Genetic patterns & public health implications of sickle cell anaemia across populations: A systematic review

Manisha Shrivastava; Rashmi Bathri; Naseema Shafqat; Saikat Das; Amit Agrawal

doi:10.25259/IJMR_1288_2025

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Systematic Review

162 (

); 593-613

doi:

10.25259/IJMR_1288_2025

Genetic patterns & public health implications of sickle cell anaemia across populations: A systematic review

Manisha Shrivastava^1,, Rashmi Bathri¹, Naseema Shafqat², Saikat Das³, Amit Agrawal⁴

1Department of Transfusion Medicine, Bhopal Memorial Hospital and Research Centre, Bhopal, Madhya Pradesh, India

2Department of Obstetrics and Gynaecology Nursing, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

3Department of Radiation Oncology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

4Department of Neurosurgery, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

For correspondence: Dr Manisha Shrivastava, Department of Transfusion Medicine, Bhopal Memorial Hospital and Research Centre, Bhopal 462 038, Madhya Pradesh, Indiae-mail: manishasdr@gmail.com

Received: 2025-05-20, Accepted: 2025-09-22, Published: 2025-12-31

Licence

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Abstract

Background & objectives

Sickle cell anaemia (SCA) is a serious inherited blood disorder caused by mutations in the β-globin gene, leading to abnormal haemoglobin (HbS). Understanding the genetic diversity of SCA is important for improving diagnosis, treatment, and public health planning. Our aim was to systematically review and summarise the genetic variations associated with SCA in various populations, and to explore how these differences affect clinical outcomes and inform public health responses.

Methods

A systematic search was conducted across databases, including PubMed, Scopus, Cochrane, and Science Direct, for studies published between 1990 and 2025. A total of 62 studies were included, covering populations with a high prevalence of haemoglobinopathies.

Results

Significant genetic heterogeneity was identified. Common coinherited conditions included α- and β-thalassaemia, particularly in Saudi Arabia, Iran, and Sub-Saharan Africa, influencing haemoglobin levels and disease severity. Specific βS haplotypes (e.g. Benin, Bantu, Senegal) were regionally dominant, with some (e.g. Senegal) linked to higher foetal haemoglobin levels and milder symptoms. Genetic modifiers such as BCL11A and MYH9 variants were also found to affect disease expression. Public health screening programmes in countries like the UAE and India have achieved high coverage, but diagnostic and treatment challenges persist due to ongoing genetic and environmental variation. The Quantitative findings include regional dominance of βS haplotypes: Benin (29%), Bantu (3%), Senegal (1%), with the Senegal haplotype linked to higher foetal haemoglobin (HbF) levels (average 14.6%) and the Arab Indian haplotype (6.7%). Co-inheritance of β-thalassaemia was notably common in Saudi Arabia, Iran, and Sub-Saharan Africa.

Interpretations & conclusions

Tailored, genomically informed public health strategies are needed to address the diverse genetic landscape of SCA. Clinicians should incorporate genetic profiling and culturally appropriate counselling to improve care in affected populations. Variability in study design, sample size, and genetic reporting limited the ability to perform direct comparisons across regions.

Keywords

Genetic screening

hemoglobinopathies

public health implications

sickle cell disease

tribal population

Show Related Articles from PubMed

Sickle cell anaemia (SCA) is an autosomal recessive hereditary blood disorder caused by a single point mutation in the β-globin gene (HBB) on chromosome 11, resulting in the formation of haemoglobin S (HbS) instead of normal haemoglobin, which leads to sickling of red blood cells, causing complications due to vaso-occlusion and increased mortality¹.The disease is predominant in communities of African, Mediterranean, Middle Eastern, and Indian origin².Limited healthcare access leads to exclusion from genomic research^3,4. Many possess distinct genetic ancestries due to their unique migratory histories, potentially giving rise to novel or less-studied haemoglobin variants and genetic heterogeneity^2,5,6. Current screening and public health strategies are typically based on data from well-researched populations, which may not apply to genetically diverse indigenous groups^4,7. Variants such as HbS, HbC, and co-inheritance with thalassaemia, along with genetic modifiers like BCL11A (B-cell lymphoma/leukaemia 11A) and MYH9 (myosin heavy chain 9), contribute to variations in disease severity and outcomes^1,3,8.

This systematic review aims to synthesise existing evidence on the prevalence, genetic variability, diagnostic accuracy of screening techniques, and their relevance for genetic counselling and public health planning and health implications of sickle cell anaemia (SCA) among Indigenous populations worldwide, so as to generate evidence-based insights for reducing the burden of disease. The specific objectives of the review are to (a) assess the prevalence and geographical distribution of SCA-related genetic mutations in Indigenous populations; (b) evaluate genetic variations in the HBB gene and compare these patterns with those observed in non-Indigenous groups; (c) explore the implications of genetic diversity for genetic counselling and targeted public health interventions; and (d) provide recommendations to improve SCA surveillance, early diagnosis, and management strategies tailored to the needs of Indigenous communities.

Materials & Methods

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the protocol was prospectively registered with PROSPERO (registration number: CRD420251028364)⁹.The review, being a secondary analysis of published data, adhered to the ethical standards of the Helsinki Declaration (2013 revision) and complied with the ICMR’s Ethical Guidelines for Biomedical Research on Human Participants (2017) where relevant.

Study design, duration and setting

A systematic review design, guided by the PICO framework with Population (P): individuals with sickle cell anaemia (SCA), Intervention/Exposure (I): genetic screening and molecular analysis, Comparison (C): prevalence across different populations, Outcomes (O): prevalence, genetic diversity, and clinical implications is adopted.

Eligibility criteria

Studies from database inception to March 2025 were included based on the PICOT (population, intervention, comparator, outcome, time) framework. Eligible studies comprised observational studies (e.g., cross-sectional, cohort,) and genetic surveys involving indigenous populations, specifically reporting on the prevalence of sickle cell anaemia (SCA), allele and genotype frequencies of the HBB gene or related haemoglobin variants, as well as public health outcomes such as disease burden, screening uptake, and genetic counselling efficacy, reporting on prevalence, allele/genotype frequencies, or public health outcomes related to SCA.

