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Homozygosity Mapping in Patients with Cone–Rod Dystrophy: Novel Mutations and Clinical Characterizations

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Homozygosity Mapping in Patients with Cone–Rod Dystrophy: Novel Mutations and Clinical Characterizations Retina Homozygosity Mapping in Patients with Cone–Rod Dystrophy: Novel Mutations and Clinical Characterizations Karin W. Littink,1,2,3 Robert K. Koenekoop,3,4 L. Ingeborgh van den Born,1 Rob W. J. Collin,2,5,6 Luminita Moruz,2,7 Joris A. Veltman,2,8 Susanne Roosing,2 Marijke N. Zonneveld,1,2 Amer Omar,4 Mahshad Darvish,4 Irma Lopez,4 Hester Y. Kroes,9 Maria M. van Genderen,10 Carel B. Hoyng,6 Klaus Rohrschneider,11 Mary J. van Schooneveld,12,13 Frans P. M. Cremers,2,5 and Anneke I. den Hollander2,5,6,8 PURPOSE. To determine the genetic defect and to describe the located within a homozygous region were screened for muta- clinical characteristics in a cohort of mainly nonconsanguine- tions. Patients in whom a mutation was detected underwent ous cone–rod dystrophy (CRD) patients. further ophthalmic examination. METHODS. One hundred thirty-nine patients with diagnosed RESULTS. Homozygous sequence variants were identified in CRD were recruited. Ninety of them were screened for known eight CRD families, six of which were nonconsanguineous. mutations in ABCA4, and those carrying one or two mutations The variants were detected in the following six genes: ABCA4, were excluded from further research. Genome-wide homozy- CABP4, CERKL, EYS, KCNV2, and PROM1. Patients carrying gosity mapping was performed in the remaining 108. Known mutations in ABCA4, CERKL, and PROM1 had typical CRD genes associated with autosomal recessive retinal dystrophies symptoms, but a variety of retinal appearances on funduscopy, optical coherence tomography, and autofluorescence imaging. CONCLUSIONS. Homozygosity mapping led to the identification From the 1The Rotterdam Eye Hospital, Rotterdam, The Nether- of new mutations in consanguineous and nonconsanguineous lands; the Departments of 2Human Genetics and 6Ophthalmology, the patients with retinal dystrophy. Detailed clinical characteriza- 5Nijmegen Centre for Molecular Life Sciences, and the 8Institute for tion revealed a variety of retinal appearances, ranging from Genetic and Metabolic Disease, Radboud University Nijmegen Medical nearly normal to extensive retinal remodeling, retinal thinning, Centre, Nijmegen, The Netherlands; the 4McGill Ocular Genetics Lab- and debris accumulation. Although CRD was initially diagnosed oratory, Montreal Children’s Hospital Research Institute, McGill Uni- in all patients, the molecular findings led to a reappraisal of the versity Health Centre, Montreal, Quebec, Canada; the 7Center for diagnosis in patients carrying mutations in EYS, CABP4, and Biomembrane Research, Department of Biochemistry and Biophysics, 9 KCNV2.(Invest Ophthalmol Vis Sci. 2010;51:5943–5951) DOI: Stockholm University, Stockholm, Sweden; the Department of Medi- 10.1167/iovs.10-5797 cal Genetics, University Medical Centre Utrecht, Utrecht, The Nether- lands; the 10Bartime´us Institute for the Visually Impaired, Zeist, The Netherlands; the 11Department of Ophthalmology, University of Hei- one–rod dystrophies (CRDs) belong to a heterogeneous 12 delberg, Heidelberg, Germany; the Netherlands Institute of Neuro- group of inherited retinal dystrophies, characterized by 13 C science, Amsterdam, The Netherlands; and the Department of Oph- the primary dysfunction or loss of cone photoreceptors fol- thalmology, Academic Medical Centre, Amsterdam, The Netherlands. 3These authors contributed equally to the work reported here and lowed by the dysfunction or loss of rod photoreceptors. The therefore should be regarded as equivalent authors. diagnosis is established by documenting decreased visual acu- Supported by the Stichting Wetenschappelijk Onderzoek Oog- ity—usually noticed during childhood—dyschromatopsia, ziekenhuis, the Prof. Dr. H. J. Flieringa Foundation, The Rotterdam Eye central scotomas on visual field testing, and an electroretino- Hospital Grant 2005-13 (LIvdB, AIdH, FPMC), Netherlands Organiza- gram (ERG) that shows more severely reduced cone than rod tion for Scientific Research Grant 916.56.160 (AIdH), Foundation Fight- responses.1 The clinical course involves progressive loss of ing Blindness USA Grant BR-GE-0507-0381-RAD (AIdH), the Landelijke central vision, followed by peripheral visual field loss and Stichting voor Blinden en Slechtzienden (FPMC), Algemene Neder- progressive nyctalopia as more rod photoreceptors become landse Vereniging ter Voorkoming van Blindheid (FPMC), Canadian involved in the disease process and eventually may lead to Institutes of Health Research (RKK), Foundation Fighting Blindness Canada (RKK), Fonds de la Recherche en Sante´ Quebec (RKK), Na- complete blindness. CRD often presents as an isolated disease, but can be part of a syndrome as well, as in Bardet-Biedl or Jalili tional Institutes of Health (RKK), and Re´seau de Vision (RKK). 