ZNF292

Gene Facts

• HGNC Symbol: ZNF292 (HGNC:18410)
• HGNC Name: zinc finger protein 292
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: KIAA0530, ZFP292, bA393I2.3, Zn-15, Zn-16
• %HI: 26.56
• pLI: 1
• LOEUF: 0.16
• Cytoband: 6q14.3
• Genomic Coordinates:

  GRCh37/hg19:	chr6:87865283-87975661
  GRCh38/hg38:	chr6:87155565-87265943

• MANE Select Transcript: NM_015021.3 ENST00000369577.8
• Function: May be involved in transcriptional regulation. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-12336
• ClinGen Curation ID: CCID:008144
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 10/25/2023

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• complex neurodevelopmental disorder

HI Evidence

• PUBMED: 31723249
  Mirzaa et al. (2020): 28 families with intellectual disabilities were found to have “putatively pathogenic” ZNF292 (NM_015021.3) variants which were identified via targeted or exome sequencing. 27 of these variants were de novo in origin, while one frameshift variant was inherited from an affected mother. In total 19 frameshift variants and 7 nonsense variants were found to reside in the final 3’ exon of ZNF292, while 1 individual was found to have a de novo frameshift variant in exon 4 and another individual was found to have a de novo nonsense variant in exon 2. 12 additional families with intellectual disability were found to have missense, nonsense, or frameshift variants within ZNF292 but were excluded from analysis by the authors due to incomplete parental testing, lack of phenotypic data for the parent of origin, presence of a missense variant within ZNF292, or lack of segregation within the family (see supplemental table 3). Of note all of the variants identified in these families were in the final 3’ exon. In two families (17-017 and 17-020) exhibiting lack of segregation, the authors note only targeted sequencing was conducted; however, in one instance (17-020) three affected siblings inherited the variant from an unaffected father.
• PUBMED: 22495311
  Neale et al. (2012): Trio studies of 175 ASD probands. One individual (09C98975) was found to have 5 de novo variants, including a nonsense variant (c.265C>T, p.R89X) in exon 2 of ZNF292. Of interest, this variant was also identified in a patient from Mirzaa et al. (2020, PMID: 31723249; see above). Of the five genes found to have de novo variants in this patient, only ZNF292 is currently associated with a phenotype in OMIM.
• PUBMED: 28191889
  Stessman et al. (2017): Large cohort analysis (>11,730 NDD patients and >2867 controls) investigating the role of 208 candidate genes in neurodevelopmental disorders. One nonsense variant of unknown inheritance was identified in exon 7 of ZNF292 (NM_015021.3) in one patient, while nonsense and frameshift variants were identified in the final exon (exon 8) of ZNF292 (supplemental tables 11 and 12) in other patients. Additionally, a nonsense variant was also identified in exon 8 of an unaffected control (supplemental table 18). These ZNF292 variants were found to be significant in the authors likely gene disruptive (LGD) analysis (p-value: 1.88E-02).
• PUBMED: 25849321
  Li et al. (2016): Study investigated the role of 17,104 de novo variants from 3555 trios extracted from numerous other studies across four neuropsychiatric disorders: ASD, ID, SCZ, and EE. Authors identified ZNF292 as a potential candidate gene for association (p-value < 0.05) with ASD and ID. In total two ZNF292 variants were identified: a frameshift in the final exon (exon 8) in an individual with ID, and the p.R89X nonsense variant also observed in Mirzaa et al. (2020, PMID: 31723249; see above) and Neale et al. (2012; PMID: 22495311; see above). Of note, this study lists Neale 2012 as one of its sources for patient samples, so it is likely this is the same patient mentioned above.
• PUBMED: 35982159
  Zhou et al. (2022): Study sought to identify novel moderate-risk genes by analyzing de novo and inherited coding variants in 42,607 autism cases. The study used a two-stage approach in which the findings from the discovery dataset informed the second stage meta-analysis which looked at 404 genes. After correcting for multiple testing, ZNF292 variants were not found to be enriched in the case population (p<8.69E-06). Of note, this study overlaps other datasets reported above; notably patient 09C98975 from Neale et al. (2012; PMID: 22495311) was identified in the discovery dataset. Additionally, of the 23 nonsense and frameshift variants of ZNF292 seen in this study, 21 are within the final exon, and likely escape NMD.

• HI Evidence Comments: The relationship between variation in ZNF292 and complex neurodevelopmental disorder has been evaluated by the ClinGen Intellectual Disability/Autism gene curation expert panel; they found that there was definitive evidence to support this gene-disease relationship. However, it is unclear the exact mechanism of action for these causal variants. While, at present, no whole gene deletions involving only ZNF292 were identified, there have been numerous truncating variants (de novo and inherited) affecting ZNF292 observed in individuals with neurodevelopmental phenotypes (PMIDs: 31723249, 34312540, 33004838, 28191889, 22495311, 36477409, 33875846, 31785789, 28191890, 29158550, 25849321, 27824329, 30564305, 35982159). These phenotypes most commonly include intellectual disability, developmental delay, and speech delays, as well as other less common phenotypes such as autism spectrum disorder (ASD), and minor dysmorphic features (PMID: 31723249). However, the overwhelming majority of nonsense and frameshift variants were found to reside in the final 3’ exon of ZNF292, and thus are likely to escape nonsense mediated decay (NMD). Of note, the last exon of ZNF292 is much larger than the others, and contains more than 75% of the amino acids in the protein. As no functional studies which investigated the effects of these variants on the truncated transcript were identified, a dominant-negative or gain-of-function mechanism cannot be ruled out as a cause for the association between ZNF292 and neurodevelopmental disorders. *Of note, as many of the reports identifying ZNF292 variants in patients with ASD use overlapping datasets, care should be taken when enumerating the number of observed variants so as not to count the same patient multiple times. There have been reports of somatic variation in this gene in gastric cancer, colorectal cancer, chronic lymphocytic leukemia, and others (https://www.ncbi.nlm.nih.gov/gene/23036).

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity