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Abstract #58892 Published in IGR 16-3
Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhäuser syndrome and central corneal thickness
Davidson AE; Cheong SS; Hysi PG; Venturini C; Plagnol V; Ruddle JB; Ali H; Carnt N; Gardner JC; Hassan H; Gade E; Kearns L; Jelsig AM; Restori M; Webb TR; Laws D; Cosgrove M; Hertz JM; Russell-Eggitt I; Pilz DT; Hammond CJ; Tuft SJ; Hardcastle AJPLoS ONE 2014; 9: e104163
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.
UCL Institute of Ophthalmology, London, United Kingdom.
Full articleClassification:
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
9.1.1 Congenital glaucoma, Buphthalmos (Part of: 9 Clinical forms of glaucomas > 9.1 Developmental glaucomas)
10 Differential diagnosis e.g. anterior and posterior ischemic optic neuropathy
