The prevalence of consanguineous marriage and genetic disorders are high in Saudi Arabia. There were records on the practices of Saudis toward prenatal diagnosis (PND) and termination of pregnancy (TOP), however the sample sizes are small. This study has targeted the Saudi Arabian community and family history of genetic disorders to determine the practices toward PND and TOP. The cross-sectional survey was conducted among Saudis (n = 2761) to determine their practices toward reproductive-decision making. Regression analysis was conducted to identify the association of the limiting factors, relative merits and family history on the outcomes. Total of 2507 participants returned completed questionnaire. The practice towards PND (68%) were more favorable than TOP (33%). PND was found to be a good opportunity for early diagnosis and gives parent’s choice. Education, history with affected baby, prior knowledge and religious belief were significant deciding factors of PND and TOP. Down syndrome (n = 161) and sickle cell anemia (n = 152) were commonly available genetic disorder among participant’s family. Respondents with autistic cases in their family have higher acceptance rate for TOP. Non-consanguineous are more willing to consider TOP than consanguineous. Participants with abnormal fetus, aged of > 36 years, married and educated Saudis were more likely consider TOP. Though, religion is the most influencing factor for not accepting TOP, comparatively willingness to PND and TOP have increased recently. Awareness campaigns about PND and TOP may increase the chances of accepting prenatal genetic diagnosis.

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Genetic disorder prenatal diagnosis and pregnancy termination practices among high consanguinity population, Saudi Arabia.

Objectives To investigate the mutational spectrum in the HBB gene in Arab patients with β-thal. Methods Authors searched five databases (PubMed, Science Direct, Scopus, Web of Science, and Google Scholar) from the time of inception until March 2020. Results The authors search strategy yielded 3,229 citations, of which 48 eligible studies captured. 105 mutations were captured, of these, 99 were shared between Arabs and other ethnic groups, six mutations were unique to Arabs (c.92 + 2 T > G, c.-240 G > A, c.150delC, c.420dupT, deletion of 192 bp spanning exon 1, intron 1, and the first two bases of exon 2 of HBB gene, and deletion of 9.6 kb, including exon 1 and intron 2 of HBB gene). The most common HBB gene mutations among Arabs were c.93-21 G > A, c.118 C > T, c.92 + 1 G > A, c.92 + 6 T > C, c.92 + 5 G > C, c.315 + 1 G > A, and c.27dupG. Consanguinity is high among Arab patients with β-thal. Migration into Arab countries led to allelic heterogeneity among Arab patients with β-thal. Conclusion Our findings present a platform for further genetic epidemiological studies for Arab patients with β-thal.

https://www.tandfonline.com/doi/pdf/10.1080/17474086.2021.1860003

The spectrum of beta-thalassemia mutations in the 22 Arab countries: a systematic review.

Beta-thalassemia is a genetic disorder that is caused by variations in the beta-hemoglobin ( HBB ) gene. Saudi Arabia is among the countries most affected bybeta-thalassemia, and this is particularly problematic in the Eastern regions. This review article is an attempt to compile all the reported mutations to facilitate further national-level studies to prepare a Saudi repository of HBB gene variations. In Saudi Arabians, IVSI-5 (G greater than C) and Cd 39 (C greater than T) are the most prevalent HBB gene variations out of 42 variations. The coinheritance of HBB gene variations with ATRX , HBA1 , HBA2 , HBA12 , AHSP , and KLF1 gene variations were observed to be common in the Saudi population. National surveys on the molecular nature of hemoglobinopathies should be set up through collaborations between research centers from various regions to create a well-documented molecular data bank. This data bank can be used to develop a premarital screening program and lead to the best treatment and prevention strategies for beta-thalassemia. Saudi Med J 2018; Vol. 39 (4): 329-335 doi: 10.15537/smj.2018.4.21360 How to cite this article: Alaithan MA, AbdulAzeez S, Borgio JF. A comprehensive review of the prevalence of beta globin gene variations and the co-inheritance of related gene variants in Saudi Arabians with beta-thalassemia. Saudi Med J . 2018 Apr;39(4):329-335. doi: 10.15537/smj.2018.4.21360.

