Increasing the Genetic Diagnosis Yield in Inherited Retinal Dystrophies: Assigning Pathogenicity to Novel Non-canonical Splice Site Variants
Por:
Toulis V, Cortés-González V, Castro-Miró M, Sallum JF, Català-Mora J, Villanueva-Mendoza C, Ciccioli M, Gonzalez R, Valero R and Marfany G
Publicada:
1 abr 2020
Ahead of Print:
31 mar 2020
Resumen:
Aims: We aimed to validate the pathogenicity of genetic variants identified in inherited retinal dystrophy (IRD) patients, which were located in non-canonical splice sites (NCSS). Methods: After next generation sequencing (NGS) analysis (target gene panels or whole exome sequencing (WES)), NCSS variants were prioritized according to in silico predictions. In vivo and in vitro functional tests were used to validate their pathogenicity. Results: Four novel NCSS variants have been identified. They are located in intron 33 and 34 of ABCA4 (c.4774-9G>A and c.4849-8C>G, respectively), intron 2 of POC1B (c.101-3T>G) and intron 3 of RP2 (c.884-14G>A). Functional analysis detected different aberrant splicing events, including intron retention, exon skipping and intronic nucleotide addition, whose molecular effect was either the disruption or the elongation of the open reading frame of the corresponding gene. Conclusions: Our data increase the genetic diagnostic yield of IRD patients and expand the landscape of pathogenic variants, which will have an impact on the genotype-phenotype correlations and allow patients to opt for the emerging gene and cell therapies.
Filiaciones:
Toulis V:
DBGen Ocular Genomics, 08011 Barcelona, Spain
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 643, 08028 Barcelona, Spain
Cortés-González V:
DBGen Ocular Genomics, 08011 Barcelona, Spain
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 643, 08028 Barcelona, Spain
Departamento de Genética, Asociación para Evitar la Ceguera en México, Ciudad de México 04030, Mexico
Castro-Miró M:
DBGen Ocular Genomics, 08011 Barcelona, Spain
Sallum JF:
Instituto de Genética Ocular and Ophthalmology Department Federal University of São Paulo (UNIFESP), São Paulo 04552-050, Brazil
Català-Mora J:
Hospital Sant Joan de Deu, Esplugues de Llobregat, 08950 Barcelona, Spain
Villanueva-Mendoza C:
Departamento de Genética, Asociación para Evitar la Ceguera en México, Ciudad de México 04030, Mexico
Ciccioli M:
Stargardt APNES-Retina, Buenos Aires, Argentina
Gonzalez R:
DBGen Ocular Genomics, 08011 Barcelona, Spain
Valero R:
DBGen Ocular Genomics, 08011 Barcelona, Spain
Marfany G:
DBGen Ocular Genomics, 08011 Barcelona, Spain
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 643, 08028 Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona 08028, Spain
IBUB-IRSJD, Barcelona 08028, Spain
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