Hyper IgE syndrome – not only a STAT3 deficiency

Introduction: Hyper IgE syndrome (HIES) is a group of rare primary immunodeficiency syndromes characterized by high levels of serum IgE, cold abscess, pulmonary infections, and eczema. Those disorders include autosomal dominant STAT3 deficiency, autosomal recessive (AR) DOCK8 deficiency, AR Phosphoglucomutase 3 (PGM3) deficiency and AR Zinc finger 341 (ZNF341) deficiency. AR ZNF341 deficiency was first described in 2018 in 11 patients diagnosed previously with HIES but without a genetic diagnosis. Eight of those patients are from three families who live in the same Muslim village in Israel which has approximately 20,000 residents. All the patients are offspring of consanguineous couples.

The aim of our study was to evaluate the prevalence of ZNF341 mutation in the population of that village.

Methods: 300 DNA samples of females who referred for prenatal carrier genetic testing before pregnancy during 2017-2019 in Meir Medical center were included in the study: 200 samples were from the village, and 100 samples of Muslim females were from other villages.

All samples tested by Sanger sequencing for the ZNF341 mutation (c.904C>T, NM_001282933.1) described as causing HIES.

Results: Heterozygous nonsense mutation in ZNF341 was found in 10 samples (5%) of the study group compared to zero in the control group (p<0.05).

Conclusion: A founder mutation causing HIES was found in one village in Israel. The carrier frequency in this population is 1:20.

The results were presented to the Ministry of Health for decision regarding a possible addition of the test for ZNF341 mutation to the panel of the genetic screening tests of the village population.