Whole genome sequencing unveils genetic heterogeneity in optic nerve hypoplasia

PLoS One. 2020 Feb 10;15(2):e0228622. doi: 10.1371/journal.pone.0228622. eCollection 2020.


Optic nerve hypoplasia (ONH) is a congenital malformation with a reduced number of retinal ganglion cell axons in a thin optic nerve. It is a common cause of visual impairment in children and ONH is associated with neurodevelopmental disorders, pituitary hormone deficiencies, and brain malformations. In most cases, the aetiology is unknown, but both environmental factors and genetic causes have been described. This study aimed to identify genetic variants underlying ONH in a well-characterised cohort of individuals with ONH. We performed array comparative genomic hybridization and whole genome sequencing in 29 individuals with ONH. Rare variants were verified by Sanger sequencing and inheritance was assessed in parental samples. We identified 11 rare single nucleotide variants (SNVs) in ten individuals, including a homozygous variant in KIF7 (previously associated with Joubert syndrome), a heterozygous de novo variant in COL4A1 (previously described in an individual with porencephaly), and a homozygous variant in COL4A2. In addition, one individual harboured a heterozygous variant in OPA1 and a heterozygous variant in COL4A1, both were inherited and assessed as variants of unknown clinical significance. Finally, a heterozygous deletion of 341 kb involving exons 7-18 of SOX5 (associated with Lamb-Schaffer syndrome) was identified in one individual. The overall diagnostic yield of pathogenic or likely pathogenic variants in individuals with ONH using whole genome sequencing was 4/29 (14%). Our results show that there is a genetic heterogeneity in ONH and indicate that genetic causes of ONH are not rare. We conclude that genetic testing is valuable in a substantial proportion of the individuals with ONH, especially in cases with non-isolated ONH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Comparative Genomic Hybridization
  • Cross-Sectional Studies
  • Exons
  • Female
  • Genetic Heterogeneity*
  • Genetic Testing
  • Genome, Human
  • Heterozygote
  • Humans
  • Male
  • Optic Nerve / diagnostic imaging
  • Optic Nerve / pathology*
  • Optic Nerve Hypoplasia / genetics*
  • Pedigree
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Retinal Ganglion Cells / pathology
  • SOXD Transcription Factors / genetics
  • Sweden / epidemiology
  • Whole Genome Sequencing
  • Young Adult


  • SOX5 protein, human
  • SOXD Transcription Factors

Grant support

This research was supported by the Swedish Research Council [2013-2603] (AL), the Swedish Society for Medical Research (AL), Marianne and Marcus Wallenberg Foundation [2014.0084] (AL), Stockholm County Council (AL), the Swedish Brain Foundation (AL), SciLifeLab National projects (AL), Linnea och Josef Carlsson Foundation (SD, BMA), Sunnerdahl’s Handicap Foundation (SD, RW), Sällskapet Barnavård (SD), Frimurare barnhuset Foundation (SD, BMA), HRH Crown Princess Lovisa and Axel Tielman’s Foundation (BMA), and Sigvard och Marianne Bernadotte Foundation (KTF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.