Hidden splice variants in inborn errors of immunity: Uncovering diagnoses and therapeutic targets

Advancements in high-throughput DNA sequencing have drastically accelerated the discovery of novel genetic disorders, transforming the field of clinical immunology. Over 500 monogenic inborn errors of immunity (IEIs) have been identified thus far, yet 60% to 90% of patients who present clinically with an IEI lack a genetic diagnosis. Recent genome sequencing data in large patient cohorts indicate that deep intronic and synonymous splice variants contribute significantly to undiagnosed cases. While genome sequencing detects most variants missed by exome sequencing and targeted gene panels, bioinformatic pipelines for noncoding and synonymous splice variant analysis remain underdeveloped, limiting its diagnostic yield. This review examines the landscape of splice variants hiding outside intron-exon junctions in patients with IEIs and provides a practical diagnostic approach for the clinical immunologist. We explore how advances in genome sequencing, artificial intelligence, and RNA sequencing are improving the detection of disease-causing splice variants and discuss the potential of splice-modulating antisense oligonucleotides as personalized treatments for IEIs. While integrating advanced sequencing technologies, bioinformatics, and targeted therapies into clinical practice remains challenging, these efforts represent critical steps toward precision and personalized medicine for patients with IEIs and other rare genetic diseases.