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Sek Shir Cheong, Alice Davidson, Vincent Plagnol, Jonathan B Ruddle, Hala Ali, Jessica Clare Gardner, Jens M Hertz, Daniela T Pilz, Stephen J Tuft, Alison J Hardcastle; Association of CHRDL1 Mutations with X-linked Megalocornea and Megalocornea-Mental Retardation (MMR) Syndrome. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1002.
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CHRDL1 mutations have previously been reported to cause X-linked megalocornea (MGC1). In this study, eight MGC1 families were ascertained and screened for CHRDL1 mutations. Megalocornea is also a key pathognomonic feature of Megalocornea-Mental Retardation (MMR) syndrome. MMR is a rare, phenotypically heterogeneous condition and the underlying genetic cause(s) are unknown. We therefore performed whole exome sequencing (WES) to identify the causative gene(s) in a male patient diagnosed with MMR.
After informed consent was obtained genomic DNA was isolated from whole blood. All coding exons and splice sites of CHRDL1 were amplified by PCR, followed by Sanger sequencing. WES was performed for the MMR patient. The WES dataset was filtered for rare variants with a minor allele frequency ≤0.01 and cross-referenced with genes that have been reported to cause intellectual disability, hypotonia or seizures that are features of MMR. This dataset was generated with reference to the KEGG disease database. Candidate variants were then validated by PCR and Sanger sequencing.
In each MGC1 family, a novel CHRDL1 mutation was identified which included nonsense mutations (p.Cys80X and p.Cys99X), missense mutations (p.Cys289Arg and p.Cys291Tyr), a frameshift mutation (p.Glu101Glyfs*42), a splice site mutation (c.1247_1247-1delGG) and an entire CHRDL1 gene deletion. Interestingly, analysis of the WES dataset for the MMR patient resulted in identification of a novel missense mutation in CHRDL1 (p.Cys155Tyr) that was subsequently validated. The mother of the MMR proband was found to be a carrier of the CHRDL1 mutation. Although his ocular phenotype could therefore be attributed to CHRDL1, his non-ocular phenotypes (including intellectual disability and seizures) are unlikely to be caused by CHRDL1. The WES dataset was also interrogated for rare variants in genes known to cause these conditions, but no likely causative mutations were identified.
All MGC1 families investigated were found to have a mutation in CHRDL1. The missense mutations identified are located at conserved cysteine residues within von Willebrand factor C domains. We describe the first mutation causing the ocular component of MMR syndrome. CHRDL1 screening in other male MMR patients will reveal the contribution of mutations in this gene.
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