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Current genetic defects in common variable immunodeficiency patients on the geography between Europe and Asia: a single-center experience

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Abstract

Identification of the causes of monogenetic common variable immunodeficiency (CVID) patients has rapidly increased in the last years by means of worldwide availability of appropriate genetic diagnostic methods. However, up to date, very limited numbers of reports demonstrating the role of geography, ethnicity, and consanguinity have been published. Here, we reported the first study of Turkish CVID patients and compared them with the results of three countries from America, Europe, and Asia. A total of 100 children diagnosed as CVID according to the criteria of European Society for Immunodeficiencies were enrolled, and they were genetically analyzed by using targeted next-generation sequencing and whole-exome sequencing. The median age of our patients was 5.8 years (range, 3.0–16.0 years) at clinical diagnosis and 9.0 years (range, 4.8–21.0 years) at the time of genetic diagnosis. The consanguinity rate was 24%. Disease-causing pathogenic variants were defined in 40% of patients in a total of 17 different genes. Sixteen of 40 identified pathogenic variants were novel (40%). We determined 18 surface molecular defects, 10 cytosolic defects, 9 nuclear defects, and 3 others. In our cohort, the most common gene was TACI (15/40 in pathogenic variant identified cases and 15/100 in all cases) followed by the others such as PLCү2, LRBA, TCF3, and STAT1. In contrast to our expectations, our results were more similar to American and European population rather than Asians, although we also have high consanguinity rates and live on the geography between Europe and Asia. Genetic investigation is a great challenge, because of the complexity and heterogeneity of the disease, and each country has to know their own current genetic landscape in CVID for a better and successful management of the patients.

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Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.

Abbreviations

CVID:

Common variable immunodeficiency

ACMG:

American College of Medical Genetics and Genomics

VUS:

Variant of unknown significance

PM2:

Moderate evidence of pathogenicity absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes, or ExAC

PM1:

Moderate evidence of pathogenicity located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation

PP2:

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease

PP3:

Supporting evidence of pathogenicity where multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)

BP4:

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)

TNGS:

Targeted next-generation sequencing

WES:

Whole-exome sequencing

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Acknowledgements

The authors thank the Jeffrey Modell Foundation for their precious support.

Funding

This work was partly supported by the Jeffrey Modell Foundation (JMF).

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Authors and Affiliations

  1. Faculty of Medicine, Department of Pediatric Immunology, Ege University, 35100, Bornova, Izmir, Turkey

    Ayse Aygun, Ezgi Topyıldız, Mehmet Geyik, Neslihan Edeer Karaca, Guzide Aksu & Necil Kutukculer

  2. Faculty of Medicine, Department of Medical Genetics, Ege University, Izmir, Turkey

    Asude Durmaz & Ayca Aykut

Authors
  1. Ayse Aygun
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  2. Ezgi Topyıldız
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  3. Mehmet Geyik
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  6. Guzide Aksu
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  7. Ayca Aykut
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  8. Necil Kutukculer
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Contributions

Ayse Aygun: study conception, design, and write the manuscript. Ezgi Topyıldız: data collection. Necil Kutukculer, Neslihan Edeer Karaca: analysis and interpretation of results, data collection. Mehmet Geyik: material preparation. Asude Durmaz, Guzide Aksu, Ayca Aykut: data collection. Necil Kutukculer: study design, supervised the work, performed the analysis, contributed data, and analysis tools. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Necil Kutukculer.

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Ethics approval

The study was approved by the local ethics committee (Ege University Faculty of Medicine Clinical Ethical Board Approval No: 23-7.IT/33).

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Aygun, A., Topyıldız, E., Geyik, M. et al. Current genetic defects in common variable immunodeficiency patients on the geography between Europe and Asia: a single-center experience. Immunol Res 72, 225–233 (2024). https://doi.org/10.1007/s12026-023-09426-9

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