Clinical implications of rare mutations in Northern Iraqi pediatric immunodeficiency cases: retrospective observational study

Abstract Background Primary immunodeficiencies (PIDs) are a heterogeneous group of rare disorders that compromise immune function, leading to recurrent infections, autoimmunity, and malignancy. Due to their broad clinical spectrum, timely molecular diagnosis is essential to guide clinical management. We hypothesized that whole-exome sequencing (WES) would provide a high diagnostic yield in a cohort of suspected pediatric PID cases from Northern Iraq, a population characterized by high rates of consanguinity. This study evaluates the role of WES in identifying rare and novel mutations and assesses its clinical utility in this specific population. Results A molecular diagnosis (Pathogenic or Likely Pathogenic variants) was achieved in 66.7% (10/15) of the patients. A total of 14 clinically relevant variants were identified, including 5 novel and 9 rare variants. These variants were distributed across key genes including IL12RB1, CYBB, DCLRE1C, MSN, MRTFA, IL6ST, MALT1, and LRBA. The high diagnostic yield was largely driven by the identification of homozygous variants in consanguineous families. In several cases, the genetic findings corrected initial clinical misdiagnoses (e.g., cystic fibrosis), directly influencing treatment strategies such as targeted antimicrobial prophylaxis and referrals for hematopoietic stem cell transplantation. Conclusion Exome sequencing proved highly effective in uncovering the genetic basis of pediatric PIDs in Northern Iraq, demonstrating a diagnostic yield of 66.7%. The identification of these variants enhances genetic counseling, informs family risk assessment, and supports precision management. These findings advocate for the integration of WES early in the diagnostic workup of PIDs to improve clinical outcomes and highlight the need for a national immunodeficiency registry in the region.