Biallelic ZNFX1 variants are associated with a spectrum of immuno-hematological abnormalities

Salem Alawbathani, Ana Westenberger, Natalia Ordonez-Herrera, Mariam Al-Hilali, Homoud Al Hebby, Fahad Alabbas, Amal M. Alhashem, Ghaleb Elyamany, André Megarbane, Melis Kose, Nadia Alhashmi, Nashat Al Sukaiti, Mohammed Al-Raqad, Samah Al-Tawalbeh, Omar Abu Adas Blanco, Fadiah Alkhattabi, Danielle Sng, Ruslan Al-Ali, Suliman Khan, Hasan TawamieKornelia Tripolszki, Vasiliki Karageorgou, Roberta Trunzo, Fuad Al Mutairi, Bruno Reversade, Peter Bauer, Aida M. Bertoli-Avella

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and (iii) illustrate the utility of large, well-curated, and continually updated genotype–phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings.
Original languageEnglish (US)
Pages (from-to)247-254
Number of pages8
JournalClinical Genetics
Issue number2
StatePublished - Feb 1 2022
Externally publishedYes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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