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Start Over Author "Zeinab Fadaie" Journal molecular genetics & genomic medicine
2 results on '"Zeinab Fadaie"'

1. The identification of a RNA splice variant in TULP1 in two siblings with early‐onset photoreceptor dystrophy

Author

Sanne K. Verbakel, Zeinab Fadaie, B. Jeroen Klevering, Maria M. van Genderen, Ilse Feenstra, Frans P. M. Cremers, Carel B. Hoyng, and Susanne Roosing

Subjects
early‐onset retinal dystrophy, intronic variant, TULP1, whole exome sequencing, Genetics, QH426-470
Abstract

Abstract Background Early‐onset photoreceptor dystrophies are a major cause of irreversible visual impairment in children and young adults. This clinically heterogeneous group of disorders can be caused by mutations in many genes. Nevertheless, to date, 30%–40% of cases remain genetically unexplained. In view of expanding therapeutic options, it is essential to obtain a molecular diagnosis in these patients as well. In this study, we aimed to identify the genetic cause in two siblings with genetically unexplained retinal disease. Methods Whole exome sequencing was performed to identify the causative variants in two siblings in whom a single pathogenic variant in TULP1 was found previously. Patients were clinically evaluated, including assessment of the medical history, slit‐lamp biomicroscopy, and ophthalmoscopy. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay. Results Clinical assessment showed a typical early‐onset photoreceptor dystrophy in both the patients. Whole exome sequencing identified two pathogenic variants in TULP1, a c.1445G>A (p.(Arg482Gln)) missense mutation and an intronic c.718+23G>A variant. Segregation analysis confirmed that both siblings were compound heterozygous for the TULP1 c.718+23G>A and c.1445G>A variants, while the unaffected parents were heterozygous. The midigene assay for the c.718+23G>A variant confirmed an elongation of exon 7 leading to a frameshift. Conclusion Here, we report the first near‐exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic TULP1 variant in two patients with an early‐onset photoreceptor dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases.

Published
2019
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2. The identification of a RNA splice variant in TULP1 in two siblings with early‐onset photoreceptor dystrophy

Author

B. Jeroen Klevering, Zeinab Fadaie, Susanne Roosing, Maria M. van Genderen, Ilse Feenstra, Carel B. Hoyng, Frans P.M. Cremers, and Sanne K Verbakel

Subjects
Male, 0301 basic medicine, 030105 genetics & heredity, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], whole exome sequencing, Retinal Rod Photoreceptor Cells, Exome, Genetics(clinical), Cone Dystrophy, Child, Frameshift Mutation, Genetics (clinical), Exome sequencing, Early onset, Genetics, intronic variant, Homozygote, early‐onset retinal dystrophy, Exons, Pedigree, Female, Original Article, early-onset retinal dystrophy, Identification (biology), Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], medicine.medical_specialty, Adolescent, lcsh:QH426-470, RNA Splicing, Biology, 03 medical and health sciences, Molecular genetics, Exome Sequencing, TULP1, Journal Article, medicine, Humans, Genomic medicine, Eye Proteins, Molecular Biology, Siblings, fungi, Alternative splicing, RNA, Dystrophy, Original Articles, lcsh:Genetics, 030104 developmental biology, Mutation, RNA Splice Sites
Abstract

Contains fulltext : 205532.pdf (Publisher’s version ) (Open Access) BACKGROUND: Early-onset photoreceptor dystrophies are a major cause of irreversible visual impairment in children and young adults. This clinically heterogeneous group of disorders can be caused by mutations in many genes. Nevertheless, to date, 30%-40% of cases remain genetically unexplained. In view of expanding therapeutic options, it is essential to obtain a molecular diagnosis in these patients as well. In this study, we aimed to identify the genetic cause in two siblings with genetically unexplained retinal disease. METHODS: Whole exome sequencing was performed to identify the causative variants in two siblings in whom a single pathogenic variant in TULP1 was found previously. Patients were clinically evaluated, including assessment of the medical history, slit-lamp biomicroscopy, and ophthalmoscopy. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay. RESULTS: Clinical assessment showed a typical early-onset photoreceptor dystrophy in both the patients. Whole exome sequencing identified two pathogenic variants in TULP1, a c.1445G>A (p.(Arg482Gln)) missense mutation and an intronic c.718+23G>A variant. Segregation analysis confirmed that both siblings were compound heterozygous for the TULP1 c.718+23G>A and c.1445G>A variants, while the unaffected parents were heterozygous. The midigene assay for the c.718+23G>A variant confirmed an elongation of exon 7 leading to a frameshift. CONCLUSION: Here, we report the first near-exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic TULP1 variant in two patients with an early-onset photoreceptor dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases.

Published
2019

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