated with vascular complications in SCD. <b>Conclusions:</b> NCVs are fundamental when determining the clinical measures of haemoglobinopathies, in addition to coding variants. NCV screening should be integrated for clinical prognosis for the accurate prediction of haemoglobinopathy severity and associated high-risk complications. NCVs may represent promising targets for next-generation gene editing and therapeutic intervention strategies aimed at modifying the severity of β-thal, α-thal and SCD.