Submission Details

Variants in ZNF292 were first reported in humans with autosomal dominant complex neurodevelopmental disorder as early as 2012 (PMIDs 23033978, 22495311). Over 20 unique de novo truncating variants have been reported in over 30 probands (PMIDs 23033978, 22495311, 28135719, 31723249). Evidence supporting this gene-disease relationship is derived from case-level data. Individuals with ZNF292 truncating variants present with neurodevelopmental phenotypes (including intellectual disability/developmental delay, speech delays and autism spectrum disorder) and minor dysmorphic features. Although most reported variants are de novo, one ZNF292 truncating variant was inherited from an affected mother with mild ID (PMID 31723249). In addition, three affected siblings inherited a ZNF292 truncating variant from a reportedly unaffected father, suggesting reduced penetrance (PMID 31723249). ZNF292 is highly intolerant to truncating variants (pLI = 1 in gnomAD). Currently, there are no experimental data delineating the disease mechanism. Most reported variants are located in the last exon, which encodes for a DNA binding domain; these variants are predicted to escape nonsense-mediated decay, leading to the expression of a truncated protein with potential dominant-negative or gain-of function effects (PMID 31723249). However, the possibility of loss of function cannot be ruled out, and functional studies will be necessary to determine the molecular mechanism of pathogenicity. Reports of a large number of independent probands ascertained from various geographic locations with de novo truncating ZNF292 variants and consistent neurodevelopmental phenotypes provided convincing evidence of the gene-disease relationship. In summary, there is sufficient evidence to support a definitive gene-disease relationship between ZNF292 and complex neurodevelopmental disorders. The classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 05/06/20 (SOP Version 7).