Genetics Genetic Heterogeneity for Recessively Inherited Congenital Cataract Microcornea with Corneal Opacity Kamron Khan,1,2,3 Ahmed Al-Maskari,1,2,3 Martin McKibbin,1,2 Ian M. Carr,1 Adam Booth,1,4 Moin Mohamed,1,5 Salina Siddiqui,1,2 James A. Poulter,1 David A. Parry,1 Clara V. Logan,1 Anwar Hashmi,6 Tehseen Sahi,6 Hussain Jafri,7 Yasmin Raashid,8 Colin A. Johnson,1 Alex F. Markham,1 Carmel Toomes,1 Aine Rice,1,2 Eamonn Sheridan,1 Chris F. Inglehearn,1 and Manir Ali1 PURPOSE. To investigate whether three consanguineous families CONCLUSIONS. The authors have identified two new loci, one on from the Punjab province of Pakistan, with affected members chromosome 10cen and the other on 2ptel or 20p, that are with recessively inherited congenital cataract microcornea associated with recessively inherited congenital cataract-micro- with corneal opacity, are genetically homogeneous. cornea with corneal opacity. This phenotype is genetically METHODS. An ophthalmic examination was performed on each heterogeneous in the Pakistani population. Further genetic family member to establish the diagnosis. The two largest studies of this kind, combined with a detailed phenotypic families were analyzed by homozygosity mapping using SNP description, will contribute to more precise classification cri- arrays. Linkage was confirmed using polymorphic microsatel- teria for anterior segment disease. (Invest Ophthalmol Vis Sci. lite markers, and logarithm of odds (LOD) scores were calcu- 2011;52:4294–4299) DOI:10.1167/iovs.10-6776 lated. Candidate genes were prioritized using the ENDEAVOUR program. ongenital cataracts are a major cause of childhood blind- Cness in the developing world.1,2 There are many causes, RESULTS. Autosomal recessive congenital cataract-microcornea and approximately one-third have a genetic basis. Most of the with corneal opacity mapped to chromosome 10cen for family inherited forms that have been described are inherited in an MEP57 and to either chromosomes 2ptel or 20p for family autosomal dominant manner, though autosomal recessive and MEP60. For MEP57, the refined interval was 36.8 Mb flanked by X-linked cases have also been reported.3 To date, 39 genetic D10S1208 (35.3 Mb) and D10S676 (72.1 Mb). For MEP60, the loci have been mapped and 26 genes have been identified.4 interval containing the mutation was either 6.7 Mb from the The severity and morphology of congenital cataracts can vary telomere of chromosome 2 to marker D2S281 or 3.8 Mb between families even with the same mutation, reflecting dif- flanked by D20S906 (1.5 Mb) and D20S835 (5.3 Mb). Maximum ferences due to genetic background and environmental factors. multipoint LOD scores of 3.09, 1.94, and 3.09 were calculated Cataracts can exist in isolation, alongside other ocular anoma- at D10S567, D2S281, and D20S473 for families MEP57 and lies, or as part of a syndrome with systemic features. Microcor- MEP60. Linkage to these loci was excluded for family MEP68. nea is one of the ocular abnormalities that can occur with SLC4A11 was excluded as a candidate gene for the observed congenital cataract, highlighting the close interrelationship be- phenotype in MEP60. tween the lens and the cornea during development.5 Corneal opacification is also another feature that can sometimes accom- pany this developmental abnormality.6 Genetic heterogeneity From the 1Leeds Institute of Molecular Medicine, Leeds, United of the microcornea-cataract phenotype with dominant inheri- 2 tance (CCMS; Mendelian Inheritance in Man [MIM] #116150) Kingdom; Eye Department, St. James’s University Hospital, Leeds, 7 United Kingdom; 4Peninsula Medical School, Plymouth, United King- has already been documented. However, this combination of dom; 5St Thomas’ Hospital, London, United Kingdom; the Departments phenotype with corneal opacity and recessive inheritance has of 6Ophthalmology and 7Obstetrics and Gynaecology, King Edward not been reported before. Reports on cataracts have tended to Medical University, Lahore, Pakistan; and 8Gene Technology Labora- overlook corneal diameters and have instead focused on the tory 146/1, Lahore, Pakistan. sight-threatening cataract. For recessively inherited nonsyn- 3 These authors contributed equally to the work presented here dromic congenital cataracts, mutations in seven genes have and should therefore be regarded as equivalent authors. been implicated, and five other loci have been mapped. These Supported by the Wellcome Trust Grant 090224, Yorkshire Eye ϩ 8 ϩ 9,10 Research Grant 022, and The Sir Jules Thorn Charitable Trust Grant are CRYAA (MIM 123580), CRYBB1 (MIM 600929), CRYBB3 (MIM *123630),11 HSF4 (MIM *602438),12,13 GJA8 09/JTA. 14 15 Submitted for publication October 24, 2010; revised January 19, (MIM ϩ600897), GCNT2 (MIM *600429) and LIM2 (MIM 