A comprehensive review of the prevalence of beta globin gene variations and the co-inheritance of related gene variants in Saudi Arabians with beta-thalassemia

There is inconsistency in the exact definition of diagnostic levels of HbA2 for β thalassemia trait. While many laboratories consider HbA2 ≥4.0 % diagnostic, still others consider HbA2 ≥3.3 % or HbA2 ≥3.5 % as the cut-off for establishing β thalassemia carrier diagnosis. This is because, over the years, studies have described β thalassemia carriers showing HbA2 levels that lie above the normal range of HbA2 but below the typical carrier range of β thalassemia. These, “borderline HbA2 levels”, though not detrimental to health, are significant in β thalassemia carrier diagnosis because they can lead to misinterpretation of results. In this review, we have evaluated the prevalence of borderline HbA2 levels and discussed the causes of borderline HbA2 values. We have also compiled an extensive catalogue of β globin gene defects associated with borderline HbA2 levels and have discussed strategies to avoid misdiagnosing borderline HbA2 β thalassemia carriers. Our analysis of studies that have delineated the cause of borderline HbA2 levels in different populations shows that 35.4 % [626/1766] of all individuals with borderline HbA2 levels carry a molecular defect. Among the positive samples, 17 % [299/1766] show β globin gene defects, 7.7 % [137/1766] show α thalassemia defects, 2.7 % [49/1766] show KLF1 gene mutations, 2.3 % [41/1766] show the co-inheritance of β and α thalassemia, 2.0 % [37/1766] show the co-inheritance of β and δ thalassemia and 1.8 % [32/1766] show α globin gene triplication. It appears that a comprehensive molecular work up of the β globin gene is the only definite method to detect borderline HbA2 β thalassemia carriers, especially in populations with a high prevalence of the disease. The presence of associated genetic or acquired determinants may subsequently be assessed to identify the cause of borderline HbA2.

Borderline HbA2 levels: Dilemma in diagnosis of beta-thalassemia carriers

Introduction: Abnormality in HBB results in an inherited recessive blood disorder, which can be caused by variants at the transcriptional or translational level affecting the stability and the production of the HBB chain. The severity of the disease relies on the variant's characteristics. This study aimed to identify the common β-globin HBB variants in the population of the Eastern Province, which has the highest prevalence of blood diseases in Saudi Arabia. 

Material and methods: Direct sequence of β-globin HBB gene, and alpha-globin HBA1 and HBA2 genes was performed on a total of 545 blood samples (transfusion-dependent: 215, 106 men and 109 women; normal healthy subjects: 330, 197 men and 133 women) collected from Saudi Arabian participants in the Eastern region. 

Results: A total of 36 variants in HBB gene were revealed with 11 variants that have been reported for the first time in Saudi Arabia, including 7 novel variants that have been identified for the first time in HBB gene. The novel variants consisted of two exonic (HBB:c.252C>T; HBB:c.281G>T) and five intronic variants (c.316-183_316-168del; c.315+241T>A; c.315+376T>C; c.316-114C>G; c.315+208T>G) at HBB gene. The novel exonic variants and three (c.316-183_316-168del; c.315+241T>A; c.315+376T>C) intronic variants were co-inherited with α deletion. 

Conclusions: This current study updated the HBB gene variations with newly identified variants of HBB gene and co-inheritance with α-globin deletions. The identified β-globin mutations will strengthen the genetic reference that could aid in characterizing mutations that are associated with phenotype of thalassemia in a specific region.

https://www.archivesofmedicalscience.com/pdf-95285-55097?filename=Identification of seven.pdf

Identification of seven novel variants in the β-globin gene in transfusion-dependent and normal patients.

Introduction: Detection of β-thalassemia trait or carriers (β-TT) depends significantly on an increase in Hemoglobin A2 (HbA2) levels, which is found at low levels (<3%) in normal healthy individua...

Nazish Rafique Ahmed

Papers

Hemoglobin A2 (HbA2) has a measure of unreliability in diagnosing β-thalassemia trait (β-TT).

Identification of seven novel variants in the β-globin gene in transfusion-dependent and normal patients.