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Inborn errors of immunity (IEI) cause susceptibility to severe infections,  autoimmunity and cancer, leading to poor survival. An early molecular diagnosis is key to developing precision medicine and guiding personalized treatments, determining the need for curative allogeneic hematopoietic stem cell transplantation (HSCT). HSCT carries risk of mortality but, when warranted, delays increase the risk of fatal complications. In Sweden, more than 220 patients undergo genome sequencing for suspected IEI each year. Only 29% obtain a molecular diagnosis. Current bioinformatical analyses largely ignore vast non-coding genome sequences. Based on expertise in bioinformatics and gene regulation, we have developed a unique functional genomic pipeline optimized to uncover pathogenic non-coding IEI variants. Within a national program, we aim to use this innovative pipeline to increase the diagnostic yield of pediatric patients with suspected IEI. Children with early onset severe disease yet lacking a molecular diagnosis by established clinical genome sequencing are eligible. In a prospective Phase I trial, we will target 60 patients that lack a molecular diagnosis after standard clinical genome analyses. We aim to achieve a molecular diagnosis in at least 20% of unexplained paitents. Importantly, our proof-of-principle methodology can be adapted for improved diagnostics of other forms of genetic diseases, increasing the efficacy of genetic investigations.