Genetic Landscape of Rare Autoinflammatory Disease Variants in Qatar and Middle Eastern Populations Through the Integration of Whole-Genome and Exome Datasets.

Parul Sharma,Abhinav Jain,Vinod Scaria

doi:10.3389/fgene.2021.631340

Abstract

Rare monogenic autoinflammatory diseases are a group of recurrent inflammatory genetic disorders caused due to genetic variants in over 37 genes. While a number of these disorders have been identified and reported in Middle Eastern populations, the carrier frequency of these genetic variants in the Middle Eastern population is not known. The availability of whole-genome and exome datasets of over 1,000 individuals from Qatar persuaded us to explore the genetic epidemiology of rare autoinflammatory genetic variants. We have systematically analyzed genetic variants in genome-scale datasets from Qatar with a compendium of variants associated with autoinflammatory diseases. The variants were systematically reclassified according to the American College of Medical Genetics and Genomics guidelines for interpretation of variant pathogenicity. Our analysis identified seven pathogenic and likely pathogenic variants with significant differences in their allele frequencies compared to the global population. The cumulative carrier frequency of these variants was found to be 2.58%. Furthermore, our analysis revealed that five genes, implicated in rare autoinflammatory diseases, were under natural selection. To the best of our knowledge, this is the first and most comprehensive study on the population-scale analysis and genetic epidemiology of genetic variants that cause rare autoinflammatory disease in Middle Eastern populations.

Highlights

Autoinflammatory disorders are genetically heterogeneous groups of disorders caused due to the presence of disease-causing variants in the genes responsible for regulating the inflammatory response
These variants were further filtered based on the list of 37 genes associated with monogenic autoinflammatory diseases resulting in 270 variants
The Infevers database had 1,254 genetic variants from 29 rare autoinflammatory genes excluding MEFV [Accessed: 15/11/2017]. These Infevers genetic variants were identified in the Qatar dataset that resulted in an overlap of 95 variants

Summary

Introduction

Autoinflammatory disorders are genetically heterogeneous groups of disorders caused due to the presence of disease-causing variants in the genes responsible for regulating the inflammatory response. Monogenic autoinflammatory disorders are a group of Mendelian genetic disorders characterized by recurrent inflammatory episodes due to an abnormal innate immune system. Until recently, these disorders have only been defined by phenotypic traits including. The most common among all monogenic autoinflammatory diseases is Familial Mediterranean Fever (FMF). It is caused by the pathogenic variants in the MEFV gene and is highly prevalent in Middle Eastern countries (The International FMF Consortium, 1997; Salehzadeh, 2015). A recent study from our group has estimated the population-specific frequencies of MEFV variants associated with FMF among 2,000 Mediterranean individuals (Koshy et al, 2018)

Methods

Results

Discussion

Conclusion