HPE5_ZIC2
- Gene
- ZIC2
- Disease
- HPE5
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 11.5
- Publications Reviewed
- 3
- Publication Span
- 8 years
- Last Updated
- 03/02/2026
- Curator(s)
- Macayla Weiner, Laurel Hiatt
Description
Heterozygous ZIC2 variants, including a recurrent C-terminal polyalanine tract expansion from 15 to 25 alanines, are associated with autosomal dominant holoprosencephaly 5 (HPE5). Reported genetic evidence includes ZIC2 mutations in 16 affected individuals from 15 unrelated HPE families, with frameshift/null alleles, an in-frame deletion, a missense variant, and alanine-tract expansions including de novo and paternal mosaic cases. Functional studies support a dosage-sensitive transcription factor mechanism, with HPE-associated ZIC2 mutations altering DNA binding and ZIC2-mediated transcriptional activation.
Genetic evidence
Total: 7
| Singular Evidence | Probands | PMID:11285244 | 6 | Screened 509 unrelated HPE patients with normal chromosomes; 16 affected individuals from 15 unrelated families had ZIC2 mutations. Seven mutations were frameshift/null alleles, and a recurrent C-terminal alanine-tract expansion occurred in seven patients from six families, including de novo and paternal mosaic cases. |
| Collective Evidence | Computational | PMID:19177455 | 1 | Compilation of 83 HPE-specific ZIC2 variants absent from controls showed recurrent predicted loss-of-function, including frequent frameshift/truncating variants (>55%), zinc-finger missense clustering at conserved DNA-binding residues, and COOH-terminal/polyalanine variants predicted or shown to impair ZIC2 function. |
Experimental evidence
Total: 4.5
| Function | Biochemical function | PMID:15590697 | 0.5 | In vitro ZIC2 reporter assays showed that HPE-associated mutations altered transcriptional activation; the naturally occurring 25-alanine expansion reduced apoE promoter transactivation to ~5% of wild-type activity. |
| Function | Protein interaction | PMID:15590697 | 0.5 | |
| Function | Regulatory impact | PMID:15590697 | 0.5 | C-terminal deletion/truncation and alanine-tract length changes altered ZIC2-mediated transcriptional activation in a promoter-specific manner; the C-terminal contains activation/repression domains and the alanine tract modulates DNA binding. |
| Functional Alteration | Patient cells | PMID:15590697 | 1 | |
| Models | Non-human model organism | PMID:15590697 | 2 | Gene-level, not tandem-repeat/locus-specific: PMID 15590697 discusses Zic2 mouse mutations with forebrain defects and mimics a murine C370S mutation in vitro; no new in vivo model of the alanine-tract expansion was generated. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.