ZARD is caused by harmful changes of the X chromosome linked ZC4H2 gene. Males and females can be affected. ZC4H2 gene variants can be inherited or occur spontaneously, meaning there is no family history of the disorder (de novo). 1
Males have one X chromosome and one Y chromosome. If a male has a pathogenic ZC4H2 gene variant (inherited from his mother or de novo), he will develop the disease.
In very rare cases, healthy males may have somatic/germline mosaicism for a pathogenic ZC4H2 gene variant. They will pass this variant to all their daughters, who will be carriers. Males cannot pass the ZC4H2 gene variant to their sons because they always pass their Y chromosome instead of their X chromosome to male offspring.
Females have two X chromosomes but many genes of one of the X chromosomes are silenced to correct a dosage imbalance through a process which is called X-inactivation. ZC4H2 is one of these many genes which is silenced through this process (subject to X-inactivation). 3 Results obtained so far by performing X-inactivation studies in blood and skin fibroblasts of carrier females indicated that X-inactivation status does not predict the clinical outcome. 1
Variants of the ZC4H2 gene can be inherited from the healthy or mildly affected mother who carries the variant on one of her X chromosomes. 1 Female carriers have a 25% chance with each pregnancy to pass on the ZC4H2 variant to a daughter, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with ZARD, and a 25% chance to have an unaffected son.
Females with a maternally inherited ZC4H2 gene variant may be unaffected or mildly affected. In contrast, females who carry a de novo pathogenic ZC4H2 variant can present with a highly variable clinical expression which ranges from mild to severe 1
In very rare cases, healthy females who carry a ZC4H2 variant in a small number of somatic cells and germ cells (gonosomal mosaicism) can pass the variant to their children. 1
The ZC4H2 gene is expressed in all human tissues. Understanding of ZC4H2’s gene functions and the functions of its corresponding ZC4H2 protein is currently limited. There is currently no evidence for a clear relationship between the genetic abnormality and the clinical features.
The spectrum of ZC4H2 gene abnormalities comprises novel (not reported before) and recurrent (present in at least two unrelated families) mostly inherited missense variants which cause a single amino acid exchange in the ZC4H2 protein in affected male individuals, and de novo missense, splicing, frameshift, nonsense and partial ZC4H2 deletions on one of the X chromosomes in carrier females and are predicted to be loss-of function alleles in affected female individuals suggesting ZC4H2 insufficiency as the most likely pathological mechanism leading to the clinical phenotype in females.
Thus far, missense variants cluster in the last exon of the ZC4H2 gene, which encodes the zinc-finger domain and the most C-terminal part of the protein.
Analysis of the in vivo expression pattern of the mouse Zc4h2 gene during neurodevelopment in various brain regions and spinal cord of different developmental stages revealed that in all brain areas investigated, Zc4h2 gene expression was highest during embryonic development and declined after birth, suggesting an important function during mouse brain development. 3
In zebrafish zc4h2 is primarily expressed in brain cells called “myelinating oligodendrocytes”, with decrease in expression as these mature into another type of brain cells. 6 This may suggest a function of ZC4H2 in myelination – which has not been studied to date.
It is believed that the ZC4H2 protein plays an important role in the development of the neurologic system during the early stages of human development, particularly through the development of neuromuscular junctions, spinal cord motor-neuron differentiation and neural tube formation. 3,6,8