ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000013.10) (NC_000013.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
9771712 Brown et al. (1998) analyzed 150 patients with sporatic HPE and 63 patients with familial HPE for mutations in ZIC2. In one patient with sporadic HPE, they found a de novo 56 bp insertion in exon 1, predicted to destroy the reading frame. In a second patient with sporadic HPE, they found a de novo single base pair insertion, resulting in a frameshift. In a third patient with sporadic HPE, they found a de novo 7 bp deletion in the zinc-finger region, which destroyed the reading frame. In a family with 2 affected sibs, they found a 30 bp insertion in exon 3, resulting in an expansion of the alanine tract from 15 to 25 residues. The father was a mosaic carrier, with normal brain by computed tomography scan, no physical evidence of HPE, and subnormal intelligence.
11479728 Orioli et al. (2001) analyzed 30 unrelated patients with HPE for mutations in SIX3, SHH, TGIF, and ZIC2. They found a de novo 2 bp deletion in the zinc-finger region of ZIC2.
21638761 Ramocki et al. (2011) identified a 7 bp deletion resulting in a frameshift of ZIC2 (Pro131fsX84) in 2 half sibs with HPE and partial rhombencephalosynapsis. The mother did not carry the deletion in her peripheral blood, suggesting germline mosaicism.
  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

PMID22105922: Jobanputra et al. (2012) identified a 564 kb duplication including ZIC2 (and 3 other genes) as part of a complex chromosomal rearrangement in a fetus referred for prenatal counseling. The child was born without holoprosencephaly and showed normal development at age 3 months. After review of the phenotypes of 7 additional patients with large (>18 Mb) gains of 13q containing ZIC2, the authors concluded that duplication of ZIC2 is not associated with holoprosencephaly.