Studies not published in English, lacking genetic data, case reports, editorials, letters, reviews, or animal studies were excluded. Studies lacking such components were deemed to have insufficient public health relevance for inclusion. A detailed summary of inclusion and exclusion criteria is presented in supplementary Tables I and II. Public health relevance was assessed based on the study’s reporting of one or more of the following indicators: population-level prevalence or burden of SCA; uptake or accessibility of screening programs; availability and effectiveness of genetic counselling services; documented health disparities in SCA-related outcomes; or implications for public health interventions or policies.

Supplementary Table I

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Supplementary Table II

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Information sources and search strategy

A comprehensive search was conducted across the following databases: PubMed, Scopus, ScienceDirect, and Cochrane. Search terms included combinations of relevant keywords and Medical Subject Headings (MeSH) such as “sickle cell anaemia”, “genetic screening”, “HBB mutations”, and “Indigenous populations”. Boolean operators (AND, OR) were used to optimize results. Since inception to analysis “[All Fields])) AND (1000/1/1:2025/3/12[pdat]). Grey literature, government reports, and reference lists of included articles were manually screened for additional eligible studies. The full search strategy is available in supplementary table III.

Supplementary Table III

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Screening and study selection

Search results were imported into EndNote™ reference management software, and duplicates were removed. Two independent reviewers (RB and NS) screened the titles and abstracts. Full texts of potentially eligible articles were assessed against the criteria. Disagreements were resolved through discussion with two senior reviewers (MS and AA), who also contributed to the final selection consensus. List of excluded studies with reasons are provided in supplementary table IV.

Supplementary Table IV

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Data extraction

Data were independently extracted by two reviewers (RB and NS) using a pre-designed standardised form. Extracted variables included: study characteristics: author, publication year, country, population studied, sample size, and study design; Genetic outcomes: allele frequencies (HbS, HbC), genotype distribution (HbSS, HbAS, HbAC), diagnostic techniques; and Public health outcomes: morbidity/mortality rates, access to healthcare, screening initiatives, and policy implications. Cross-checks were performed for accuracy. Authors were contacted for clarification when required. Discrepancies were resolved by consensus with support from a third and fourth reviewer (MS and AA).

Quality assessment and risk of bias

The quality of included studies was evaluated using the Joanna Briggs Institute (JBI) critical appraisal tools, selected according to study design (Supplementary Table V). Tools used included JBI checklists for: cross-sectional studies, cohort studies, case-control studies, studies reporting prevalence data, and genetic association studies. Each study was evaluated against a series of criteria. Appraisals were independently conducted by RB and NS. Disagreements were resolved through consensus or by involving a third reviewer MS. Studies were categorized as: high quality (low risk of bias): if they fulfilled most or all criteria; moderate quality: if they met most criteria but had minor limitations or unclear aspects imitations; Low quality (high risk of bias): if they had significant methodological flaws supplementary table VI.

Supplementary Table V

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Supplementary Table VI

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Data synthesis and statistical analysis

Due to heterogeneity in study designs, populations, and outcomes, meta-analysis was not performed. Instead, a descriptive synthesis of data was undertaken. Prevalence rates, allele frequencies, and genotype distributions were summarized by geographical region, population ancestry, and study setting (e.g., neonatal vs. adult cohorts). Special attention was paid to variations in HBB mutations, β-thalassaemia alleles, and haplotype distributions. These genetic findings were interpreted in light of public health relevance, including disparities in care, screening coverage, and implications for future genetic counselling and policy initiatives.

Results

The study selection process is summarized in figure 1, in accordance with the PRISMA flow diagram. Characteristics of the included studies are summarised in table I^10-71 .Overall, the evidence base was dominated by high-quality cross-sectional designs, while longitudinal and retrospective approaches were less represented, highlighting a reliance on descriptive methodologies within the available literature. The wide array of mutations and regulatory SNPs in sickle cell disease (SCD) directly influence clinical severity, organ complications, and therapeutic response. Understanding these variants—especially compound heterozygosity and HbF-modulating loci—is crucial for accurate diagnosis, prognosis, and personalised care strategies.

