# Genome and transcriptome sequencing for inborn errors of immunity: a feasible multi-omics diagnostic approach

## TL;DR

Combining genome and transcriptome sequencing helps diagnose rare immune disorders but only improves diagnosis in about 14% of cases.

## Contribution

Demonstrates the complementary value of transcriptome sequencing in clarifying genomic findings for inborn errors of immunity.

## Key findings

- Genetic etiology was identified in 14% of 37 inborn errors of immunity cases.
- Transcriptome sequencing helped clarify a complex structural variant in SH2D1A.
- Three initial CVID/PAD diagnoses were revised using multi-omics data.

## Abstract

Inborn errors of immunity (IEI), a diverse group of rare inborn disorders involving over 500 genes, pose diagnostic challenges despite next-generation sequencing advancements. Accurate molecular diagnosis is crucial for personalized treatment. This study aimed to assess the complementary role of genome and transcriptome sequencing in improving diagnostic yield for inborn errors of immunity. A cohort of 37 suspected IEI cases mainly consisting of predominantly primarily antibody deficiency (PAD) (27/37) underwent genome and transcriptome sequencing. We validated transcriptome sequencing analysis using positive controls and showed limitations of current methods. Among the 37 IEI cases, genetic etiology was identified in 14% (5/37). Genome and transcriptome sequencing prompted diagnostic changes in three initially diagnosed common variable immunodeficiency (CVID)/PAD cases, including showing RAS-associated autoimmune leukoproliferative disorder presenting as a novel CVID mimic disorder. The spectrum of identified pathogenic variants included STAT1, ADA2, SH2D1A, NRAS, and NR2F1. A complex structural variant in SH2D1A was characterized, demonstrating the significance of transcriptome sequencing in clarifying the genomic findings. While genome and transcriptome sequencing provided critical insights and allowed to provide correct diagnosis for at least 14% of the patients, the overall improvement in diagnostic yield over exome sequencing is limited. Transcriptome sequencing proved efficient in variant effect interpretation. Our findings underscore the evolving landscape of primary immunodeficiency genetics, necessitating ongoing exploration for novel genes and atypical phenotypes. The integration of genome and transcriptome sequencing holds promise but requires further refinement to enhance the diagnostic yield.