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

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

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.

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