Publication Date
11-1-2023
Journal
Journal of Medical Genetics
DOI
10.1136/jmg-2022-109127
PMID
37316189
PMCID
PMC11206234
PubMedCentral® Posted Date
11-1-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Developmental Disabilities, Ikaros Transcription Factor, Hearing Loss, Syndrome, Humans, DNA-Binding Proteins, Craniofacial Abnormalities, Breast Diseases, l IKZF2, Helios, bilateral sensorineural hearing loss, immune dysregulation, craniofacial differences, syndrome, exome sequencing, genome sequencing
Abstract
Background:
Helios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. 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 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.
Methods:
We performed detailed phenotypic, genomic, and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss, and congenital abnormalities.
Results:
Genome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZF) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). 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.
Conclusion:
This 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).