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- Title
Association of <i>CHRDL1</i> Mutations and Variants with X-linked Megalocornea, Neuhäuser Syndrome and Central Corneal Thickness.
- Authors
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.
- 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.
- Subjects
BONE morphogenetic proteins; CORNEA diseases; DIAGNOSTIC ultrasonic imaging; CONGENITAL glaucoma; INTELLECTUAL disabilities; MISSENSE mutation; SINGLE nucleotide polymorphisms; DIAGNOSIS
- Publication
PLoS ONE, 2014, Vol 9, Issue 8, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0104163