Th152 - Whole Genome Sequencing in 25 Families with Suspected Inborn Errors of Immunity: Diagnostic Yield and Clinical Relevance of Genome-wide Analysis

Abstract Text: Introduction
Inborn errors of immunity (IEIs) represent a broad spectrum of 485 disorders caused by more than 500 different responsible genes, most of which are known to be monogenic. Next-generation sequencing-based exome sequencing has facilitated the identification of causative genetic variants in IEIs, achieving diagnostic yields of up to 40%.
Methods
We analyzed data from 25 probands with suspected IEIs based on clinical phenotypes, recruited as part of National Bio-Big Data Program's whole genome sequencing (WGS) project between July 2020 and February 2022 from Samsung medical center. The analysis followed a sequential approach, starting with candidate gene panel analysis to identify both small variants and structural variants, then progressing to a genotype-driven strategy using in-house pipelines. The pathogenicity of the identified variants was evaluated by clinical and laboratory manifestations and presence of family history.
Results
Causative variants were identified in 10 (40%) probands through candidate gene panel analysis including BTK, CYBB, DKC1, DNAH11, DNAH5, IL2RG, NFKB2, PIK3CD and SH2D1A, in two (8%) proband through genotype-driven analysis including NF1 and PTPN11, and in three (12%) probands through structural variant analysis including BTK and LRBA. Overall, the pathogenic or likely pathogenic variants implicated in monogenic IEI were detected in 60%. Four variants of uncertain significance were identified in three probands (12%). The structural variants were confirmed by RNA sequencing or protein expression.
Conclusion
WGS enabled the effective identification of causative genetic variants including complex structural variants. This indicate a potential diagnostic gain by performing WGS from patients with suspected IEIs.