ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000011.9) (NC_000011.10)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: ANIRIDIA 1; AN1

Haploinsufficiency phenotype comments:

Heterozygous deletions and loss of function mutations in PAX6 cause isolated aniridia. Larger deletions that also encompass the WT1 gene lead to WAGR syndrome (Wilms tumor-aniridia-genital anomalies-retardation). Rare reports of homozygous loss of function mutations have been reported in association with severe craniofacial anomalies, anophthalmia, absent adrenal glands, and central nervous system malformations. Additionally, missense and other mutations in PAX6 have been found in individuals with other types of eye abnormalities (see Gene Reviews). Deletions downstream of PAX6 not including its coding region disrupt a putative enhancer causing sporadic, and familial isolated aniridia. This cis-regulatory element, termed the PAX6 downstream regulatory region (DRR), was initially mapped from the 3' end of PAX6 for approximately 1 Mb, including the genes: ELP4, IMMP1L, DPH4, DCDC1, and others (Davis LK, 2008; Byrakli, 2009; Lauderdale, 2000). A recent study (Balay et al., 2015; PMID 26419218) suggests that the PAX6 DRR lies closer to the PAX6 gene, within the gene ELP4.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
21271670 Aradhya (2010): report of a girl with a de novo duplication encompassing all of PAX6 and the first non-coding exon of the adjacent ELP4. The patient has a history of seizures, developmental delay, hyptonia, microcephaly, ADHD, autistic features, mild ocular findings, and mild dymorphic facial features. All other metabolic and molecular testing was normal.

Triplosensitivity phenotype comment:

Other reports of duplications including PAX6 are rare and have been large duplications that include a number of other genes (PMID: 9415682).