Table 1. Characteristics of Included Studies

Study authors (yr)	Country	Type of study	Study population	sample size	Inclusion criteria	Gender	Geographical regions	Genetic markers	Key findings
Chou¹⁰, 2009	Global	(RH Locus Study) Genetic Diversity Analysis	SCD patients & general population	Not specified	Adult	Both male and female	Diverse populations	RHD & RHCE alleles	Over 120 RHD and 60 RHCE alleles identified; crucial for transfusion compatibility in SCD.
Pereira Mdel¹¹, 2009	Spain	Epidemiological prevalence study	Residents across 19 regions	Not specified	Adults	Not specified	African immigrants, autochthonous individuals	Variant haemoglobins (HbS)	SCD prevalence has tripled in 4 years; universal neonatal screening is recommended in high-risk regions.
Dash¹², 2018	India	Genetic association study	HbS-β-thalassemia patients	62	Not specified	Not specified	Not Specified	Globin haplotypes, α-thalassemia	Elevated HbF has a protective role in reducing the frequency of painful episodes in sickle cell disease.
Colah¹³, 2005	India	Neonatal Screening	Cou-ples at risk	85	Adult	Both	Tribal group	Not specified	PND identified 23.5% affected foetuses; all opted for termination, raising ethical dilemmas given the milder disease course in some tribal groups.
Ayatollahi¹⁴, 2005	Not speci-fied	Observational, Molecular Genetics Study	Sus-pec-ted sick-le cell dis-ease pa-tients and nor-mal con-trols	104 (52 normal, 52 pa-tients)	Adult	Both male & female	Not specified	β-globin gene mutation (Codon 6, Glu → Val)	PCR-based assay successfully detected sickle cell disease (Hb SS, n=15) and carriers (Hb AS, n=37). Normal individuals (Hb AA) confirmed. The method is rapid, sensitive, and useful for prenatal diagnosis.
Akhter¹⁵, 2021	Saudi Arabia	Observational, Molecular Genetics	Individuals with sickle cell trait from the premarital from the premarital screening clinic	100	Adult	Both male & female	predominantly Arab	βS haplotypes: Benin (29%), Bantu (3%), Senegal (1%), Atypical haplotypes (31%)	Atypical haplotypes were found in 31% of cases (29% heterozygous, 2% homozygous), suggesting genetic diversity affecting SCD severity in Jazan. Further studies are needed to correlate haplotypes with clinical outcomes.
Dixit¹⁶, 2022	India	Cross-sectional study	Particular Vulnerable Tribal groups (PVTGs)	1461	Adult	Both male and female	Tribal groups in Odisha	Sickle cell, β-thalassaemia, α-thalassaemia, G6PD deficiency	Prevalence: AS (3.4%), SS (0.1%), β-thal heterozygotes (0.3%), HbS/β-thal (0.07%), HbS-α-thal (2.1%), G6PD deficiency (3.2%), malaria (8.1%). Arab-Indian haplotype found in all HbS cases. High frequency of G6PD Orissa (97.9%). 57.4% of G6PD-deficient individuals and 16% of AS were malaria positive.
Jinks¹⁷, 1989	USA	Genetic Screening Study	Newborns are screened for the Sickle Cell Disease	Not specified	Neonates	Not specified	Not specified	β-globin gene mutation (sickle cell mutation)	Developed a rapid and specific genotypic diagnosis method using DNA from dried blood spots, enabling early confirmation of sickle cell disease without requiring a liquid blood sample, improving efficiency and reducing follow-up costs.
Hassan¹⁸, 2014	Oman	Genetic Screening Study	Unrelated Omani cases with suspected hemoglobinopathies	297	Adult	Both	Omani	HBB gene mutations	Ion Torrent PGM sequencing effectively and rapidly identified HBB mutations, proving to be a cost-efficient and scalable alternative to Sanger sequencing for hemoglobinopathy diagnosis.
Abuamer¹⁹, 2017	Bahrain	Observational, Cross-sectional	Adult SCD patients	200	Adult	Both male & female	Predominantly Middle Eastern/Arab	α-thalassemia (α³.⁷, α⁴.², αᵀ-Saudia, αᴴᵖʰᵃ), β-thalassemia (β⁰)	One-third of SCD patients had α- or β-thalassemia. Sickle-thalassemia association increased Hb, Hct, and RBC count but reduced MCV and reticulocytes. Increased pain frequency in α-thalassemia (three-gene group); higher transfusion needs in β-thalassemia and females.
Al Hosani²⁰, 2013	United Arab Emirates	National Neonatal Screening Program	Newborns screened for genetic/metabolic disorders	750365	Neonates	Both male & female	Predominantly Arab	Various genetic markers for 16 disorders	Screening saved 717 babies from morbidity/mortality. Incidence rates: 1:1,873 for congenital hypothyroidism, 1:2,384 for sickle-cell disease, 1:121 for sickle-cell trait. Coverage reached 95% in 2010.
Ben Mustapha²¹, 2012	Tunisia	Molecular Genetics Study	Sickle cell disease individuals and controls	124 β-globin chromosomes (49 βS carriers, 13 normal individuals)	Not specified	Both male and female	Tunisian	β-LCR-HS2 region, SNPs (rs7119428, rs9736333, rs60240093), and microsatellite (AT)XN12(AT)Y	Benin haplotype configuration (AT)8N12GT(AT)7 was strongly associated with βS chromosomes and higher Hb F (14.6%) levels, potentially modulating disease severity. The β-LCR-HS2 could serve as a genetic marker for Tunisian βS chromosomes and aid in molecular diagnosis.
Hariharan²², 2021	India	Genetic Association Study	β-thalassemia homozygotes, Sickle Cell Anaemia patients, Healthy controls	200 patients (100 β-thalassemia, 100 SCA) + 50 controls	Adult	Both	Indian	γ-Globin promoter (-158 C → T, +25 G → A), BCL11A (rs1427407 G → T), HBS1L-MYB (rs66650371, rs9399137 T → C)	Higher HbF levels are linked to milder disease, delayed transfusion need, potential for prognostic markers, and personalized therapy.
Marchetti²³, 2023	Italy	Retrospective cohort study (antenatal and preconception evaluation)	Couples referred for hemoglobinopathy risk evaluation	351 couples	Median: 34 years	Mixed	Highly diverse (from 48+ countries; mainly Italy, Nigeria, Bangladesh, Ivory Coast)	β-thalassemia, HbS, HbC, α-gene triplication	12% couples are at risk of severe hemoglobinopathies; 18% foetal thalassemia diagnoses, 9% SCD; α-triplication was found in 5.8% of tested individuals; the median gestational age was late (18 weeks), limiting reproductive options; this highlights the importance of timely screening and counselling.
Upadhye²⁴, 2016	India	Genetic association study	Sickle cell anaemia patients, central India (Nagpur)	Not specified	Not specified	Not specified	Indian	SNPs in BCL11A & HBS1L-MYB genes influencing HbF and clinical severity	Specific SNPs in BCL11A and HBS1LMYB linked to higher HbF and milder clinical severity in central Indian SCA Patients
Khurana²⁵, 2011	India (Gujarat)	Genetic Diversity and Hemoglobinopathy Study	Individuals from eight tribal groups	431	Not specified	Not specified	Tribes of Gujarat	Haptoglobin (Hp) locus, HbS (sickle cell)	The Hp2 allele was predominant in all tribes, similar to other Indian populations. Genetic differentiation (GST) was moderately high (5.6%). AMOVA showed genetic affinities between Gujarat tribes and Dravidian-speaking groups. High frequency (92.7%) of the Hp 0-0 phenotype among SS individuals suggests a selective advantage of HbAS in haemolytic disorders.
Mahmoud²⁶, 2022	Mauritania	Molecular and epidemiological study	Patients with hemoglobinopathies	40	Adults	Both	Predominantly Heratin and Pular	HbS (HBB:c.20A>T), Cd44 -C, −29A>G, −α-3.7, IVS-II-849A>G, Cd24T>A, Hb Siirt, HbC; HbS haplotypes: Senegal, Benin, Arab-Indian, Bantu, and two atypical ones	nan
Borges²⁷, 2019	Angola (Bengo region)	Prevalence and genetic study	Newborns	Not specified	Newborns	Both male and female	Not specified	Hb S, β-thalassemia (IVS I-110 (G>A), codon 39 (C>T))	High HbS mutation prevalence (68.75%) with the Senegal haplotype most common (66.7%). Findings support targeted prevention strategies, including screening, genetic counselling, and prenatal diagnosis in Mauritania.
