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

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.

• Authors: Alice E Davidson, Sek-Shir Cheong, Pirro G Hysi, Cristina Venturini, Vincent Plagnol, Jonathan B Ruddle, Hala Ali, Nicole Carnt, Jessica C Gardner, Hala Hassan, Else Gade, Lisa Kearns, Anne Marie Jelsig, Marie Restori, Tom R Webb, David Laws, Michael Cosgrove, Jens M Hertz, Isabelle Russell-Eggitt, Daniela T Pilz, Christopher J Hammond, Stephen J Tuft, Alison J Hardcastle
• Journal: PloS one (PLoS One) Vol. 9 Issue 8 Pg. e104163 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25093588 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CHRDL1 protein, human
• Eye Proteins
• Nerve Tissue Proteins

Topics

• Adolescent
• Adult
• Cerebral Palsy (diagnostic imaging, genetics)
• Child, Preschool
• Corneal Diseases (diagnostic imaging, genetics)
• Corneal Pachymetry
• Epilepsy (complications, genetics)
• Exome (genetics)
• Eye Diseases, Hereditary (diagnostic imaging, genetics)
• Eye Proteins (genetics)
• Family
• Female
• Genes, X-Linked
• Genetic Association Studies
• Genetic Diseases, X-Linked (diagnostic imaging, genetics)
• Genetic Predisposition to Disease
• Glaucoma (congenital, genetics)
• Humans
• Intellectual Disability (complications, diagnostic imaging, genetics)
• Male
• Megalencephaly (diagnostic imaging, genetics)
• Middle Aged
• Muscle Hypotonia (complications, genetics)
• Mutation (genetics)
• Nerve Tissue Proteins (genetics)
• Pedigree
• Phenotype
• Ultrasonography
• Young Adult