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<p>Primary immunodeficiency diseases (PIDs) are monogenic inborn immune disorders. Of currently listed 555 genetic inborn errors of immunity (IEI) in 10 IUIS categories, PIDs range from life-threatening severe combined immunodeficiency (SCID) to milder antibody deficiencies. PIDs increase mortality risk and demand genetic/immunological testing. In Iran, high consanguinity rates may warrant influence of genetic factors. Diagnostic challenges due to heterogeneity necessitate application of advanced tools like whole exome sequencing (WES). This study was carried out on Eastern Iran’s PIDs and similar approaches should be employed worldwide in populations that are highly consanguineous. This study focused on 99 patients from Eastern Iran clinically diagnosed with PIDs who were referred for genetic evaluations between 2016 and 2025. Genetic analyses involved DNA extraction from blood samples, WES using Illumina platforms, and in-house bioinformatic pipelines for variant identification and classification. Sanger sequencing and co-segregation studies further validated findings. Medical records, family histories, and pedigrees were thoroughly analyzed. Also we have delineated syndromic and non-syndromic PID disorders. The significant findings were as follows: Finding of 47 novel disease-causing variants; High consanguinity rates (76%) correlated with an 82.8% diagnostic yield and a mortality rate of 8% amongst patients. SCID-associated mutations, as the most common discovered PIDs, found in 16 cases; other common disorders were AR <i>LRBA</i> LOF, AR <i>ATM</i> LOF, and AR <i>EPG5</i> (possibly hypomorphic LOF). Additionally, certain mutations may link to pregnancy loss which may need further functional studies. Around 70% of unresolved cases were syndromic. The most frequently suspected pathogenic variants (n = 5), all novel and in homozygosity with matching phenotype, were noted in <i>EPG5</i> and linked to Vici syndrome. In highly consanguineous populations, WES may reach a definite or highly probable genetic diagnosis in over 80% of cases, and that some IEIs may be associated with pregnancy loss.</p>

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Genetic and epidemiological patterns of primary immunodeficiency diseases in Eastern Iranian patients

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月2日

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  • Mohammad Salehi,
  • Hamid Ahanchian,
  • Ehsan Ghayoor Karimiani,
  • Mohammad Hassan Aelami,
  • Nasrin Moazzen,
  • Zeinab Neshati,
  • Alireza Pasdar

摘要

Primary immunodeficiency diseases (PIDs) are monogenic inborn immune disorders. Of currently listed 555 genetic inborn errors of immunity (IEI) in 10 IUIS categories, PIDs range from life-threatening severe combined immunodeficiency (SCID) to milder antibody deficiencies. PIDs increase mortality risk and demand genetic/immunological testing. In Iran, high consanguinity rates may warrant influence of genetic factors. Diagnostic challenges due to heterogeneity necessitate application of advanced tools like whole exome sequencing (WES). This study was carried out on Eastern Iran’s PIDs and similar approaches should be employed worldwide in populations that are highly consanguineous. This study focused on 99 patients from Eastern Iran clinically diagnosed with PIDs who were referred for genetic evaluations between 2016 and 2025. Genetic analyses involved DNA extraction from blood samples, WES using Illumina platforms, and in-house bioinformatic pipelines for variant identification and classification. Sanger sequencing and co-segregation studies further validated findings. Medical records, family histories, and pedigrees were thoroughly analyzed. Also we have delineated syndromic and non-syndromic PID disorders. The significant findings were as follows: Finding of 47 novel disease-causing variants; High consanguinity rates (76%) correlated with an 82.8% diagnostic yield and a mortality rate of 8% amongst patients. SCID-associated mutations, as the most common discovered PIDs, found in 16 cases; other common disorders were AR LRBA LOF, AR ATM LOF, and AR EPG5 (possibly hypomorphic LOF). Additionally, certain mutations may link to pregnancy loss which may need further functional studies. Around 70% of unresolved cases were syndromic. The most frequently suspected pathogenic variants (n = 5), all novel and in homozygosity with matching phenotype, were noted in EPG5 and linked to Vici syndrome. In highly consanguineous populations, WES may reach a definite or highly probable genetic diagnosis in over 80% of cases, and that some IEIs may be associated with pregnancy loss.