ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
28513610 Weiss et al (2017) identified predicted loss of function (LOF) variants in ZNF462 in eight patients from six families with ptosis, metopic ridging, craniosynostosis, dysgenesis of the corpus callosum, and developmental delay using whole-exome sequencing. In five families predicted LOF variants were de novo. In a family, the proband and her elder sister, with a paternally inherited nonsense variant, had normal growth and development. Her physical features included a pointed forehead (metopic ridging), bilateral ptosis, arched eyebrows, synophrys, a small upturned nose, long philtrum, and a thin upper lip. Her sister had pointed forehead, ptosis, down-slanted palpebral fissures, and a congenital capillary malformation (port wine stain) involving the right side of her neck, shoulder, and upper left arm. The father inherited the nonsense variant from his mother, and had a pointed forehead and mild left ptosis, but no other dysmorphic features. The paternal grandmother had bilateral ptosis, without metopic ridging or dysmorphic features. The paternal great grandfather was not examined but was reported to have a pointed forehead. Shared features include metopic ridging or lambdoid craniosynostosis (5/8), dysgenesis of the corpus callosum (3/8), ptosis (7/8), and developmental delay with or without autistic features (4/8).The authors proposed that ZNF462 plays an important role in embryonic development, and is associated with craniofacial and neurodevelopmental abnormalities.
31361404 Kruszka et al. report 14 additional individuals with loss of function variants in ZNF462. Thirteen of the 14 were detected via exome sequencing; 1/14 was detected via genome sequencing. Ten of the variants were de novo, 2 were of unknown inheritance, 1 was paternally inherited with a positive family history (father with history of ptosis requiring surgery), and 1 was inherited from a mosaic mother. This article further clarified the range of phenotypic presentations observed in individuals with LOF variants in ZNF462: 79% demonstrated developmental delay; 33% with autism spectrum disorders; 83% with ptosis; and 33% and 25%, respectively, with metopic ridging/craniosysnostis or dysgenesis of the corpus callosum, which were two predominantly observed features in the original case report.

Haploinsufficiency phenotype comments:

De novo loss of function sequence variants have been detected in patients with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay (PMID: 28513610). In addition to the cases reported above, a de novo balanced translocation disrupting ZNF462 in a patient with syndromic intellectual disability and autism spectrum disorder was reported (Cosemans et al. 2018). The clinical features included metopic craniosynostosis, a corpus callosum dysgenesis and dysmorphic facial features, most notably ptosis. This translocation case is noted but not counted as evidence here as there were no functional studies proving that KLF12 was not disrupted. There were also two multi-genic deletions involving ZNF462 reported in Weiss et al. with phenotypes consistent with those observed in individuals with LOF sequence variants in ZNF462.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

At this time there is no evidence that supports the triplosensitivity of ZNF462