2,3 Submitted for publication April 28, 2010; revised June 7, 2010; syndrome. Isolated CRD can be inherited as an autosomal accepted June 7, 2010. recessive, autosomal dominant, or X-linked trait and is geneti- Disclosure: K.W. Littink, None; R.K. Koenekoop, None; L.I. cally heterogeneous. Currently, autosomal recessive (ar)CRD is van den Born, None; R.W.J. Collin, None; L. Moruz, None; J.A. associated with mutations in five genes, of which ABCA4 is the Veltman, None; S. Roosing, None; M.N. Zonneveld, None; A. major contributing gene (40%).4–7 The other four genes Omar, None; M. Darvish, None; I. Lopez, None; H.Y. Kroes, None; (ADAM9, CERKL, PROM1, and RPGRIP1) together account for M.M. van Genderen, None; C.B. Hoyng, None; K. Rohrschneider, only a few cases (1%–2% each).8–11 None; M.J. van Schooneveld, None; F.P.M. Cremers, None; A.I. den Hollander, None Autosomal recessive disorders such as CRD can be caused Corresponding author: Anneke I. den Hollander, Radboud Univer- by homozygous or compound heterozygous mutations. Ho- sity Nijmegen Medical Centre, Department of Human Genetics, Route mozygous mutations are most frequently detected in patients 855, PO Box 9101, 6500 HB Nijmegen, The Netherlands, 6500 HD; of consanguineous parents or in patients from relatively iso- [email protected]. lated populations, where the chance that the parents have a Investigative Ophthalmology & Visual Science, November 2010, Vol. 51, No. 11 Copyright © Association for Research in Vision and Ophthalmology 5943 Downloaded from iovs.arvojournals.org on 07/06/2021 5944 Littink et al. IOVS, November 2010, Vol. 51, No. 11 common ancestor is relatively high. However, homozygous Regions of homozygosity were determined by PLINK software,27 with mutations are also detected in patients of nonconsanguineous a sliding window of 50 SNPs and allowing 2 heterozygous SNPs (mis- unions, and on the basis of several genetic studies in large calls) and 10 missing SNPs (no calls) per window. Because the 250K cohorts of patients with autosomal recessive diseases from and 6.0 arrays contain different SNP densities, we defined regions to be Western European countries, it is estimated that ϳ35% carry homozygous when they contained 200 or more consecutive homozy- the mutations homozygously.12–16 A homozygous mutation is gous SNPs on the 250K array and 600 or more consecutive homozy- likely to reside within a homozygous region that is detectable gous SNPs on the 6.0 array. The minimum length of the regions with a high-resolution single nucleotide polymorphism (SNP) appeared to be ϳ3 Mb, on average. array.17,18 Mapping of these homozygous regions (homozygos- ity mapping) may lead to the identification of the genetic Analysis of Homozygous Regions defect in consanguineous and in nonconsanguineous patients, Homozygous regions were ranked based on the number of SNPs. SNP as shown as proof of principle in patients with autosomal 19 positions were derived from the UCSC human genome browser build recessive kidney diseases, and as a successful method for the hg18, March 2006 (http://genome.ucsc.edu provided in the public detection of new disease genes20–23 and new mutations in 24 domain by UCSC Genome Bioinformatics, University of California at known genes implicated in retinal dystrophies. Santa Cruz, Santa Cruz, CA). All arCRD and autosomal dominant (ad) The goal of this study was to identify and map homozygous CRD genes residing in a homozygous region were selected for muta- regions in a large cohort of CRD patients, mainly born of tion analysis. We also analyzed all autosomal recessive retinal dystro- nonconsanguineous marriages, and to subsequently identify phy genes (derived from RetNet: http://www.sph.uth.tmc.edu/Ret- the causal mutations. Using this approach, we identified eight Net; provided in the public domain by the University of Texas Houston genetic variants, of which seven were novel, in four families Health Science Center, Houston, TX) residing in the six largest ho- and four sporadic patients, respectively. All patients carrying mozygous regions of each patient or, in case of multiple affected disease-causing mutations were clinically re-evaluated. siblings, in the six largest homozygous regions shared by the siblings. Finally, we determined overlap of the detected homozygous regions METHODS with known, published retinal dystrophy loci (RetNet). Subjects Sequence Analysis A total of 126 probands and 13 affected siblings with known or We selected a total of 15 retinal dystrophy genes for mutation analysis. suspected arCRD or isolated CRD were included in this study by Six genes known to be associated with arCRD and adCRD were ana- ophthalmologists from The Netherlands (LIvdB, MMvG, CBH, MJvS), lyzed (arCRD genes: ABCA4, two patients; ADAM9, three patients; and Germany (KR),
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