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Novel Synonymous Variant in IL7R Causes Preferential Expression of the Soluble Isoform

journal contribution
submitted on 2024-07-29, 08:23 and posted on 2024-07-29, 11:05 authored by Rafah Mackeh, Yasmin El Bsat, Asha Elmi, Hani Bibawi, Mohammed Yousuf Karim, Amel Hassan, Bernice Lo

Purpose

The interleukin-7 receptor (IL-7R) is primarily expressed on lymphoid cells and plays a crucial role in the development, proliferation, and survival of T cells. Autosomal recessive mutations that disrupt IL-7Rα chain expression give rise to a severe combined immunodeficiency (SCID), which is characterized by lymphopenia and a TB+NK+ phenotype. The objective here was to diagnose two siblings displaying the TB+NK+ SCID phenotype as initial clinical genetic testing did not detect any variants in known SCID genes.

Methods

Whole genome sequencing (WGS) was utilized to identify potential variants causing the SCID phenotype. Splicing prediction tools were employed to assess the deleterious impact of the mutation. Polymerase Chain Reaction (PCR), Sanger sequencing, flow cytometry, and ELISA were then used to validate the pathogenicity of the detected mutation.

Results

We discovered a novel homozygous synonymous mutation in the IL7R gene. Our functional studies indicate that this variant is pathogenic, causing exon 6, which encodes the transmembrane domain, to be preferentially spliced out.

Conclusion

In this study, we identified a novel rare synonymous mutation causing a loss of IL-7Rα expression at the cellular membrane. This case demonstrates the value of reanalyzing genetic data based on the clinical phenotype and highlights the significance of functional studies in determining the pathogenicity of genetic variants.

Other Information

Published in: Journal of Clinical Immunology
License: https://creativecommons.org/licenses/by/4.0
See article on publisher's website: https://dx.doi.org/10.1007/s10875-024-01688-8

Funding

Open Access funding provided by the Qatar National Library.

Qatar National Research Fund (PPM-04–0128-200015), Unlocking precision medicine potential through functional genomic studies in the diagnosis of inherited immunodeficiency diseases.

History

Language

  • English

Publisher

Springer Nature

Publication Year

  • 2024

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Sidra Medicine
  • Clinical Research Centre - Sidra Medicine
  • Qatar University
  • Qatar University Health - QU
  • College of Medicine - QU HEALTH

Methodology

Whole genome sequencing (WGS) was utilized to identify potential variants causing the SCID phenotype. Splicing prediction tools were employed to assess the deleterious impact of the mutation. Polymerase Chain Reaction (PCR), Sanger sequencing, flow cytometry, and ELISA were then used to validate the pathogenicity of the detected mutation.