Inborn errors of immunity with DNA repair disorders: at the interface of immune deficiency, immune dysregulation, and...

DNA repair disorders are characterized by defective DNA damage response and DNA replication pathways due to pathogenic variants in multiple genes involved in DNA repair, such as base excision, nucleotide excision, mismatch, non-homologous end joining repair machineries, as well as the homologous recombination process. They comprise a group of inborn errors of immunity of variable severity from hypogammaglobulinemia to severe combined immunodeficiency, accompanied by immune dysregulation and increased risk of malignant transformation. Clinical conditions present with a spectrum of syndromic features, including dysmorphism, microcephaly, neurodevelopmental delay, short stature, cutaneous lesions, and skeletal malformations. This review is aimed at defining the molecular underpinnings of DNA repair disorders, with special emphasis on clinical aspects and immune deficiency, immune dysregulation, and carcinogenesis. With the ever-increasing progress in immunogenetics and understanding the molecular pathology of DNA instability syndromes, due to the rarity and complexity of phenotype-genotype relationships, the diagnosis in affected patients remains challenging for clinicians. Increased awareness and vigilance in diagnosing and implementing the therapy are therefore required in individuals affected with notorious and multifaceted inborn errors of immunity and DNA repair disorders.