Multiomics strategy in clinical immunology aiding unsolved antibody deficiencies

Sammanfattning: Clinical and immunological phenotyping of a cohort of consecutive dysgammaglobulinemic patients with unknown genetic defects underwent genomic (e.g. whole-exome sequencing) and other relative multiomics (e.g. transcriptomics, proteomics, epigenomics and immunomics) investigations after having been subjected to classical targeted sequencing. Exome sequencing analysis was performed on 126 PAD probands (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) and thus expected to carry homozygous mutations with an autosomal recessive pattern of inheritance. This genomic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%), however, 27 of these patients (31.4%) carried autosomal dominant (7%) and X-linked (24.4%) gene defects. Using this advanced method and multiomics confirmatory studies, we described new phenotypes of known genes (Paper I, III), new inheritance pattern of known genes (Paper II) and discovered a new gene in human disorder (Paper IV). Clinical and immunologic phenotypes of the remaining unsolved 40 patients were compared with patients with identified molecular defects. Medical implications of the definite molecular diagnosis were reported in ~50% of the patients, including hematopoietic stem cell transplantation, follow-up visits schedule and tertiary preventive screening tests (such as reducing radiation exposure for radiosensitive patients), targeted medication and prenatal diagnosis. Finally, we propose a clinical/immunologic workup followed by a standard genomic and multiomics analysis for an approach to PAD patients (Paper V). Due to misclassification of the conventional clinical and immunological phenotyping for targeted sequencing, employing next generation sequencing as a preliminary step of molecular diagnosis approach to patients with dysgammaglobulinemia is essential and could help in many facets of management and treatment of the patients and their family members. This study also illustrates the power of exome sequencing in the identification of novel and candidate genes underlying primary antibody deficiency and nesciciate confirmatory multiomics functional assays. The findings of this study demonstrate a new workup and clinical guideline to approach patients with different types of dysgammaglobulinemia and highlight the importance of multiomics approach in the filed of clinical immunology