el-Hazmi²⁸, 1999	Saudi Arabia	Cohort Study	Sickle cell disease individuals and controls	26 SCD and 19 Controls	Children	Both male and female	Yemeni	Sickle cell, α-thalassaemia,	α-thalassaemia occurs frequently in Yemeni SCD patients.
Svidnicki²⁹, 2017	Brazil	Next-Generation Sequencing (NGS) Study	Patients with hereditary anemia	43	Not specified	Not specified	Not specified	58 genes screened	SPTB, ANK1, SPTA1, SLC4A1, PKLR, CDAN1, G6PD, HFE, KIF23
Colombatti³⁰, 2019	Italy	Newborn Screening Study	Newborns	5466	Newborns	Both male and female	65% Italians, 9% mixed couples, 26% immigrants	β-globin gene mutations (HbS)	High incidence of SCD and carriers detected. 15% of HbS carriers were Caucasian (Italian, Albanian). The feasibility of a multicentric screening program was demonstrated. Supports the need for universal NBS in Italy.
Nouraie³¹, 2010	Multicenter (Region unspecified)	Genetic association study	Children and adolescents with Hb SS	261	Pediatric/adolescent	Male & Female	Predominantly African descent	G6PD202A,376G (G6PD A-) α-thalassemia deletions	Associations of G6PD and sickle cell anemia
Bean³², 2014	United States	Observational, Genetic Confirmation Study	Adults self-reporting SCD and controls	126 (51 self-reported SCD, 75 controls)	40–69 years (median 53)	29% male	Predominantly African American	β-globin gene sequencing	Only 5.9% of those self-reporting SCD actually had it; 62.7% had SCT, 5.9% had haemoglobin C trait, and 25.5% had neither. Those reporting no SCD were 100% accurate. Highlights the need for better public awareness and education about SCD.
Hassan³³, 2003	Iraq	Prevalence and genetic study	Adults	1064	Adult	Both	Iraqi	G6PD with other other hemoglobinopathies	10% risk with beta thal or SCD
Papachatzopoulou³⁴, 2010	Greece (Achaia, Ilia, Etoloakarnania)	Genetic mutation analysis	β-thalassemia (β-thal) & β-thal/sickle cell disease patients	199 total (157 from three SW prefectures)	Adults	Both	Greek population	HBB gene mutations (codon 39 C>T, IVS-I-6 T>C, Hb S β6 Glu→Val)	Distinct distribution of mutations in Achaia and Ilia. Highlights the need for regional genetic screening and prenatal diagnosis
Silvy³⁵, 2011	Comoros, Afro-Caribbean	Genotyping Study	Blood donors	Not specified	Adults	Both	Comorian, Afro-Caribbean	RHCEce, ces, (C)ces Type 1, DIII Type 5 ces, KEL6/*7	58.69% of Comorians and 41.23% of Afro-Caribbeans had RHCEce variant alleles. High prevalence of the ces allele and (C)ces Type 1. Identified new RHCEces(712) variant.
Uda³⁶, 2008	Sardinia	Genome-wide association study (GWAS)	Sardinian individuals with β-thalassemia and sickle cell disease	4,305	Adults	Both	Sardinian	SNP rs11886868 in BCL11A gene	Strong association with elevated HbF level
Trent³⁷, 2000	Australia	Genetic Study	Patients with β-thalassemia major & SCD	Not specified	Not specified	Not specified	Predominantly Mediterranean	HFE (C282Y, H63D, S65C)	Highlighting genetic, screening and diagnostic implications
Shook³⁸, 2021	United States	Cohort Study	Newborns identified through NBS for presumed SCA	44	Newborns (median first clinic visit at 8 weeks)	Not specified	Not specified	HbS, gene-deletion hereditary persistence of foetalhaemoglobin (HbS/HPFH)	12% of newborns presumed to have SCA had a different diagnosis; 7% had HbS/HPFH. Genetic testing ensured correct diagnoses, preventing unnecessary therapy.
Zhou³⁹, 2021	Alberta, Canada	Retrospective analysis of newborn screening (NBS)	Newborns screened for SCD from April 2019 onward	80,314 infants	Newborns (≤10 days for most, ≤21 days for transfused infants)	Not specified	Not specified	Beta-globin gene (HBB)	The study confirmed 34 SCD cases (1:2400 incidence) and 608 carriers (1:130 frequency). A screening algorithm enabled accurate detection, even in transfused infants.
Ashley-Koch⁴⁰, 2011	Not specified (likely U.S./African descent cohort)	Observational, Genetic Association Study	Adult SCD patients screened for proteinuria	521	18–83 years	Both male & female	Predominantly African American	MYH9 and APOL1 SNPs	MYH9 SNPs are more strongly associated with proteinuria than APOL1. A risk haplotype was linked to proteinuria. Glomerular filtration rate negatively correlated with proteinuria. Findings could help early identification of at-risk patients and guide new therapies.
Antoniadi⁴¹, 2002	Not specified (likely European cohort)	Observational, Molecular Genetics	Prenatal diagnosis cases for 8 monogenic disorders	135	Fetal samples	N/A	Predominantly Caucasian	Polymorphic loci: 3k-HVR/APO B, D1S80, THO1, VNTRI of vWf	Polymorphic loci: 3k-HVR/APO B, D1S80, THO1, VNTRI of vWf study
Dadheech⁴², 2016	India	Genetic Association Study	Patients with β-thalassaemia major and sickle cell anemia (SCA)	620 (420 β-thalassaemia major, 200 SCA)	Adult	Both male and female	Not specified	SNP rs11886868 (T/C) in BCL11A gene	Severity of beta Thal with SCD
Azarkeivan⁴³, 2020	Iran	Cross-sectional, Molecular Genetics Study	Patients with Hb S abnormality are referred to a thalassemia clinic	47	Adult	Both male & female	Predominantly Iranian	Hb S (HBB: c.20A>T), Hb S/β-thal, Hb S/Hb D-Punjab (HBB: c.364G>C), α³.⁷ deletion	Hb SS (44.7%), Hb S/β-thal (48.9%), and Hb S/Hb D-Punjab (6.4%) were identified. α-thal mutations are present in some cases. Coinheritance of sickle cell disease with α- and β-thalassemia is common. Pre-marriage screening is crucial for diagnosis and management.
Moorchung⁴⁴, 2013	India	Diagnostic study	Patients with suspected hemoglobinopathies	68	Adult	Both	Not specified	β-globin gene mutations: IVS1/5, IVS1/1, codon 41/42, codon 8/9, del 22, codon 15, -619 bp deletion	HbS IVS1/5 mutation was the most common (38.23%). 100% concordance between HPLC and molecular testing for sickle cell trait. Molecular testing is crucial, especially where compound heterozygosity (e.g., HbS + β-thalassemia) may exist.
Munshi⁴⁵, 2009	India	Diagnostic/molecular epidemiology	Suspected hemoglobinopathy patients	1592	Adult	Both	Indian population	β-globin gene mutations including IVS1-5(G–C), 619 bp deletion	Found 119 β-thalassemia major and 347 β-thalassemia trait cases; also detected sickle cell, HbD, HbE, and HPFH; IVS1-5 and 619 bp deletion were the most common mutations; essential for targeted prenatal diagnosis.
Patra⁴⁶, 2010	Raipur, India	Large-scale population screening	Villagers in high-risk areas	50	Children and Adult	Not specified	Indian	Sickle cell gene	low hematological parameters with significant inverse corelation with HbA2 and HbF
Freire⁴⁷, 2024	Cape Verde	Newborn screening & Hematological study	Newborns & SCA patients	346 (newborns)	Newborns & diagnosed SCA patients	Both male and female	Not specified	HbS, HbF, Beta S-globin haplotypes	Positive impact of high HbF on reducing the severity of SCA
Dezan⁴⁸, 2017	Not specified	Genetic Sequencing Study	Sickle cell disease (SCD) patients with unexplained Rh antibodies	35	Adult	Both male and female	Caucasian	RHD and RHCE genetic variants	NGS identified 10 RHD and 25 RHCE variant alleles. 62% of cases were misclassified by serology, with 73.1% of those posing transfusion risks. NGS improved transfusion compatibility.
Bzdok⁴⁹, 2024	Germany	Genetic Newborn Screening (NBS)	Newborns	1 million+	Newborns	Both male and female	Not specified	SMA, SCID, SCD, β-thalassemia	121 cases of SMA, 15 cases of SCID, and 77 cases of SCD or β-thalassemia were identified. The use of multiplex qPCR for screening was effective, with a detailed discussion on costs, turnaround times, and process optimization. The results provide a clearer picture of the prevalence of these diseases in Germany.
