Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhäuser syndrome and central corneal thickness.

Alice E Davidson,Hala Hassan,Nicole Carnt,Alison J Hardcastle,Tom R Webb,Else Gade,Marie Restori,Christopher J Hammond,Anne Marie Jelsig,Cristina Venturini,Michael Cosgrove,Vincent Plagnol,Jessica C Gardner,Daniela T Pilz,David Laws,Pirro G Hysi,Lisa S Kearns ,Stephen Tuft ,Hala R Ali ,Jens Michael Hertz ,Isabelle Russell‐Eggitt ,Jonathan B Ruddle ,Sek‐Shir Cheong

doi:10.1371/journal.pone.0104163

Abstract

We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1). Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG). Megalocornea is also a feature of Neuhäuser or megalocornea-mental retardation (MMR) syndrome, a rare condition of unknown etiology. In a male patient diagnosed with MMR, we performed targeted and whole exome sequencing (WES) and identified a novel missense mutation in CHRDL1 that accounts for his MGC1 phenotype but not his non-ocular features. This finding suggests that MMR syndrome, in some cases, may be di- or multigenic. MGC1 patients have reduced central corneal thickness (CCT); however no X-linked loci have been associated with CCT, possibly because the majority of genome-wide association studies (GWAS) overlook the X-chromosome. We therefore explored whether variants on the X-chromosome are associated with CCT. We found rs149956316, in intron 6 of CHRDL1, to be the most significantly associated single nucleotide polymorphism (SNP) (p = 6.81×10−6) on the X-chromosome. However, this association was not replicated in a smaller subset of whole genome sequenced samples. This study highlights the importance of including X-chromosome SNP data in GWAS to identify potential loci associated with quantitative traits or disease risk.

Highlights

X-linked megalocornea (MGC1; MIM 309300) is an inherited congenital disorder, characterised by bilateral enlarged corneas with a horizontal diameter of $13 mm and reduced central corneal thickness in the absence of raised intraocular pressure (IOP) [1]
whole exome sequencing (WES) analysis of genes previously associated with ID, epilepsy, seizures and hypotonia we considered the possibility that the extraocular phenotypes may be due to a mutation in an X-linked intellectual disability (XLID) gene in linkage disequilibrium (LD) with the CHRDL1 mutation, or an autosomal ID gene
All MGC1 families ascertained in this study were found to have unique CHRDL1 mutations including nonsense mutations p.(Glu34*), p.(Arg77*), p.(Cys80*) and p.(Cys99*), missense mutations p.(Cys289Arg) and p.(Cys291Tyr), a frameshift mutation p.(Glu101Glyfs*42), a splice site mutation (c.1247-1_1247del) and deletions encompassing the entire CHRDL1 transcript

Summary

Introduction

X-linked megalocornea (MGC1; MIM 309300) is an inherited congenital disorder, characterised by bilateral enlarged corneas with a horizontal diameter of $13 mm (measured after the age of two years) and reduced central corneal thickness in the absence of raised intraocular pressure (IOP) [1]. Adult-onset cataract typically develops between 30–50 years [2]. The condition was genetically linked to the long arm of the X-chromosome over twenty years ago (Xq12-q26; MGC1) [2,4] but the underlying genetic cause, mutations in CHRDL1 (MIM 300350), has only recently been discovered [3]. To date, presumed loss-of-function mutations in CHRDL1 have been described in eight unrelated families affected with MGC1 [3,6]

Methods

Results

Conclusion