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Purpose <p>In this eight-year study, children with unclassified inborn errors of immunity (IEI) who have no pathogenic variants in targeted next-generation sequencing (tNGS) were re-evaluated by using singleton whole exome sequencing (sWES) and followed-up at least five years. They were also investigated if they had affected family members or not. In addition, all patients had detailed immunological and clinical work-up.</p> Methods <p>In 2017, 108 children with probable diagnosis of IEI had tNGS and pathogenic variants were detected in 38 (35.1%) patients who were not included into the study. The rest 70 patients were continued to be immunologicaly followed-up (67.0 <i>±</i> 19.7 months) and 15 of them (21.4%) recovered spontaneously. Fifty-five patients were divided into two groups; (i) familial patients (n = 30); (ii) non-familial patients (n = 25). In all of them, sWES analysis was performed.</p> Results <p>There were 19 affected fathers, 9 mothers and 16 siblings whereas consanguinity rate for parents was 8.5%. In sWES analysis, no genetic alterations were detected in 28 (50.9%) patients and 14 cases showed predefined pathogenic variants which are not associated with IEI. Probable IEI causing variants were found in 13 of 55 cases. However, after genotype/phenotype examinations and segregation analysis by sanger sequencing for their parents, we were able to define only three pathogenic variants in three cases, namely two for <i>IKBKB</i> gene and one for <i>PRKDC</i> in familial cases. Fifty-five cases were screened with sWES and only three pathogenic variants were revealed (3/55, 5.45%). When we add this result to tNGS finding (35.1%), all together 40.55% of unclassifed IEI cases could be defined by both of these genetic investigations.</p> Conclusion <p>Even with NGS-based approaches improving IEI diagnoses, detection rates still remain below 50%. Whole genome sequencing in the near future would offer the advantage of much more comprehensive and accurate variant detections.</p>

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Unclassified Inborn Errors of Immunity Patients without any Pathogenic Variant in Targeted Next-Generation Sequencing: Long-Term Follow-up and Whole Exome Sequencing Results

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月31日

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  • Ilke Bas,
  • Ezgi Topyildiz,
  • Emine Ulgen,
  • Pinar Sahin,
  • Gamze Tokgoz Erdis,
  • Asude Durmaz,
  • Neslihan Edeer Karaca,
  • Guzide Aksu,
  • Ayca Aykut,
  • Necil Kutukculer

摘要

Purpose

In this eight-year study, children with unclassified inborn errors of immunity (IEI) who have no pathogenic variants in targeted next-generation sequencing (tNGS) were re-evaluated by using singleton whole exome sequencing (sWES) and followed-up at least five years. They were also investigated if they had affected family members or not. In addition, all patients had detailed immunological and clinical work-up.

Methods

In 2017, 108 children with probable diagnosis of IEI had tNGS and pathogenic variants were detected in 38 (35.1%) patients who were not included into the study. The rest 70 patients were continued to be immunologicaly followed-up (67.0 ± 19.7 months) and 15 of them (21.4%) recovered spontaneously. Fifty-five patients were divided into two groups; (i) familial patients (n = 30); (ii) non-familial patients (n = 25). In all of them, sWES analysis was performed.

Results

There were 19 affected fathers, 9 mothers and 16 siblings whereas consanguinity rate for parents was 8.5%. In sWES analysis, no genetic alterations were detected in 28 (50.9%) patients and 14 cases showed predefined pathogenic variants which are not associated with IEI. Probable IEI causing variants were found in 13 of 55 cases. However, after genotype/phenotype examinations and segregation analysis by sanger sequencing for their parents, we were able to define only three pathogenic variants in three cases, namely two for IKBKB gene and one for PRKDC in familial cases. Fifty-five cases were screened with sWES and only three pathogenic variants were revealed (3/55, 5.45%). When we add this result to tNGS finding (35.1%), all together 40.55% of unclassifed IEI cases could be defined by both of these genetic investigations.

Conclusion

Even with NGS-based approaches improving IEI diagnoses, detection rates still remain below 50%. Whole genome sequencing in the near future would offer the advantage of much more comprehensive and accurate variant detections.