Familial epilepsy with anterior polymicrogyria as a presentation of COL18A1 mutations

Eur J Med Genet. 2017 Aug;60(8):437-443. doi: 10.1016/j.ejmg.2017.06.002. Epub 2017 Jun 8.


Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected individuals in the family. Identification of COL18A1 mutations in individuals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.

Keywords: COL18A1; Epilepsy; Exome sequencing; Knobloch syndrome; Polymicrogyria; Retina.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Collagen Type VIII / genetics*
  • Encephalocele / diagnosis
  • Encephalocele / genetics*
  • Female
  • Heterozygote
  • Humans
  • Lennox Gastaut Syndrome / diagnosis
  • Lennox Gastaut Syndrome / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Pedigree
  • Phenotype
  • Retinal Degeneration
  • Retinal Detachment / congenital*
  • Retinal Detachment / diagnosis
  • Retinal Detachment / genetics


  • COL18A1 protein, human
  • Collagen Type VIII

Supplementary concepts

  • Knobloch syndrome