Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population

Clin Genet. 2020 Nov;98(5):499-506. doi: 10.1111/cge.13830. Epub 2020 Sep 3.


Next-generation sequencing strategies have resulted in mutation detection rates of 21% to 61% in small cohorts of patients with microphthalmia, anophthalmia and coloboma (MAC), but despite progress in identifying novel causative genes, many patients remain without a genetic diagnosis. We studied a cohort of 19 patients with MAC who were ascertained from a population with high rates of consanguinity. Using single nucleotide polymorphism (SNP) arrays and whole exome sequencing (WES), we identified one pathogenic variant in TENM3 in a patient with cataracts in addition to MAC. We also detected novel variants of unknown significance in genes that have previously been associated with MAC, including KIF26B, MICU1 and CDON, and identified variants in candidate genes for MAC from the Wnt signaling pathway, comprising LRP6, WNT2B and IQGAP1, but our findings do not prove causality. Plausible variants were not found for many of the cases, indicating that our current understanding of the pathogenesis of MAC, a highly heterogeneous group of ocular defects, remains incomplete.

Keywords: Anophthalmia; CDON; Coloboma; Microphthalmia; TENM3; cataract.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anophthalmos / genetics*
  • Anophthalmos / pathology
  • Calcium-Binding Proteins / genetics
  • Cation Transport Proteins / genetics
  • Cell Adhesion Molecules / genetics*
  • Coloboma / genetics*
  • Coloboma / pathology
  • Consanguinity
  • Exome / genetics
  • Exome Sequencing
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Kinesins / genetics
  • Male
  • Membrane Proteins / genetics*
  • Microphthalmos / genetics*
  • Microphthalmos / pathology
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Tumor Suppressor Proteins / genetics*


  • CDON protein, human
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • Cell Adhesion Molecules
  • MICU1 protein, human
  • Membrane Proteins
  • Mitochondrial Membrane Transport Proteins
  • Nerve Tissue Proteins
  • TENM3 protein, human
  • Tumor Suppressor Proteins
  • KIF26B protein, human
  • Kinesins