Molecular classification of blood and bleeding disorder genes

Abstract

The advances and development of sequencing techniques and data analysis resulted in a pool of informative genetic data, that can be analyzed for informing decision making in designing national screening, prevention programs, and molecular diagnostic tests. The accumulation of molecular data from different populations widen the scope of utilization of this information. Bleeding disorders are a heterogeneous group of clinically overlapping disorders. We analyzed the targeted sequencing data from ~1285 Saudi individuals in 17 blood and bleeding disorders genes, to determine the frequency of mutations and variants. We used a replication set of ~5000 local exomes to validate pathogenicity and determine allele frequencies. We identified a total of 821 variants, of these 98 were listed in HGMD as disease related variants and 140 were novel variants. The majority of variants were present in VWF, followed by F5, F8, and G6PD genes, while FGG, FGB, and HBA1 had the lowest number of variants. Our analysis generated a priority list of genes, mutations and novel variants. This data will have an impact on informing decisions for screening and prevention programs and in management of vulnerable patients admitted to emergency, surgery, or interventions with bleeding side effects.

Phenotypic and Genotypic Signatures of VWF Exon 18 in Eastern Saudi Patients Previously Diagnosed with Type 1 von Willebrand Disease

“…The study could conclude that VWF levels are influenced by blood group and presence of certain gene variants indicating that both routine hematology testing and genetic analysis are important to decide on clinical management and classification of patients. 24–26 The results of the current study as well as other studies identified a few gene variants of VWF exon 18 that could be protective from VWD; therefore, individual’s genotyping is advocate to screen for high-risk group that allows early diagnosis and therapeutic intervention.…”

“…VWF gene was observed with highest number of novel HGMD heterozygous variants among the blood and bleeding disorder genes reported from the Saudi population. 23 , 24 Further analysis of other exons in VWF gene in the study subjects can reveal the molecular basis of VWD.…”

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

“…Molecular defects blood disorders, beta thalassemia, sickle cell disorder, alpha thalassemia and G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency are the most common in the Arab population are extensively listed and reviewed earlier [1,[59][60][61][62][63]. The large-scale (~5000) WES analysis by the SHGP on the 1285 cases with 17 blood and bleeding disorders reveals more novel variants (n=140) than previously reported pathogenic variants (n=98) (Table 1) among the 821 variants [9]. VWF, F8, F5, G6PD, F2, F7, F10, F13B, FGA, and HBA2 genes observed with novel variants.…”

“…VWF , F8 , F5 , G6PD , F2 , F7 , F10 , F13B , FGA , and HBA2 genes were observed with novel variants. The authors prioritized the list of genes and novel variants in their study, which will definitely be a source of genetic data and will aid in the development of molecular variants’ screening and to enhance the efficiency of the preventive programs for the blood and bleeding disorders prevalent in the kingdom [ 9 ]. These molecular data will also have a significant impact on developing molecular diagnostic tools for the clinically overlapping disorders with blood and bleeding disorders and to design treatment strategies.…”

“…The central laboratory of SHGP in 2018, is one of the first national initiatives and the largest genomic project in the Middle East; details can be obtained from the freely available database (https://shgp.kacst.edu.sa/index.en.html) [7]. The SHGP initiative revealed >3000 new nucleotide variants to the literature, that are associated with >1200 rare genetic disorders [7], [8], [9]. Earlier reviews on population structure and prevalent genetic disorders can help to understand the initial studies on Mendelian genes and P r e p r i n t associated traditions in the high consanguineous community of Kingdom of Saudi Arabia and other Arab populations [10][11][12].…”