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The utility of massively parallel sequencing for posterior polymorphous corneal dystrophy type 3 molecular diagnosis

L. Dudakova, CJ. Evans, N. Pontikos, NJ. Hafford-Tear, F. Malinka, P. Skalicka, A. Horinek, FL. Munier, N. Voide, P. Studeny, L. Vanikova, T. Kubena, KE. Rojas Lopez, AE. Davidson, AJ. Hardcastle, SJ. Tuft, P. Liskova,

. 2019 ; 182 (-) : 160-166. [pub] 20190307

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc20006540

The aim of this study was to identify the molecular genetic cause of disease in posterior polymorphous corneal dystrophy (PPCD) probands of diverse origin and to assess the utility of massively parallel sequencing in the detection of ZEB1 mutations. We investigated a total of 12 families (five British, four Czech, one Slovak and two Swiss). Ten novel and two recurrent disease-causing mutations in ZEB1, were identified in probands by Sanger (n = 5), exome (n = 4) and genome (n = 3) sequencing. Sanger sequencing was used to confirm the mutations detected by massively parallel sequencing, and to perform segregation analysis. Genome sequencing revealed that one proband harboured a novel ∼0.34 Mb heterozygous de novo deletion spanning exons 1-7 and part of exon 8. Transcript analysis confirmed that the ZEB1 transcript is detectable in blood-derived RNA samples and that the disease-associated variant c.482-2A>G leads to aberrant pre-mRNA splicing. De novo mutations, which are a feature of PPCD3, were found in the current study with an incidence rate of at least 16.6%. In general, massively parallel sequencing is a time-efficient way to detect PPCD3-associated mutations and, importantly, genome sequencing enables the identification of full or partial heterozygous ZEB1 deletions that can evade detection by both Sanger and exome sequencing. These findings contribute to our understanding of PPCD3, for which currently, 49 pathogenic variants have been identified, all of which are predicted to be null alleles.

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$a The utility of massively parallel sequencing for posterior polymorphous corneal dystrophy type 3 molecular diagnosis / $c L. Dudakova, CJ. Evans, N. Pontikos, NJ. Hafford-Tear, F. Malinka, P. Skalicka, A. Horinek, FL. Munier, N. Voide, P. Studeny, L. Vanikova, T. Kubena, KE. Rojas Lopez, AE. Davidson, AJ. Hardcastle, SJ. Tuft, P. Liskova,
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$a The aim of this study was to identify the molecular genetic cause of disease in posterior polymorphous corneal dystrophy (PPCD) probands of diverse origin and to assess the utility of massively parallel sequencing in the detection of ZEB1 mutations. We investigated a total of 12 families (five British, four Czech, one Slovak and two Swiss). Ten novel and two recurrent disease-causing mutations in ZEB1, were identified in probands by Sanger (n = 5), exome (n = 4) and genome (n = 3) sequencing. Sanger sequencing was used to confirm the mutations detected by massively parallel sequencing, and to perform segregation analysis. Genome sequencing revealed that one proband harboured a novel ∼0.34 Mb heterozygous de novo deletion spanning exons 1-7 and part of exon 8. Transcript analysis confirmed that the ZEB1 transcript is detectable in blood-derived RNA samples and that the disease-associated variant c.482-2A>G leads to aberrant pre-mRNA splicing. De novo mutations, which are a feature of PPCD3, were found in the current study with an incidence rate of at least 16.6%. In general, massively parallel sequencing is a time-efficient way to detect PPCD3-associated mutations and, importantly, genome sequencing enables the identification of full or partial heterozygous ZEB1 deletions that can evade detection by both Sanger and exome sequencing. These findings contribute to our understanding of PPCD3, for which currently, 49 pathogenic variants have been identified, all of which are predicted to be null alleles.
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$a Evans, Cerys J $u UCL Institute of Ophthalmology, 11-43 Bath Street, EC1V 9EL, London, United Kingdom.
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$a Pontikos, Nikolas $u UCL Institute of Ophthalmology, 11-43 Bath Street, EC1V 9EL, London, United Kingdom.
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$a Skalicka, Pavlina $u Research Unit for Rare Diseases, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 128 08, Prague 2, Czech Republic; Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 128 08, Prague, Czech Republic.
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$a Horinek, Ales $u 3rd Department of Medicine - Department of Endocrinology and Metabolism, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 1, 128 08, Prague 2, Czech Republic; Institute of Biology and Human Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Albertov 4, 128 00, Prague, Czech Republic.
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$a Munier, Francis L $u Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Avenue de France 15, 1004, Lausanne, Switzerland.
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$a Voide, Nathalie $u Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Avenue de France 15, 1004, Lausanne, Switzerland.
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$a Studeny, Pavel $u Ophthalmology Department, Third Faculty of Medicine, Charles University and Teaching Hospital Kralovske Vinohrady, Srobarova 1150/50, 100 34, Prague, Czech Republic.
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$a Vanikova, Lucia $u Center for Eye Microsurgery, Gagarinova 7/B, 821 03, Bratislava, Slovakia.
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$a Kubena, Tomas $u Ophthalmology Clinic of Dr. Tomas Kubena, U Zimniho Stadionu 1759, 760 00, Zlin, Czech Republic.
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$a Rojas Lopez, Karla E $u UCL Institute of Ophthalmology, 11-43 Bath Street, EC1V 9EL, London, United Kingdom.
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$a Davidson, Alice E $u UCL Institute of Ophthalmology, 11-43 Bath Street, EC1V 9EL, London, United Kingdom.
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$a Hardcastle, Alison J $u UCL Institute of Ophthalmology, 11-43 Bath Street, EC1V 9EL, London, United Kingdom.
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$a Tuft, Stephen J $u Moorfields Eye Hospital, 162 City Road, EC1V 2PD, London, United Kingdom.
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$a Liskova, Petra $u Research Unit for Rare Diseases, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 128 08, Prague 2, Czech Republic; UCL Institute of Ophthalmology, 11-43 Bath Street, EC1V 9EL, London, United Kingdom; Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 128 08, Prague, Czech Republic. Electronic address: petra.liskova@lf1.cuni.cz.
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