Book ChapterDOI
Scaling New Heights in the Genetic Diagnosis of Inherited Retinal Dystrophies
Roser Gonzàlez-Duarte,Marta de Castro-Miró,Miquel Tuson,Valeria Ramírez-Castañeda,Rebeca Valero Gils,Gemma Marfany +5 more
TLDR
Reliable detection of genomic rearrangements and copy number variants (partial or complete), deep intronic mutations, variants that cause aberrant splicing events in retina-specific transcripts, functional assessment of hypomorphic missense alleles, mutations in regulatory sequences, the contribution of modifier genes to the IRD phenotype, and detection of low heteroplasmy mtDNA mutations are among the new challenges to be met.Abstract:
During the last 20 years, our group has focused on identifying the genes and mutations causative of inherited retinal dystrophies (IRDs). By applying massive sequencing approaches (NGS) in more than 500 familial and sporadic cases, we attained high diagnostic efficiency (85%) with a custom target gene panel and over 75% using whole exome sequencing (WES). Close to 40% of pathogenic alleles are novel mutations, which demand specific in silico tests and in vitro assays. Notably, missense variants are by far the most common type of mutation identified (around 40%), with small in-frame indels being less frequent (2%). To fill the gap of unsolved cases, when no candidate gene or only a single pathogenic allele has been identified, additional scientific and technical issues remain to be addressed. Reliable detection of genomic rearrangements and copy number variants (partial or complete), deep intronic mutations, variants that cause aberrant splicing events in retina-specific transcripts, functional assessment of hypomorphic missense alleles, mutations in regulatory sequences, the contribution of modifier genes to the IRD phenotype, and detection of low heteroplasmy mtDNA mutations are among the new challenges to be met.read more
Citations
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Journal ArticleDOI
New Omics-Derived Perspectives on Retinal Dystrophies: Could Ion Channels-Encoding or Related Genes Act as Modifier of Pathological Phenotype?
Luigi Donato,Concetta Scimone,Simona Alibrandi,Ebtesam M. Abdalla,Karim Mahmoud Nabil,Rosalia D'Angelo,Antonina Sidoti +6 more
TL;DR: In this paper, the probands of seven Italian and Egyptian families affected by not completely defined forms of inherited retinal dystrophies were investigated by whole exome sequencing (WES) experiments, and found interesting variants in already known causative genes probably able to impair retinal functionalities.
Journal ArticleDOI
Next-Generation Sequencing Applications for Inherited Retinal Diseases.
TL;DR: In this article, the authors provide an overview of cutting-edge next-generation sequencing techniques and strategies currently in use to maximise the effectivity of gene screening for hereditary retinal diseases.
Journal ArticleDOI
The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes.
Cristina Villanueva-Mendoza,Miquel Tuson,David Apam-Garduño,Marta de Castro-Miró,Raul Tonda,Jean Remi Trotta,Gemma Marfany,Rebeca Valero,Vianney Cortés-González,Roser Gonzàlez-Duarte +9 more
TL;DR: In this paper, a large cohort of patients affected with inherited retinal dystrophies (IRDs) from Mexico were analyzed by next-generation sequencing using target gene panels (overall including 346 genes and 65 intronic sequences).
Journal ArticleDOI
Impact of Next Generation Sequencing in Unraveling the Genetics of 1036 Spanish Families With Inherited Macular Dystrophies
Marta Del Pozo-Valero,Rosa Riveiro-Alvarez,Inmaculada Martin-Merida,Fiona Blanco-Kelly,Saoud Tahsin Swafiri,Isabel Lorda-Sanchez,María José Trujillo-Tiebas,Ester Carreño,Belen Jimenez-Rolando,Blanca Garcia-Sandoval,Marta Corton,Almudena Avila-Fernandez,Carmen Ayuso +12 more
TL;DR: The analysis of >200 genes associated with retinal dystrophies and the entire locus of ABCA4 increase the rate of characterization, even regardless of available clinical and familiar data.
Journal ArticleDOI
Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies
Malena Daich Varela,James Bellingham,Fabiana Louise Motta,Neringa Jurkute,Jamie M Ellingford,Mathieu Quinodoz,Kate Oprych,Michael Niblock,Lucas Janeschitz-Kriegl,Karolina Kamińska,Francesca Cancellieri,Hendrik P. N. Scholl,Eva Lenassi,Elena R. Schiff,Hannah Knight,Graeme C.M. Black,Carlo Rivolta,Michael E. Cheetham,Michel Michaelides,Omar A. Mahroo,Anthony T. Moore,Andrew R. Webster,Gavin Arno +22 more
TL;DR: MDT-led, phenotype driven, non-coding variant re-analysis of GS is effective in identifying missing causative alleles in inherited retinal dystrophy genes.
References
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Journal ArticleDOI
Mutations in the CEP290 (NPHP6) Gene Are a Frequent Cause of Leber Congenital Amaurosis
Anneke I. den Hollander,Robert K. Koenekoop,Suzanne Yzer,Irma Lopez,Maarten L. Arends,Krysta Voesenek,Marijke N. Zonneveld,Tim M. Strom,Thomas Meitinger,Han G. Brunner,Carel B. Hoyng,L. Ingeborgh van den Born,Klaus Rohrschneider,Frans P.M. Cremers +13 more
TL;DR: The CEP290 mutations represent one of the most frequent causes of LCA identified so far and are localized in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290).
Journal ArticleDOI
Molecular findings from 537 individuals with inherited retinal disease
Jamie M Ellingford,Jamie M Ellingford,Stephanie Barton,Sanjeev S. Bhaskar,James O'Sullivan,James O'Sullivan,Simon G. Williams,Janine A. Lamb,Binay Panda,Panagiotis I. Sergouniotis,Panagiotis I. Sergouniotis,Rachel L. Gillespie,Rachel L. Gillespie,Stephen P. Daiger,Georgina Hall,Theodora Gale,I. Christopher Lloyd,I. Christopher Lloyd,Paul N. Bishop,Paul N. Bishop,Simon C Ramsden,Graeme C.M. Black,Graeme C.M. Black +22 more
TL;DR: It is shown that clinically analysed variants indicated as rare in dbSNP and the Exome Variant Server remain rare in ExAC, and that genes discovered as a cause of IRD in the post-NGS era are rare causes ofIRD in a population of clinically surveyed individuals.
Journal ArticleDOI
ABCA4 midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease.
Riccardo Sangermano,Mubeen Khan,Mubeen Khan,Stéphanie S. Cornelis,Valerie Richelle,Silvia Albert,Alejandro Garanto,Duaa Elmelik,Raheel Qamar,Dorien Lugtenberg,L. Ingeborgh van den Born,Rob W.J. Collin,Frans P.M. Cremers +12 more
TL;DR: The strategy to generate large overlapping splice vectors carrying multiple exons, creating a toolbox for robust and high-throughput analysis of splice variants, can be applied to all human genes.
Journal ArticleDOI
A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa.
S. Amer Riazuddin,Muhammad Iqbal,Yue J. Wang,Tomohiro Masuda,Yuhng Chen,Sara J. Bowne,Lori S. Sullivan,Naushin Waseem,Shomi S. Bhattacharya,Stephen P. Daiger,Kang Zhang,Shaheen N. Khan,Sheikh Riazuddin,J. Fielding Hejtmancik,Paul A. Sieving,Donald J. Zack,Nicholas Katsanis,Nicholas Katsanis +17 more
TL;DR: It is shown that an in-frame splice mutation in BBS8, one of the genes involved in pleiotropic Bardet-Biedl syndrome, is sufficient to cause nonsyndromic retinitis pigmentosa (RP) and the role of this additional sequence might inform the mechanism of retinal degeneration in patients with syndromic BBS or other related ciliopathies.
Journal ArticleDOI
North Carolina Macular Dystrophy Is Caused by Dysregulation of the Retinal Transcription Factor PRDM13
Kent W. Small,Adam P. DeLuca,S. Scott Whitmore,Thomas Rosenberg,Rosemary Silva-Garcia,Nitin Udar,Bernard Puech,Charles A. Garcia,Thomas A. Rice,Gerald A. Fishman,Elise Héon,James C. Folk,Luan M. Streb,Christine M. Haas,Luke A Wiley,Todd E. Scheetz,John H. Fingert,Robert F. Mullins,Budd A. Tucker,Edwin M. Stone +19 more
TL;DR: Four of these strongly implicate the involvement of PRDM13 in macular development, whereas the pathophysiologic mechanism of the fifth remains unknown but may involve the developmental dysregulation of IRX1.
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