ZFX

Inheritance Pattern: XL

Disease ID:MONDO:0958322

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:1040018

Submitter: ClinGen

*ZFX*, located on chromosome Xp22.11, encodes a transcription factor that has been implicated in oncogenesis and self-renewal of stem cells. *ZFX* was first reported in relation to X-linked syndromic complex neurodevelopmental disorder in 2024 (Shepherdson et al., PMID: 38325380). Affected males exhibit developmental delay, intellectual disability, behavioral abnormalities (including autism spectrum disorder and ADHD), hypotonia, overlapping facial features, congenital anomalies (including skeletal, genitourinary, cardiac, and renal abnormalities), and abnormal brain MRI. Other features include hyperparathyroidism, various tumor types and vascular anomalies. Female mutation carriers have highly skewed X-inactivation and tend to show a milder presentation that may include learning disabilities and hyperparathyroidism; some may even be asymptomatic. Four recurrent missense variants (p.Arg764Trp, p.Thr771Met, p.Tyr774Cys, and p.Arg786Gln) and seven frameshift and nonsense variants reported in 17 probands in two publications (PMIDs: 38325380, 39056049) are included in this curation. Eight variants were identified as *de novo*. The ZFX protein consists of an amino-terminal transactivation domain followed by 13 zinc finger domains, the last three of which are necessary and sufficient for recruitment to promoter regions (PMID: 32406922). All variants included in this curation disrupt or remove the zinc finger domains 11 to 13, located in the last exon of the gene. The mechanism of pathogenicity is loss of function for truncating variants, whereas missense variants may exert both loss- and gain-of-function mechanisms. Indeed, missense variants in the DNA binding domain induced differential expression of a small set of target genes compared to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity (PMID: 38325380). In summary, there is strong evidence supporting the relationship between *ZFX* and X-linked syndromic complex neurodevelopmental disorder. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 20, 2024 (SOP Version 11).

Inheritance Pattern: XL

Disease ID:MONDO:0958322

Submitter: PanelApp Australia