ZFPM2

Gene Facts

• HGNC Symbol: ZFPM2 (HGNC:16700)
• HGNC Name: zinc finger protein, FOG family member 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: FOG2, hFOG-2, ZNF89B, ZC2HC11B
• %HI: 0.93
• pLI: 1
• LOEUF: 0.28
• Cytoband: 8q23
• Genomic Coordinates:

  GRCh37/hg19:	chr8:106330666-106816767
  GRCh38/hg38:	chr8:105318438-105804539

• MANE Select Transcript: NM_012082.4 ENST00000407775.7
• Function: Transcription regulator that plays a central role in heart morphogenesis and development of coronary vessels from epicardium, by regulating genes that are essential during cardiogenesis. Essential cofactor that acts via the formation of a heterodimer with transcription factors of the GATA family GATA4, GATA5 and GATA6. Such heterodimer can both activate or repress transcriptional activity, depending on the cell and promoter context. Also required in gonadal differentiation, possibly be regulatin... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-9713
• ClinGen Curation ID: CCID:008132
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Yes
  The ZFPM2 gene has been implicated in autosomal dominant congenital pathogenesis of diaphragmatic hernia with reduced penetrance.
• Last Evaluated: 09/20/2021

Haploinsufficiency (HI) Score Details

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

HI Disease

• Congenital Diaphragmatic Hernia

HI Evidence

• PUBMED: 16103912
  Ackerman et al (2005) performed sequence analysis of the FOG2/ZFMP2 gene on tissue from 30 of 32 deceased children with an anatomic diagnosis of diaphragmatic defect. Authors identified one patient with a de novo R112X variant resulting in a truncated peptide without a zinc finger and a phenotype of severe bilateral pulmonary hypoplasia and diaphragmatic eventration was present on the left side. Authors also demonstrated that a variant in the FOG2/ZFPM2 gene in mice embryos also caused pulmonary hypoplasia and abnormal diaphragmatic development. Authors suggest that pathogenic variants in the FOG2/ZFPM2 gene may result in primary pulmonary and diaphragmatic defects.
• PUBMED: 21525063
  Wat et al (2011) looked at 45 patients with congenital diaphragmatic hernias (CDH) or diaphragmatic eventrations of varying severity by array CGH or SNP based copy number analysis. Eight patients were found to have genomic changes that likely contributed to their phenotype. Patient 1 was diagnosed with intestinal malrotation and a left-sided diaphragmatic eventration. The patient was found to have an ~1 MB deletion that only included the ZFPM2 gene. The father also carried the deletion and appeared unaffected. No sequence changes were noted in the other ZFMP2 allele. Patient 2 was prenatally diagnosed with left-sided CDH, SNP microarray identified a deletion that included the 3' portion of the ZFPM2 gene and the first coding exon of the OXR1 gene. Quantitative PCR analysis determined that exons 7 and 8 of the ZFPM2 gene were included. No sequence changes were noted in the other ZFMP2 allele. Deletion appeared to be maternally inherited (no clinical information on the mother was provided).
• PUBMED: 2470247
  Longoni et al (2015) performed exome sequencing on 275 patients with congenital diaphragmatic hernia (CDH). They identified 14 heterozygous ZFPM2 sequence variants from 13 unrelated CDH patients. The majority of variants identified were missense variants mapped to highly conserved nucleotides or known functional domains. Patient CDH4 was identified to have a paternally inherited variant resulting in a premature stop (p.E58X). Patient CDH13 was identified to have frame shift variant which was expected to result in the loss of the fifth ZFPM2 zinc finger domain. Inheritance is unknown for CDH13. In addition CDH13 had an additional variant (p.R213C) in the NRF2 gene also associated with CDH. The NRF2 variant maps to the protein domain thought to bind to ZFPM2. All 14 patients presented with posterolateral CDH, except Patient CDH12 who also presented with additional heart defects and craniofacial anomalies. Authors also looked at two multigenerational families. Family 1 was identified to have an intragenic deletion of ZFPM2 (NCBI36/hg18 chr8:106,417,969-106,704,253). Authors identified the variant in 4 affected individuals, 2 unaffected obligate carriers, and 3 additional unaffected family members (not highlighted clearly in the pedigree Fig1). The intragenic deletion is predicted to result in a transcript that is 380 bp shorter than the normal transcript. Lymphoblastoid lines from two affected family members, one unaffected carrier and one family member without a deletion only detected the 672 bp band corresponding to the wild type allele suggesting that the mutant transcript was unstable or underwent nonsense mediated decay. Family 2 was identified to have a frame shift variant p.Y467fs*23 in three affected siblings with left posterolateral CDH inherited from their mother who did not have a clinical diagnosis of CDH. The frameshift variant results in the truncation of over 50% of protein. In addition 2 of the three children and the mother also had developmental delays and additional phenotypic features thought to be due to a chromosome 1 anomaly. Authors conclude that these variants are pathogenic with reduced penetrance.
• PUBMED: 21739578
  Kuechler et al. described 5 patients with overlapping deletions of 8q22.2q22.3. Two patients showed partial deletions of the ZFMP2 gene (Patient 2 and Patient 4). Patient 2 presented with moderate intellectual disability and a large hiatal hernia. Patient 4 presented with severe intellectual disability and diaphragmatic hernia.

• HI Evidence Comments: Putative loss of function variants of the ZFPM2 gene have been observed in individuals with congenital diaphragmatic hernia, as well as in their unaffected family members, suggesting reduced penetrance and/or variable expressivity. Familial studies suggest that inheritance of variants of the ZFPM2 gene may not be sufficient to cause a phenotype and other genetic and/or environmental factors may be contributing. In addition, missense variants have been implicated in patients with tetralogy of Fallot and in patients with 46,XY sex reversal.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: There have been no reports of whole gene duplications of the ZFPM2 gene associated with a clinical phenotype at this time.