7/ 📖 Monogenic disorders of immunity: Common variants are not so rare
Cell Genomics (2025)
🔗 www.cell.com/cell-genomic...
#Immunology #HumanGenetics #InbornErrorsOfImmunity #IEI #Genomics #PopulationGenetics #PrecisionMedicine

6/ This argues for stronger dialogue in clinical immunology (and other medical fields) between patient-based and population-based genetics —biology and medicine sit at their intersection.

5/ Practical consequences in the field of clinical immunology at large:
🔹 For clinical genetics: stop using frequency as an exclusion criterion.
🔹 For population genetics: common variants deserve mechanistic and clinical follow-up —in “monogenic” frameworks they can have large effect.

4/ We compile and discuss examples of common variants across 14 immunity genes, illustrating how they can cause or shape monogenic disorders with high or low penetrance.

3/ Pathogenicity should be evaluated through functional impact, penetrance, and context, not MAF thresholds alone.

2/ “Monogenic” ≠ “rare.”
Allele frequency is a population metric — not a proxy for biological or medical impact.

Thank you to all the fantastic collaborators involved in this story. @casanovalab.bsky.social, and all not on bluesky, in particular Marie Materna, Simin Seyedpour, Tom Le Voyer, Nima Parvaneh, Niloufar Yazdanpanah, Jacinta Bustamante, Mohammad Shahrooei and Nima Rezaie

Please consider submitting your work to @jhumimmunity.org, the novel journal of the “Inborn Error of Immunity” community. It is published by the nonprofit @rupress.org

🧩 Conclusion:
The absence of ⍺β T cells is sufficient to cause SCID. γδ T cells and other leukocytes cannot compensate for this loss.

🧬 Our molecular data show:
• New variants = complete loss-of-function → total absence of ⍺β T cells
• Original c.+1G>A variant = partial loss-of-function → low TCR⍺β expression & unconventional ⍺β T cells, explaining longer survival without transplant

In our study, we report 2 patients from unrelated families with novel TCR⍺ variants. Unlike earlier cases, they presented with severe combined immunodeficiency and early, life-threatening infections.

This suggested that lacking ⍺β T cells results “only” in combined immunodeficiency (CID), not severe combined immunodeficiency (SCID)—likely due to compensation by γδ T cells.

Previously, TCR⍺ deficiency was reported in 5 patients from 3 kindreds, all carrying the same variant (c.+1G>A). Despite the absence of conventional ⍺β T cells, these patients survived into childhood without early transplant.
📖 www.jci.org/articles/vie...