Whole Exome Sequencing Approach to diagnose Primary Immunodeficiency Disorders

Reference: Okano, T., Imai, K., Naruto, T. et al. Whole-Exome Sequencing-Based Approach for Germline Mutations in Patients with Inborn Errors of Immunity. J Clin Immunol (2020).

Journal: Journal of Clinical Immunology

Summary: 1. WES was done for 136 PID from PID database in Japan with negative targeted genetic screening due to atypical clinical features or intractable symptoms

                   2. A two step filtering was used, for genetic filtering was done for exonic and splice-site mutations using minor allele frequency and pathogenicity was predicted using in silico tools like CADD, Polyphen2 and SIFT 

                   3. Clinical filtering was done based on ACMG classification and IUIS phenotypic classification of  Inborn errors of immunity(IEI) and prioritized based on familial segregation, tissue distribution, animal models and compatible phenotype by clinical geneticists, clinical immunologists and bioinformaticians

                  4. The diagnostic rate was around only around 26.5% with most mutations in known IEI genes which may be due to either severe transient infections only during infancy, technical limitations because of pseudo genes (IKBKG) and non-exonic mutations (BTK) and ability to detect somatic mutations (FAS,RAS)

                  5. The genetic diagnosis  positively impacted the clinical care by early HSCT and initiation of targeted therapies  and helped in understanding the pathophysiology of disease

Bottom line: Considering cost effectiveness targeted IEI genes should be screened followed by WES if required get a genetic diagnosis especially in young patients with prolonged duration of symptoms had high frequency of pathogenic mutations