Wonkam⁵⁰, 2011	Cameroon	Cross-sectional descriptive study	Pregnant women undergoing prenatal genetic diagnosis (PND)	60 cases	Females	Female	Not specified	Sickle Cell Disease (HbS) & Chromosomal Anomalies (Trisomy 21, Trisomy 18)	The establishment of PND in Cameroon enabled genetic screening for SCD and chromosomal anomalies, revealing 6 SCD-affected foetuses and multiple trisomy cases. Advocacy and international collaboration were crucial for success.
Sahoo⁵¹, 2014	India (Odisha State)	HBB gene mutation study in a healthy population	Healthy individuals from urban Odisha	267	Adults	Both	Indian population	63 different HBB mutations (11 new ones) identified	Carrier frequency of hemoglobinopathies: 18.48%. Carrier rate for β-thalassemia: 14.13%. Most frequent mutation: HBB:c.9T>C (19.57%). Findings support population screening programs & prenatal diagnosis to reduce disease burden.
Boemer⁵², 2006	Belgium	Neonatal screening feasibility study	Newborns from Belgian maternity units	27010	5 days old	Both male and female	Not specified	Hb S, Hb C	Developed a cost-effective ELISA-based neonatal screening for sickle cell disease. Found 106 Hb S heterozygotes, 3 Hb C heterozygotes, 3 SS homozygotes (0.011%), and 17 false positives (0.063%). The test is cheap (€0.2/test) and feasible for widespread screening, especially in Central Africa.
Noizat-Pirenne⁵³, 2002	France	Molecular/genetic study	SCD patients	17	Adults	Both	Afro-Caribbean Black individuals	RHCE alleles (ceEK, ceBI, ceAR), (C)ces haplotype, ces(748), ceMO	Identified multiple RHCE alleles linked to clinically significant antibodies (anti-RH18, RH34); found partial Rhe variants increasing risk of alloimmunization; emphasized the need for genotyping Black donors to ensure transfusion safety.
Gilman⁵⁴, 1988	United States	Genetic &Hemoglobin Analysis	Sickle cell patient and family members	8	Adult	Both male and female	Not specified	Benin and Mor haplotypes, -202 (C→T) mutation	The Mor haplotype is associated with elevated HbF. The propositus (SCD patient) had 25% HbF and 68.4% HbA. AS relatives with the Mor haplotype had elevated HbF (2.5% ± 0.9%), while those with the Benin haplotype had normal HbF (0.5%). A unique -202 (C→T) mutation in the Aγ gene was identified, potentially contributing to increased HbF expression.
Krause⁵⁵, 2013	South Africa	Retrospective file analysis (1983–2012)	Individuals tested for α-thalassemia, β-thalassemia, and sickle cell anemia	1249	Adults	Both	African, Indian, Mediterranean, Mixed	α-thal: -α³.⁷; β-thal: IVS1 nt5 (G>C), IVS1 nt110 (G>A) HbS	Comprehensive molecular genetics services exist for haemoglobinopathies in SA. Testing reflects ethnic prevalence: α-thal is mostly diagnostic; β-thal is in Indian/Mediterranean; HbS is in Africans. Screening and counsellingare recommended.
Lin⁵⁶, 2015	USA	Genetic association study	SCD patients (adults and newborns)	386	Adults and newborns	Both	Not specified	SAR1A promoter SNPs: -809 C>T, -502 G>T, -385 C>A, rs2310991, rs4282891	SAR1A promoter variants are associated with differences in HbF levels and response to hydroxycarbamide (HC); potential biomarkers for predicting HC response in SCD.
Meindert⁵⁷, 2019	Europe/USA)	Case-control genetic association study	SCD patients	(cases = alloimmunized; controls = non-alloimmunized) 275 (130 controls, 145 cases)	Not specified	Not specified	Presumably of African descent	690 SNPs including TLR1, TANK, MALT1, STAT4, IFNAR1	No SNPs reached significance after multiple testing correction; 19 SNPs were moderately associated with alloimmunization. TLR1/TANK and MALT1 linked to increased risk; STAM/IFNAR1 and STAT4 linked to reduced risk.
Mbeti⁵⁸, 2024	Cameroon	Observational genetic study	SCD patients and blood donors	109 patients, 108 donors (total 217 individuals)	Not specified	Not specified	Sub-Saharan African	RHD and RHCE genes	Identified 24 RHD and 22 RHCE variant alleles; 66.3% of patients were at risk of alloimmunization due to exposure to variant RH antigens; highlights limitations of current serologic typing and calls for molecular-level screening in transfusion protocols.
Guvenc⁵⁹, 2012	Turkey (Adana)	Retrospective Study	Hemoglobinopathy patients	1130	Adult	Both	Greece	IVS-I-110	population screening and prenatal diagnosis significantly benefited by this data
Oner⁶⁰, 1992	Multinational (various countries)	Genetic haplotype study	Sickle cell anemia (SS) patients, SC disease, S-β-thalassemia, HbS heterozygotes	1,152 total (709 SS, 30 SC, 91 S-β-thal, 322 HbS heterozygotes)	Not specified	Not specified	African descent (likely)	βS haplotypes	Beta S gene arose separetly at different locations
Colah⁶¹, 2011	India	Prenatal Diagnosis Study	Pregnant women and affected families	2221 pregnancies	Indian	Both male and female	Indian Beta Thalassemia	Sickle cell Disorders	The study emphasizes the need for more data on non-invasive prenatal diagnosis methods and the importance of micromapping to assess the true burden of these disorders in the country.
Harteveld⁶², 2012	Not specified	Not specified	Not specified	Not specified	Not specified	Both	Not specified	a new nonsickling beta7Glu>Val variant.	Consequences for basic diagnostics, screening, and risk assessment when dealing with HbS-like variants
Kumkhaek⁶³, 2008	Not specified	Not specified	Not specified	Not specified	Not specified	Both	Not specified	sar1A	Fetal haemoglobin response to hydroxycarbamide treatment and sar1a promoter polymorphisms in sickle cell anaemia
Upadhye⁶⁴, 2016	Genetic association study	Sickle cell anaemia patients, central India (Nagpur)	Not specified	Not specified	Not specified	Both	Indian	SNPs in BCL11A & HBS1L-MYB genes	influencing HbF and clinical severity
Tuzmen⁶⁵, 1996	Turkey	Molecular Study Prospective	parents of Turkish descent and their fetuses	70	Adults	Both	Turkish	β-thalassemia, HbS mutations (ASO hybridization, PCR-based techniques)	Nan
Thaker⁶⁶, 2022	India (Gujarat, Madhya Pradesh)	Newborn Screening & Follow-up Study	Newborns with Sickle Cell Disease (SCD)	8,916 screened, 128 diagnosed, 87 followed	0.5–6.6 years	Not specified	Tribal groups	HbSS, HbS-β thalassemia, α-thalassemia, Xmn1 polymorphism	13.8% had severe/moderate SCD, while 86.2% had milder presentations. Hospitalization is required for 23 babies. Genetic counseling improved prenatal diagnosis acceptance. Mobile phones facilitated patient follow-up. Early diagnosis and prophylactic treatment are needed in rural areas.
Mohanty⁶⁷, 2015	India	Multicentric cross-sectional study	Primitive tribal groups across India	15140	All ages	Both	Tribal groups across India	HbS, HbE, β-thalassemia variants	Found HbS allele frequency 1.1–12.0% and β-thal trait 0.5–2.4%; higher HbS in Dravidian and Indo-European tribes; tribal SCD linked to Arab Indian haplotype, with modifiers like HbF & α-thal reducing severity.
Keser⁶⁸, 2004	Turkey (Antalya)	Genetic Screening Study	Mediterranean populations	377 postnatal and 82 prenatal cases	Not specified	Not specified	Mediterranean population	Hb variants	One new Hb variant, Hb Antalya, and one new mutation, Cod 3 (+T), were found. HbS accounted for 10.3% of all mutations.
Hockham⁶⁹, 2018	India	Spatial epidemiology	Individuals screened across India	138486	All ages	Both	scheduled population	HbS prevalence	This study mapped the geographic distribution of the sickle-cell β^S allele across India
Haj Khelil⁷⁰, 2004	Tunesia	Not specified	Not specified	Not specified	Adult	Both	Tunisian	Clinical and molecular aspects of haemoglobinopathies in Tunisia	Complement the existing knowledge
Gupta⁷¹, 1991	India	Cross-sectional genetic survey	Gond tribal groups	1228	All ages	Both	Tribal group	HbS, α- and β-thalassemia variants	Illustrated the co-inheritance of alpha/beta-thalassaemia with β chain variants among tribal groups in Central India, impacting disease phenotype.

