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

  • PLoS One. 2014 Aug 5;9(8):e104163. doi: 10.1371/journal.pone.0104163.
Alice E Davidson  1 ,  Sek-Shir Cheong  1 ,  Pirro G Hysi  2 ,  Cristina Venturini  2 ,  Vincent Plagnol  3 ,  Jonathan B Ruddle  4 ,  Hala Ali  1 ,  Nicole Carnt  5 ,  Jessica C Gardner  1 ,  Hala Hassan  5 ,  Else Gade  6 ,  Lisa Kearns  4 ,  Anne Marie Jelsig  7 ,  Marie Restori  8 ,  Tom R Webb  1 ,  David Laws  9 ,  Michael Cosgrove  10 ,  Jens M Hertz  7 ,  Isabelle Russell-Eggitt  11 ,  Daniela T Pilz  12 ,  Christopher J Hammond  2 ,  Stephen J Tuft  5 ,  Alison J Hardcastle  1
Affiliations
  • 1. UCL Institute of Ophthalmology, London, United Kingdom.
  • 2. Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital, London, United Kingdom.
  • 3. UCL Genetics Institute, London, United Kingdom.
  • 4. Department of Ophthalmology, Centre for Eye Research, University of Melbourne, Melbourne, Victoria, Australia.
  • 5. UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom.
  • 6. Department of Ophthalmology, Odense University Hospital, Odense, Denmark.
  • 7. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  • 8. Moorfields Eye Hospital, London, United Kingdom.
  • 9. Department of Ophthalmology, Singleton Hospital, Swansea, United Kingdom.
  • 10. Department of Women and Child Health, Singleton Hospital, Swansea, United Kingdom.
  • 11. Great Ormond Street Hospital for Children, London, United Kingdom.
  • 12. Institute of Medical Genetics, University Hospital of Wales, Cardiff, United Kingdom.
PMID: 25093588 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.