Molecular classification of blood and bleeding disorder genes

Batoul Baz,Dorota Monies,Tarek Owaidah,Nada Al Tassan,Majed Dasouki,Mohamed Abouelhoda

doi:10.1038/s41525-021-00228-2

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.

Highlights

Clinical molecular laboratories have focused on providing molecular testing for single gene disorders, where the phenotype can be explained by a specific mutation in a single gene[1]
More than 2000 sequence variations have been reported in the CFTR gene, and the majority of these have to be considered in diagnostic testing and reporting[2]
The development of high throughput sequencing techniques and the availability of normal population variants and patient mutation databases helps in translating genetic data into an important sensitive diagnostic tool

Summary

INTRODUCTION

Clinical molecular laboratories have focused on providing molecular testing for single gene disorders, where the phenotype can be explained by a specific mutation in a single gene[1]. Research efforts using NGS has allowed researchers to characterize the molecular basis of different monogenic and multigene disorders[9] It contributed to disease and population-specific single nucleotide variants (SNVs) databases, such as; ClinVar, the Human Genetic Variation Database (HGVD), and HbVar database of human hemoglobin variants and thalassemia mutations[9,10,11,12,13]. Variants identified in the training set and estimate the population allele frequencies This data will impact decision making for designing effective screening and prevention programs, and Previously reported pathogenic variants management plans for patients susceptible to bleeding disorders.

Baz et al 3

DISCUSSION

METHODS

Findings

CODE AVAILABILITY