Study designs and methodological profile of 62 included studies comprised a wide spectrum of research designs reflecting the multidisciplinary and evolving nature of genetic research in hemoglobinopathies. The majority of the studies (n=26; 41.9%) were observational cross-sectional studies, aimed at assessing the prevalence, distribution, or associations of specific haemoglobin variants and mutations within various populations. Molecular genetics studies (n=16; 25.80%) formed a significant portion of the reviewed literature, using techniques such as DNA sequencing, PCR-based assays, and mutation analysis to identify and characterise genetic markers linked to haemoglobinopathies. Neonatal screening and newborn screening studies (n=7; 10.4%) were also prominent, emphasizing the importance of early diagnosis and genetic counselling in preventing severe disease outcomes, done by HPLC. These studies employed a mix of biochemical and molecular methods to screen newborns for sickle cell disease and thalassemia traits. Additionally, genetic association studies (n=5; 8.06%) were used to explore the correlations between specific gene variants and disease phenotypes or severity. Other studies included prenatal diagnosis studies (n=3; 4.83%) that focused on early detection and management options for at-risk pregnancies.

A small number of studies (n=5; 8.06%) utilized feasibility or programme evaluation frameworks, especially in the context of implementing screening programmes in different populations.

Study participants/Study size and design

The included studies encompassed a diverse range of participants totalling millions of individuals across different life stages, geographic regions, and ethnic backgrounds, with the overarching focus on sickle cell disease (SCD), its variants, and related haemoglobinopathies. Sample sizes varied significantly, ranging from single case reports to population-level newborn screening initiatives involving over one million infants.

The studies included neonates, children, adolescents, adults, and prenatal (fetal) cases, with both sexes represented in nearly all cohorts. Ethnic and racial representation was broad: participants were predominantly of Middle Eastern, African, Indian, Mediterranean, and mixed ancestries, with notable subgroups such as Afro-Caribbean, tribal groups in India, and Sardinians.

