Case Report: Whole exome sequencing identifies variation c.2308G&gt;A p.E770K in RAG1 associated with B- T- NK+ severe combined immunodeficiency

Geeta Madathil Govindaraj,Revathi Raj,Riyaz Arakkal,Machinari Puthenpurayil Jayakrishnan,Sridhar Sivasubbu,Rowmika Ravi,Rijith Jayarajan,Krishnan Chakkiyar,Shamsudheen Karuthedath Vellarikkal,Vinod Scaria,Rajeevan Kunnaruvath,Ankit Verma

doi:10.12688/f1000research.9473.2

Abstract

Severe combined immunodeficiency is a large clinically heterogeneous group of disorders caused by a defect in the development of humoral or cellular immune responses. At least 13 genes are known to be involved in the pathophysiology of the disease and the mutation spectrum in SCID has been well documented. Mutations of the recombination-activating genes RAG 1 and RAG 2 are associated with a range of clinical presentations including, severe combined immunodeficiency and autoimmunity. Recently, our understanding of the molecular basis of immune dysfunction in RAG deficiency has improved tremendously with newer insights into the ultrastructure of the RAG complex. In this report, we describe the application of whole exome sequencing for arriving at a molecular diagnosis in a child suffering from B- T- NK+ severe combined immunodeficiency. Apart from making the accurate molecular diagnosis, we also add a genetic variation c.2308G>A p.E770K to the compendium of variations associated with the disease.

Highlights

Severe combined immunodeficiency (SCID) encompasses a constellation of clinically and genetically heterogeneous diseases resulting in defects of the humoral and/or cellular immune defense mechanism[1]
We describe the application of whole exome sequencing for the accurate molecular diagnosis of a case of T-B-NK+ SCID
The variation causes an amino acid change p.E770K, which lies on recombination activating gene 1 (RAG1) domain of the protein (Figure 1b)

Summary

Introduction

Severe combined immunodeficiency (SCID) encompasses a constellation of clinically and genetically heterogeneous diseases resulting in defects of the humoral and/or cellular immune defense mechanism[1]. The deficiency of recombination activating gene is associated with T-B-NK+ SCID. Recombination of activating gene enzymes plays a significant role in recombination of V(D)J segments[2]. The mutation in recombination activating gene 1 (RAG1) is associated with absence of V(D)J recombination, which in turn produces immature lymphocytes leading to SCID3. The accurate molecular diagnosis in SCID enables genetic counselling for disease[4]. Arriving at a precise molecular diagnosis has been quite cumbersome, technically challenging and expensive, as over a dozen genes are known to be implicated in the genetic disease, which would require systematic targeted sequencing of each of the gene[5,6]. The advent of generation sequencing, especially whole exome and sometimes whole genome sequencing has significantly enabled the rapid identification of the causative genetic variations in clinical settings[6]

Methods

Results

Conclusion