ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000014.8) (NC_000014.9)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24033328 In 2014, Chassaing et al. used direct sequencing and PCR on 150 individuals with anophthalmia and microphthalmia (AM) to identify variants in 7 genes related to AM including GDF6, FOXE3, PAX6, RAX, SOX2, VSX2, and OTX2. Analysis identified variants in OTX2 in 5 individuals. Variants identified in OTX2 include 2 nonsense variants, 1 frameshift variant, and 2 deletions including the OTX2 gene (coordinates not provided). The frameshift variant, 1 nonsense variant, and 1 deletion were familial cases (inherited from a symptomatic parent), while 1 deletion variant and 1 nonsense variant were of unknown inheritance (parents were not available for study, but no family history reported).
19956411 In 2009, Henderson et al. used microarray and PCR on 142 patients with either Leber congenital amaurosis (LCA) or early onset retinal dystrophy (EORD). Analysis identified a de novo nonsense variant (c.413C>G p.S138X) in an individual with EORD. Of note, the proband also had a pituitary insufficiency.
18781617 In 2008, Wyatt et al. used PCR, Multiplex Ligation-Dependent Amplification (MLPA), FISH, and oligo array-CGH on 165 individuals with anophthalmia, microphthalmia, or coloboma to identify potential variants in OTX2. The authors identified OTX2 variants in 8 individuals. Probands 1 and 2 had deletions encompassing the whole OTX2 genes and other genes. Proband 3 had a de novo nonsense variant in the first exon of OTX2 predicted to result in nonsense-mediated decay. Individuals 4 and 5 were siblings with the same frameshift variant predicted to cause nonsense-mediated decay. This variant was absent in their parents. Individuals 6 and 7 were dizygotic twins with a nonsense variant found in their father with reduced vision in a single eye. Proband 8 was found to have a frameshift variant which was also present in their unaffected mother.

Haploinsufficiency phenotype comments:

Heterozygous variants in the OTX2 gene have been observed in individuals with microphthalmia and other features, including pituitary dysfunction. Additionally, this gene has been reported in association with combined pituitary hormone deficiency (CPHD). For example, in 2009, Tajima et al. (PMID: 18854396) used sequence analysis on a child with combined pituitary hormone deficiency (CPHD) and anophthalmia to identify potential variants in OTX2. Analysis identified a de novo, novel insertion in OTX2 resulting in loss of function. Diaczok et al. (PMID: 18728160) also describes OTX2 in relation to CPHD. Additional cases: PMID: 26974134 In 2016, Lonero et al. used PCR and sequencing to investigate OTX2 and SOX2 in a proband and her parents. Per the authors, "We describe a child carrying a novel OTX2 heterozygous mutation. She presented microphthalmia, absence of retinal vascularization, vitreal spots and optic nerve hypoplasia in the right eye and mild macular dystrophy in the left eye. Midline brain structures and cerebral parenchyma were normal, except for the ectopic posterior pituitary gland." Analysis identified a de novo frameshift variant in the proband predicted to cause premature protein truncation. PMID: 24167467 In 2013, O Patat et al. used Array-CGH analysis and direct sequencing on two individuals with otocephaly-dysgnathia complex. The authors identified a de novo 400-kb deletion in 14q23.1 including only the OTX2 gene in one individual and an inherited nonsense mutation c.289C>T (p.Arg97*) in the other individual.

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

Triplosensitivity phenotype comment:

PMID:18666230: Ou et al. (2008) report a patient with DD and MCA, including features suggestive of either branchiootorenal syndrome (BOR) or oculoauriculovertebral spectrum (OAVS). CMA revealed an ~12 Mb duplication of 14q22.3-q23.3 and a loss of ~4 Mb sequence in 13q21.31-q21.32 in the proband and his abnormal father (ID, short stature, hypernasal speech, and minor craniofacial anomalies). The authors suggest that the "increased dosage of SIX1, SIX6, or OTX2 may be responsible for the BOR and OAVS-like features in this family." The duplication of chr14 contains a total of 51 genes. PMID: 24816892 In 2014, Zielinski et al. used whole exome sequencing (WES) and copy number analysis on a family with hemifacial microsomia (HFM). Analysis identified a 1.3 Mb duplication of 14q22.3 in the affected family members. The authors believe that the duplication of OTX2 is responsible for this phenotype. PMID: 23794319 In 2012, Ballesta-Mart?nez et al. used array-CGH on an individual with Treacher Collins syndrome and her family. Analysis identified a duplication at 14q23.1. This variant contained OTX2 and 6 other RefSeq genes. The authors noted that the variant, ?segregates with the phenotype within the family.? Because each of these reported cases involves genes other than OTX2 (and the effects of additional copies of the other genes cannot be ruled out), the triplosensitivity score for this gene is 0.