title: 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.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Davidson
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Sek-Shir
authors.initials: SS
authors.lastname: Cheong
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital, London, United Kingdom.
authors.forename: Pirro G
authors.initials: PG
authors.lastname: Hysi
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital, London, United Kingdom.
authors.forename: Cristina
authors.initials: C
authors.lastname: Venturini
authors.affiliation: UCL Genetics Institute, London, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Department of Ophthalmology, Centre for Eye Research, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Ruddle
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Hala
authors.initials: H
authors.lastname: Ali
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Nicole
authors.initials: N
authors.lastname: Carnt
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Gardner
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Hala
authors.initials: H
authors.lastname: Hassan
authors.affiliation: Department of Ophthalmology, Odense University Hospital, Odense, Denmark.
authors.forename: Else
authors.initials: E
authors.lastname: Gade
authors.affiliation: Department of Ophthalmology, Centre for Eye Research, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kearns
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Jelsig
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Marie
authors.initials: M
authors.lastname: Restori
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Webb
authors.affiliation: Department of Ophthalmology, Singleton Hospital, Swansea, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Laws
authors.affiliation: Department of Women and Child Health, Singleton Hospital, Swansea, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Cosgrove
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Hertz
authors.affiliation: Great Ormond Street Hospital for Children, London, United Kingdom.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Russell-Eggitt
authors.affiliation: Institute of Medical Genetics, University Hospital of Wales, Cardiff, United Kingdom.
authors.forename: Daniela T
authors.initials: DT
authors.lastname: Pilz
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital, London, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hammond
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tuft
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hardcastle
mesh_terms: D000293:Adolescent; D000328:Adult; D002547:Cerebral Palsy / Q000000981:diagnostic imaging / Q000235:genetics*; D002675:Child, Preschool; D003316:Corneal Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D063171:Corneal Pachymetry; D004827:Epilepsy / Q000150:complications / Q000235:genetics; D059472:Exome / Q000235:genetics; D015785:Eye Diseases, Hereditary / Q000000981:diagnostic imaging / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000000981:diagnostic imaging / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005901:Glaucoma / Q000151:congenital / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D008297:Male; D058627:Megalencephaly / Q000000981:diagnostic imaging / Q000235:genetics*; D008875:Middle Aged; D009123:Muscle Hypotonia / Q000150:complications / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D014463:Ultrasonography; D055815:Young Adult
chemical_list: C486602:CHRDL1 protein, human; D005136:Eye Proteins; D009419:Nerve Tissue Proteins
references.citation: Mol Med Rep. 2013 Apr;7(4):1143-8
references.pmid: 23404565
references.citation: Hum Mol Genet. 1996 Aug;5(8):1199-203
references.pmid: 8842741
references.citation: Clin Genet. 2010 Feb;77(2):141-4
references.pmid: 20002452
references.citation: Ophthalmic Paediatr Genet. 1991 Sep;12(3):153-7
references.pmid: 1754164
references.citation: Doc Ophthalmol. 1994;87(1):1-121
references.pmid: 7835180
references.citation: Hum Mol Genet. 2009 Oct 15;18(20):3969-77
references.pmid: 19656777
references.citation: Hum Genet. 1989 Oct;83(3):292-4
references.pmid: 2571565
references.citation: Genomics. 1995 Nov 20;30(2):171-7
references.pmid: 8586416
references.citation: Invest Ophthalmol Vis Sci. 2005 Aug;46(8):2748-54
references.pmid: 16043846
references.citation: Am J Ophthalmol. 1979 Sep;88(3 Pt 1):424-6
references.pmid: 484670
references.citation: Cornea. 1993 Jan;12(1):54-9
references.pmid: 8458232
references.citation: Br J Ophthalmol. 2010 Aug;94(8):971-6
references.pmid: 19556215
references.citation: Am J Hum Genet. 2009 May;84(5):664-71
references.pmid: 19361779
references.citation: Am J Hum Genet. 2007 Feb;80(2):221-31
references.pmid: 17236128
references.citation: Genet Couns. 2013;24(2):185-91
references.pmid: 24032289
references.citation: Hum Mol Genet. 2010 Nov 1;19(21):4304-11
references.pmid: 20719862
references.citation: Eur J Hum Genet. 2010 Jul;18(7):761-7
references.pmid: 20179738
references.citation: Am J Hum Genet. 2012 Feb 10;90(2):247-59
references.pmid: 22284829
references.citation: Acta Ophthalmol (Copenh). 1960;38:606-17
references.pmid: 13744427
references.citation: Am J Hum Genet. 2010 Aug 13;87(2):173-88
references.pmid: 20655035
references.citation: Exp Biol Med (Maywood). 2007 Sep;232(8):979-92
references.pmid: 17720944
references.citation: Am J Med Genet A. 2010 Jan;152A(1):175-80
references.pmid: 20014135
references.citation: PLoS Genet. 2010 May 13;6(5):e1000947
references.pmid: 20485516
references.citation: Z Kinderheilkd. 1975 Jul 1;120(1):1-18
references.pmid: 1172332
references.citation: Am J Hum Genet. 2013 Aug 8;93(2):368-83
references.pmid: 23871722
references.citation: Surv Ophthalmol. 2000 Mar-Apr;44(5):367-408
references.pmid: 10734239
references.citation: Arch Ophthalmol. 2009 Jan;127(1):88-93
references.pmid: 19139346
references.citation: Invest Ophthalmol Vis Sci. 2013 Apr 01;54(4):2435-43
references.pmid: 23493294
references.citation: Ophthalmic Genet. 2013 Mar-Jun;34(1-2):14-20
references.pmid: 22924778
references.citation: Am J Hum Genet. 2008 May;82(5):1217-22
references.pmid: 18452888
references.citation: Nat Genet. 2002 Jun;31(2):184-9
references.pmid: 11992121
references.citation: J Comput Biol. 1997 Fall;4(3):311-23
references.pmid: 9278062
references.citation: Mol Vis. 2011;17:2911-9
references.pmid: 22128238
references.citation: Am J Hum Genet. 2008 Feb;82(2):304-19
references.pmid: 18252212
references.citation: Nucleic Acids Res. 1996 Sep 1;24(17):3439-52
references.pmid: 8811101
references.citation: Genet Epidemiol. 2014 Feb;38(2):97-103
references.pmid: 24408308
references.citation: Hum Genet. 2012 Nov;131(11):1783-93
references.pmid: 22814818
references.citation: Am J Hum Genet. 2013 May 2;92(5):643-7
references.pmid: 23643377
references.citation: Am J Hum Genet. 2007 Mar;80(3):561-6
references.pmid: 17273978
references.citation: Twin Res Hum Genet. 2013 Feb;16(1):144-9
references.pmid: 23088889
references.citation: Nucleic Acids Res. 2009 May;37(9):e67
references.pmid: 19339519
references.citation: Am J Hum Genet. 2007 Feb;80(2):345-52
references.pmid: 17236139
references.citation: Clin Genet. 2005 Apr;67(4):335-40
references.pmid: 15733270
references.citation: Ophthalmic Genet. 2015 Jun;36(2):145-8
references.pmid: 24073597
references.citation: Biochem J. 2010 Jul 1;429(1):1-12
references.pmid: 20545624
references.citation: Bioinformatics. 2009 May 1;25(9):1211-3
references.pmid: 19261717
references.citation: Nat Genet. 2013 Feb;45(2):155-63
references.pmid: 23291589
references.citation: Hum Mol Genet. 1999 May;8(5):899-905
references.pmid: 10196380
references.citation: Hum Mol Genet. 2011 Feb 15;20(4):649-58
references.pmid: 21098505