Familial epilepsy with anterior polymicrogyria as a presentation of COL18A1 mutations

Abstract

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.

Introduction

Precise genetic diagnoses of rare disorders have been significantly improved by the application of massively parallel sequencing technologies (Deciphering Developmental Disorders Study, 2015, Lee et al., 2014, van Zelst-Stams et al., 2014). Sequencing of whole exomes (WES) or whole genomes (WGS) is used as a comprehensive and unbiased test for a molecular diagnosis. A robust DNA variant filtering strategy is an imperative (MacArthur et al., 2014). The patient's phenotype critically influences strategies for DNA variant filtration and interpretation, however caution is needed because as yet undocumented phenotypic variations could lead lower prioritization of genes carrying true pathogenic variants (Ha et al., 2016). Conversely, genotypic variations can be misinterpreted as pathogenic, but later identified as rare population variants with no pathogenic significance (Piton et al., 2013). This is still a substantial concern particularly for variants discovered in individuals of non-European populations whose spectrum of rare SNVs are not sufficiently well captured even by very large SNV databases, such as the genome aggregation database (gnomAD) (Lek et al., 2016).

We present a family that was initially thought to have a novel syndrome of refractory seizures, intellectual disability, anterior polymicrogyria and multiple ocular abnormalities and in which we eventually identified a compound heterozygous loss of function mutations in a known disease gene, COL18A1. The key features of the associated and clinically heterogeneous Knobloch syndrome [OMIM: (KNO1) #267750] were not obvious.