While many studies centred on adult SCD patients or individuals undergoing genetic screening, others investigated sickle cell trait carriers, suspected haemoglobinopathy cases, or healthy controls for comparative analysis. The diversity of multiple study designs.

Regional representation in haemoglobinopathies

The 62 genetic studies included in this review originated from diverse locations, covering high-prevalence regions such as South Asia, the Middle East, and Sub-Saharan Africa, as well as populations of African descent in the Americas and Europe. India was the most frequently represented country, contributing studies from Gujarat, Madhya Pradesh, Odisha, and Chhattisgarh (Raipur)^10,11,12,13.

Other South Asian countries included Iran¹⁴, Saudi Arabia^15,16,Oman¹⁷, Iraq¹⁸, Bahrain^19, and the United Arab Emirates²⁰ highlighting the high burden of inherited haemoglobin disorders in this region.

African representation included studies from Tunisia^21,22, Cameroon^23,24, South Africa²⁵, Mauritania²⁶, Angola²⁷, Cape Verde, and Comoros²⁹_, reflecting the continent’s genetic diversity in haemoglobinopathies. European countries such as Italy³⁰ France³¹ Belgium³², Germany²⁸, Netherlands³³, Greece³⁴ and Turkey^35,36,37 contributed several studies, often focusing on native populations or migrant communities. Studies from the United States^35,36,37 and Brazil^38,39 addressed haemoglobinopathies among African-American and Afro-Brazilian populations, respectively. Additional studies were from Australia⁴⁰ Canada (Alberta)^37,41, and Sardinia⁴² Multinational or global studies were also included, with either unspecified or combined participant origins^30,43-45. Some studies did not clearly mention participant origin but were inferred to involve European or African descent cohorts^{30,43-44,46-47}.

The heat map showing the distribution of sickle cell haplotypes in different geographical areas (country-wise) is presented in figure 2.

Haplotype distribution by country 1=Present, 0=Absent.

Participant characteristics, sample size, and heterogeneity

The reviewed studies demonstrate considerable heterogeneity in participant demographics, reflecting the diverse global burden of haemoglobinopathies. Sample sizes vary substantially, from single-patient case studies^9,27 to nationwide screening programmes involving hundreds of thousands of neonates^8,55,67. Participants’ ages ranged from newborns and foetuses to adults and elderly individuals, with many studies targeting adult sickle cell disease (SCD) or thalassemia patients^48,19,40. Sex distribution was generally balanced, although a few studies focused exclusively on females^49,50.

Ethnic backgrounds were diverse, including Middle Eastern^6-8,22,29. South Asia^{17,19,21,22,39,40,45,47,51,52}. African and Afro-Caribbean populations^{25,33,41,48,49,53}. And European and Mediterranean cohorts^{4,10,18,21,25,29,38,46-48,54-58}. Some studies specifically investigated tribal or indigenous groups^21,32,51 enhancing the ethnic diversity across research efforts.

Genetic variants and molecular markers

A wide range of genetic markers were employed across the studies to investigate the molecular basis of sickle cell disease (SCD). Commonly analysed mutations included the HbS variant (HBB: c.20A>T), HbC, HbD-Punjab^14,27,30,58, and β-thalassemia mutations such as IVS-I-110 (G>A), codon 39 (C>T), and various deletions, including 619 bp and 7.7 kb deletions^{27, 51,53,59}. Deletions associated with α-thalassemia included -α³.⁷, -α⁴.², and rare variants like αᴴᵖʰᵃ and αᵀ-Saudia^19,55. Haplotype analysis of the β-globin gene cluster identified regional haplotypes like Benin, Senegal, Bantu, Arab Indian, and several atypical types^26,58,60,61. Promoter region SNPs within BCL11A (e.g., rs11886868, rs1427407), γ-globin promoter variants (-158 C→T, +25 G→A), and HBS1L-MYB region markers (rs66650371, rs9399137) were examined due to their impact on foetal haemoglobin (HbF) levels and disease phenotype modulation^22,37,47 while others targeted multiple point mutations using ASO hybridization or PCR-based methods⁵².

Additional markers of clinical relevance included MYH9 and APOL1 polymorphisms associated with kidney complications in SCD⁵³ and G6PD mutations (202A, 376G) co-occurring with α-thalassemia^41.. Other explored markers included SAR1A promoter variants⁵⁶, TLR1, STAT4, and MALT1 SNPs⁵⁷ and several studies also reported compound heterozygosity (e.g., HbS/β-thalassemia, HbS/HPFH) and gene deletion^50,58 and rare haemoglobin variants such as HbE, HbD Los Angeles, and Hb Siirt^24,26,52.

Haemoglobin C (Hb C) results from a β-globin gene mutation (β6 Glu→Lys) and is rare in the Middle East, usually occurring due to African admixture. While homozygous HbCC causes mild haemolytic anaemia, the HbSC combination with Hb S produces a milder but clinically significant sickle cell phenotype. Haemoglobin S-O (Arab) arises from the co-inheritance of Hb S (β6 Glu→Val) and Hb O-Arab (β121 Glu→Lys), and is more prevalent in parts of Saudi Arabia, Sudan, Egypt, and Jordan. Although Hb O-Arab alone causes minimal symptoms, its combination with Hb S leads to severe sickle cell disease, with anaemia, vaso-occlusive crises, and organ complications similar to HbSS. Both variants highlight the genetic diversity of sickle syndromes in the Middle East and the importance of premarital screening programmes^62,63.

Discussion

This systematic review had 62 studies, mainly observational cross-sectional studies with a wide range of sample sizes, which included various diagnostic and screening tools and molecular methods, revealing that the genetic epidemiology of SCA could demonstrate the distribution of sickle cell haplotypes in various demographic and ethnic regions. This wide geographic representation underscores the importance of ethnically and regionally diverse genetic studies in understanding the complex inheritance patterns and variant distributions associated with haemoglobinopathies.

The availability of molecular diagnostic tools has further enhanced the ability to accurately identify SCA in diverse populations. Studies such as those by Hassan et al¹⁸ and Svinicki et al²⁹ underscore the role of next-generation sequencing (NGS) in identifying genetic mutations associated with haemoglobinopathies, including novel mutations that may influence disease severity. By integrating advanced genetic diagnostics with public health strategies, such as genetic counselling and prenatal screening, healthcare providers can offer more precise management plans, reducing the incidence of severe complications in affected individuals.