16 17 2011; accepted January 21, 2011. ϩ154045) together with loci at 1p34 (MIM %612968), Disclosure: K. Khan, None; A. Al-Maskari, None; M. McKibbin, 3p22 (MIM %610019),18 7q,19 9q13 (MIM %605749)20 and None; I.M. Carr, None; A. Booth, None; M. Mohamed, None; S. 19q13 (MIM %609376).21 Siddiqui, None; J.A. Poulter, None; D.A. Parry, None; C.V. Logan, Congenital corneal opacifications can either be primary, None; A. Hashmi, None; T. Sahi, None; H. Jafri, None; Y. Raashid, affecting the cornea alone, or they can be secondary, associ- None; C.A. Johnson, None; A.F. Markham, None; C. Toomes, None; ated with anterior segment abnormalities.6 Secondary corneal A. Rice, None; E. Sheridan, None; C.F. Inglehearn, None; M. Ali, None opacities without nonocular manifestations are often diag- Corresponding author: Manir Ali, Leeds Institute of Molecular nosed as Peters’ anomaly and represent kerato-irido-lenticular Medicine, Section of Ophthalmology and Neuroscience, Wellcome dysgenesis as well as developmental anomalies of the iridotra- Trust Brenner Building, St. James’s University Hospital, Leeds LS9 7TF, becular system. Some of these cases can be caused by mechan- UK; [email protected]. ical damage or infectious agents, whereas others have a genetic Investigative Ophthalmology & Visual Science, June 2011, Vol. 52, No. 7 4294 Copyright 2011 The Association for Research in Vision and Ophthalmology, Inc. Downloaded from iovs.arvojournals.org on 09/25/2021 Downloaded fromiovs.arvojournals.org on09/25/2021 glaucoma, CYP1B1 genetic basis of Peters’ anomaly include recessive mutations in aphakia and totalocular sclerocornea. phenotype, withthat patients recessive having primary congenital abnormalities. These patients fit broadlyance. into The a patients diagnosis of did CCMCO.possible, not A it have any showed systemic cataractzontal problems of or corneal the neurologic lens diametersgested and of that a these normal fundus changespresent appear- were from not birth progressive. or(Fig. They very 1, also Table early had 1). inguineous hori- All pedigrees life, with affected and a members family each history hadtenets of family variable of poor history the vision corneal were Declaration opacities sug- examined tee. of Helsinki. Participants Three gave multigenerational theirMedical consan- informed Foundation consent, in in Lahore accordance andThe with the study the Leeds was Research Ethics performed Commit- usingPatients a process approved by the Pakistan P who have corneal*601094) opacity have associated been described with inbasis. cataract. patients with Peters’ For anomaly example, dominant mutations in F IOVS, existence of yet furtherimplicating loci. two novel lociCCMCO. for These this are conditioncornea shown and with proving to corneal the a be opacity, general genetically diagnosis which of heterogeneous, nonsyndromic wePunjab congenital province cataract have micro- of abbreviated Pakistan who to have affected members with clinical descriptions are presentedmus in is Table 1. likelyGiven that to 2316 has beopacity exotropia secondary appears and to 2318 to16 shows be the esotropia, years) due the underlying to and strabis- the abnormality. 2318 sclera (aged The encroaching 8 on years) the from cornea. MEP60. Note that corneal *607108), known to be a cause of aniridia. IGURE ATIENTS AND Here we present three consanguineous families from the June 2011, Vol. 52, No. 7 1. (MIM *601771), known to cause primary congenital 26,27 Anterior segment images of affected members 2316 (aged FOXE3 and dominant mutations in M ETHODS gene mutations give rise to a severe Ͻ 11 mm. Where a clinical view was 24,25 Other examples of the 28,29 FOXE3 PAX6 22,23 (MIM (MIM Note Genetic Heterogeneity for Recessive CCMCO 4295 TABLE 1. Clinical Features of the Affected Patients Examined from the Three Consanguineous Families Cornea Globe Iris Lens Function Microcornea OD; OS Iridocorneal Iris Iridolenticular Iris Keratolenticular Family Member (mm) Vascularization Opacity Microphthalmia Adhesion Coloboma Adhesions Hypoplasia Touch Cataract Nystagmus Vision MEP57 2298 ϩϪc Ͼ p ϩ p ϪϪ Ϫ Ϫ ? ϩ PL 2299 ϩϪc Ͼ p ϩ p ϪϪ Ϫ Ϫ ? ϩ PL 2301 ϩϪc Ͼ p ϩ p ϪϪ Ϫ Ϫ ? ϩ PL 2303 ϩϪc Ͼ p ϩ p ϪϪ Ϫ Ϫ ? ϩ PL MEP60 2316 7; 7 Ϫ p Ͼ c Ϫ p ϪϪ Ϫ ϪϩϪCF 2318 7; 8 Ϫ p Ͼ c Ϫ p ϪϪ Ϫ ϪϩϪCF 2319 ϩϩp Ͼ c Ϫ p ϪϪ Ϫ ϪϩϪCF MEP68 2362 ϩϩp only ϪϪϩϪϪϪϩϩCF 2363 ϩϩp only ϪϪϪϪϪϪϩϩCF All patients had normal results on fundus examination except those from MEP57, in whom dense corneal opacity precluded retinal viewing. ϩ, present; Ϫ, absent; ?, no clinical view due to anterior opacity; c, central; p, peripheral; CF, counting fingers; PL, perception of light. 4296 Khan et al. IOVS, June 2011, Vol. 52, No. 7 blood sample was taken from both affected and unaffected family rior chambers were of near