Whole-genome copy number variation analysis in anophthalmia and microphthalmia

Clin Genet. 2013 Nov;84(5):473-81. doi: 10.1111/cge.12202. Epub 2013 Jun 17.


Anophthalmia/microphthalmia (A/M) represent severe developmental ocular malformations. Currently, mutations in known genes explain less than 40% of A/M cases. We performed whole-genome copy number variation analysis in 60 patients affected with isolated or syndromic A/M. Pathogenic deletions of 3q26 (SOX2) were identified in four independent patients with syndromic microphthalmia. Other variants of interest included regions with a known role in human disease (likely pathogenic) as well as novel rearrangements (uncertain significance). A 2.2-Mb duplication of 3q29 in a patient with non-syndromic anophthalmia and an 877-kb duplication of 11p13 (PAX6) and a 1.4-Mb deletion of 17q11.2 (NF1) in two independent probands with syndromic microphthalmia and other ocular defects were identified; while ocular anomalies have been previously associated with 3q29 duplications, PAX6 duplications, and NF1 mutations in some cases, the ocular phenotypes observed here are more severe than previously reported. Three novel regions of possible interest included a 2q14.2 duplication which cosegregated with microphthalmia/microcornea and congenital cataracts in one family, and 2q21 and 15q26 duplications in two additional cases; each of these regions contains genes that are active during vertebrate ocular development. Overall, this study identified causative copy number mutations and regions with a possible role in ocular disease in 17% of A/M cases.

Keywords: 2q14; 3q29; NF1; PAX6; SOX2; anophthalmia; copy number variation; microphthalmia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anophthalmos / genetics*
  • Anophthalmos / pathology
  • Base Sequence
  • Child, Preschool
  • Chromosome Duplication
  • DNA Copy Number Variations*
  • Eye Proteins / genetics*
  • Female
  • Genome, Human
  • Homeodomain Proteins / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Microphthalmos / genetics*
  • Microphthalmos / pathology
  • Molecular Sequence Data
  • Neurofibromin 1 / genetics*
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors / genetics*
  • Phenotype
  • Repressor Proteins / genetics*
  • SOXB1 Transcription Factors / genetics*
  • Sequence Deletion*
  • Severity of Illness Index


  • Eye Proteins
  • Homeodomain Proteins
  • Neurofibromin 1
  • PAX6 Transcription Factor
  • PAX6 protein, human
  • Paired Box Transcription Factors
  • Repressor Proteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors