Dominant Negative Variants in IKZF2 Cause ICHAD Syndrome, a New Disorder Characterized by Immunodysregulation, Craniofacial Anomalies, Hearing Impairment, Athelia, and Developmental Delay

Abstract

Helios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and the development and regulation of the immune system. Although predominantly recognized for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed at varying levels in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans. Here, we investigated two unrelated individuals with immune dysregulation combined with syndromic features including craniofacial dysmorphism, sensorineural hearing loss, and congenital abnormalities resulting from de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZF) of Helios. Proband 1 (p. Gly136_Ser191dup) had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios and Proband 2 (p.Gly153Arg) had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios. Functional studies confirmed that both these variant proteins are expressed, and that they interfere with the ability of the wild-type Helios protein to perform its canonical function—repressing IL2 transcription activity—in a dominant negative manner. Our study is the first to describe dominant-negative IKZF2 variants. These variants cause a novel genetic syndrome characterized by Immunodysregulation, Craniofacial anomalies, Hearing impairment, Athelia, and Developmental delay (ICHAD syndrome).