Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia

Abstract

X—linked agammaglobulinemia (XLA, OMIM #300755) is a primary immunodeficiency disorder caused by pathogenic variations in the BTK gene, characterized by failure of development and maturation of B lymphocytes. The estimated prevalence worldwide is 1 in 190,000 male births. Recently, genome sequencing has been widely used in difficult to diagnose and familial cases. We report a large Indian family suffering from XLA with five affected individuals. We performed complete blood count, immunoglobulin assay, and lymphocyte subset analysis for all patients and analyzed Btk expression for one patient and his mother. Whole exome sequencing (WES) for four patients, and whole genome sequencing (WGS) for two patients have been performed. Carrier screening was done for 17 family members using Multiplex Ligation-dependent Probe Amplification (MLPA) and haplotype ancestry mapping using fineSTRUCTURE was performed. All patients had hypogammaglobulinemia and low CD19+ B cells. One patient who underwent Btk estimation had low expression and his mother showed a mosaic pattern. We could not identify any single nucleotide variants or small insertion/ deletions from the WES dataset that correlates with the clinical feature of the patient. Structural variant analysis through WGS data identifies a novel large deletion of 5,296 bp at loci chrX:100,624,323–100,629,619 encompassing exons 3–5 of the BTK gene. Family screening revealed seven carriers for the deletion. Two patients had a successful HSCT. Haplotype mapping revealed a South Asian ancestry. WGS led to identification of the accurate genetic mutation which could help in early diagnosis leading to improved outcomes, prevention of permanent organ damage and improved quality of life, as well as enabling genetic counselling and prenatal diagnosis in the family.

Gene regulation in inborn errors of immunity: Implications for gene therapy design and efficacy

“…82 It is the most prevalent primary immunodeficiency in males, affecting approximately one in every 100,000 male newborns in the United States 83 with varying statistics worldwide. 84 Furthermore, XLA accounts for 85% of all early B cell defects. 85 It arises from the impaired function of the critical B cell receptor (BCR) protein, Bruton's Tyrosine Kinase (BTK).…”

“…X‐linked agammaglobulinemia (XLA) disorder is characterized by a block in early B cell development, leading to a deficiency of circulating mature B cells and antibodies 82 . It is the most prevalent primary immunodeficiency in males, affecting approximately one in every 100,000 male newborns in the United States 83 with varying statistics worldwide 84 …”

Genetic epidemiology of autoinflammatory disease variants in Indian population from 1029 whole genomes

“…However the whole genome sequencing (WGS) has the ability to identify variants in difficult-to-diagnose cases. Recently, our group has identified ~ 5 Kb deletion in the primary immunodeficiency disorder (PID) patients that could not be identified using whole exome sequencing [ 19 ]. Also, Thaventhiran et al has identified eight SVs by performing the WGS of 1318 patients affected with PID, that could be missed using the WES [ 20 ].…”