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

Anderson, Michael G., Davidson, Alice E., Cheong, Sek-Shir, Hysi, Pirro G., Venturini, Cristina, Plagnol, Vincent, Ruddle, Jonathan B., Ali, Hala, Carnt, Nicole, Gardner, Jessica C., Hassan, Hala, Gade, Else, Kearns, Lisa, Jelsig, Anne Marie, Restori, Marie, Webb, Tom R., Laws, David, Cosgrove, Michael, Hertz, Jens M., Russell-Eggitt, Isabelle, Pilz, Daniela T., Hammond, Christopher J., Tuft, Stephen J. and Hardcastle, Alison J. 2014. Association of CHRDL1 mutations and variants with X-linked megalocornea, neuhäuser syndrome and central corneal thickness. PLoS ONE 9 (8) , e104163. 10.1371/journal.pone.0104163

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Public Library of Science
ISSN: 1932-6203
Date of Acceptance: 7 July 2014
Last Modified: 06 Jul 2023 01:40

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