In regions with limited access to healthcare, the introduction of neonatal screening (NBS) programs can significantly improve early diagnosis and intervention outcomes. Columbatti et al³⁰ demonstrated the feasibility of implementing NBS programs in Italy, underscoring the importance of early detection in reducing disease-related morbidity and mortality. Pereira et al¹¹ found that the prevalence of SCD tripled in a four-year period, highlighting the need for widespread screening programmes, particularly in high-risk populations⁴⁹.

High-throughput genetic screening techniques and novel detection methods, including the use of dried blood spot DNA for early neonatal SCD diagnosis⁶⁵ were shown to improve diagnostic efficiency. One study characterized distinct HBB mutations, including 11 novel ones underscoring the mutational heterogeneity of β-globinopathies⁴⁹. In addition, large-scale analyses targeting up to 58 red cell–related genes (e.g., SPTB, ANK1, PKLR, CDAN1, HFE) reflected the complex genetic basis of hereditary anaemia syndromes overlapping with haemoglobinopathies. A recent study on neonatal screening by Thaker et al^{6 6}demonstrated the feasibility of early diagnosis and highlighted the importance of mobile-based follow up and genetic counselling in remote tribal communities

Despite the significant contributions of the studies reviewed, there are limitations to be considered, like the exclusion of non-English studies, the inclusion of observational studies in nature, which inherently limit the ability to infer causality, and relatively small sample sizes in some studies. As highlighted by Bean et al³⁸, biases in study design, such as non-randomized sampling or selection bias, are common in observational studies and can impact the accuracy of conclusions drawn about the genetic factors associated with SCA. Another limitation is the small sample size in some studies. This can lead to imprecise estimates of the prevalence of genetic mutations or disease severity. Azarkeivan⁵⁸ noted that certain studies failed to account for population heterogeneity, which may result in skewed estimates of disease burden and genetic diversity in the population. Moreover, Harteveld³⁵ raised concerns about the underreporting of certain genetic variants in SCA patients, particularly in underrepresented populations. This underreporting is likely due to a lack of comprehensive genetic screening in many low-resource settings, where the availability of genetic testing is limited. The need for more inclusive genetic databases and the standardization of diagnostic methods are critical to overcoming these gaps in knowledge. However, the strength of this review is the inclusion of observational studies examining various populations, revealing crucial insights into the genetic epidemiology of SCA, its public health burden, and the implications for genetic screening, counselling, and intervention strategies.

Given the high global burden of sickle cell anaemia, public health initiatives should prioritize improving access to diagnostic tools and expanding genetic counselling services, particularly in regions where SCA is prevalent. The development of national and regional screening programmes, such as those recommended by Chou¹⁰ and Borges²⁷, could greatly enhance early diagnosis and intervention for individuals at risk. As noted by Thaker et al⁶⁴, genetic counselling plays a crucial role in improving acceptance of prenatal diagnosis and guiding families in making informed decisions about reproductive choices that reduce the incidence of SCA in future generations. Collaboration between researchers from diverse geographic regions and ethnic backgrounds is essential for developing more comprehensive and representative data on the genetic epidemiology of sickle cell anaemia.

This review highlights the wide genetic variability in sickle cell disease and thalassaemia across global populations. Although these conditions share common molecular origins, their prevalence, clinical outcomes, and public health impact vary significantly by region and ethnicity. Recognising these differences is key to enhancing early detection, designing population-specific screening programmes, and implementing effective treatment approaches. These efforts support national and global goals, including the management of SCA and the promotion of equitable access to genetic healthcare for all communities. Finally, future research should focus on addressing the limitations of existing studies by conducting large-scale, multi-centre, randomized controlled trials to better understand the genetic mechanisms underlying SCA.

Financial support & sponsorship

None.

Conflicts of Interest

None.

Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation

The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript, and no images were manipulated using AI.

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[Google Scholar]
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[PubMed] [PubMed Central] [Google Scholar]
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[CrossRef] [PubMed] [Google Scholar]
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[CrossRef] [PubMed] [Google Scholar]
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[CrossRef] [PubMed] [Google Scholar]

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[CrossRef] [PubMed] [Google Scholar]

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[CrossRef] [PubMed] [Google Scholar]

[66] Thaker P, Colah RB, Patel J, Raicha B, Mistry A, Mehta V, et al. Newborn screening for sickle cell disease among tribal populations in the states of Gujarat and Madhya Pradesh in India: Evaluation and outcome over 6 years. Front Med (Lausanne). 2022;8:731884.
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[CrossRef] [PubMed] [Google Scholar]

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[CrossRef] [PubMed] [Google Scholar]

[69] Hockham C, Bhatt S, Colah R, Mukherjee MB, Penman BS, Gupta S, et al. The spatial epidemiology of sickle-cell anaemia in India. Sci Rep. 2018;8:17685.
[CrossRef] [PubMed] [PubMed Central] [Google Scholar]

[70] Haj Khelil A, Laradi S, Miled A, Omar Tadmouri G, Ben Chibani J, Perrin P. Clinical and molecular aspects of haemoglobinopathies in Tunisia. Clin Chim Acta. 2004;340:127-37.
[CrossRef] [PubMed] [Google Scholar]

[71] Gupta RB, Tiwary RS, Pande PL, Kutlar F, Oner C, Oner R, et al. Hemoglobinopathies among the Gond tribal groups of central India: Interaction of alpha- and beta-thalassemia with beta chain variants. Hemoglobin. 1991;15:441-58.
[CrossRef] [PubMed] [Google Scholar]

Genetic patterns & public health implications of sickle cell anaemia across populations: A systematic review

Abstract

Background & objectives

Methods

Results

Interpretations & conclusions

Keywords

Genetic screening

hemoglobinopathies

public health implications

sickle cell disease

tribal population

Materials & Methods

Study design, duration and setting

Eligibility criteria

Information sources and search strategy

Screening and study selection

Data extraction

Quality assessment and risk of bias

Data synthesis and statistical analysis

Results

Study participants/Study size and design

Regional representation in haemoglobinopathies

Participant characteristics, sample size, and heterogeneity

Genetic variants and molecular markers

Discussion

Financial support & sponsorship

Conflicts of Interest

Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation

References

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