The combination of whole‐exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies

Diab, Alaa Abu; AlTalbishi, Alaa; Rosin, Boris; Kanaan, Moien; Kamal, Lara; Swaroop, Anand; Chowers, Itay; Banin, Eyal; Sharon, Dror; Khateb, Samer

doi:10.1111/aos.14095

Cited by 17 publications

(15 citation statements)

References 61 publications

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“…WES has been established as the best approach for the study of SRD cases, as it improves molecular diagnosis and understanding due to its efficacy in identifying new variants, phenotype-genotype correlations, and causative genes (Vilboux et al 2017 ; Gupta et al 2017 ; Boczek et al 2018 ; Abu Diab et al 2019 ; Jaffal et al 2019 ; Cogné et al 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Next-generation sequencing (NGS) technologies are currently the gold-standard approach for cost-effective genetic analysis in extremely complex syndromic forms (Wright et al 2015 ). Their previous application into SRD cases has been proven to improve the diagnostic yield when compared to other traditional, time-consuming genotyping methods (Sanchez-Navarro et al 2018 ; Abu Diab et al 2019 ). Moreover, whole-exome sequencing (WES) and whole-genome sequencing (WGS) allow further reanalysis and revisions of previously-investigated cases using updated virtual panels, reanalysis with new bioinformatic tools (Wright et al 2018b ) and strategies using ontologies, which are useful for conducting targeted studies (Köhler et al 2009 ).…”

Section: Introductionmentioning

confidence: 99%

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NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases

et al. 2021

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Syndromic retinal diseases (SRDs) are a group of complex inherited systemic disorders, with challenging molecular underpinnings and clinical management. Our main goal is to improve clinical and molecular SRDs diagnosis, by applying a structured phenotypic ontology and next-generation sequencing (NGS)-based pipelines. A prospective and retrospective cohort study was performed on 100 probands with an a priori diagnosis of non-Usher SRDs, using available clinical data, including Human Phenotype Ontology annotation, and further classification into seven clinical categories (ciliopathies, specific syndromes and five others). Retrospective molecular diagnosis was assessed using different molecular and bioinformatic methods depending on availability. Subsequently, uncharacterized probands were prospectively screened using other NGS approaches to extend the number of analyzed genes. After phenotypic classification, ciliopathies were the most common SRD (35%). A global characterization rate of 52% was obtained, with six cases incompletely characterized for a gene that partially explained the phenotype. An improved characterization rate was achieved addressing prospective cases (83%) and well-recognizable syndrome (62%) subgroups. The 27% of the fully characterized cases were reclassified into a different clinical category after identification of the disease-causing gene. Clinical-exome sequencing is the most appropriate first-tier approach for prospective cases, whereas whole-exome sequencing and bioinformatic reanalysis increases the diagnosis of uncharacterized retrospective cases to 45%, mostly those with unspecific symptoms. Our study describes a comprehensive approach to SRDs in daily clinical practice and the importance of thorough clinical assessment and selection of the most appropriate molecular test to be used to solve these complex cases and elucidate novel associations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases

et al. 2021

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“…Because the early symptoms are atypical, it is di cult to make an early diagnosis among infants with CS [36]. With the popularity of WES, the accuracy of clinical diagnosis has been greatly improved.…”

Section: Discussionmentioning

confidence: 99%

“…Obviously, WES is worthwhile for early diagnosis of di cult neonatal cases and it is helpful for genetic counseling [36][37][38][39]. In recent years, the value of copy number variation analysis based on WES in phenotypic diversity of related genetic diseases has been reported [40].…”

Section: Discussionmentioning

confidence: 99%

Co-existence of Cohen Syndrome and Pendred Syndrome? Diagnostic Challenges Associated With Presence of Multiple Genomic Variants in the Newborn: A Case Report

Sun

et al. 2020

Preprint

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BackgroundCohen syndrome is a multisystem autosomal recessive hereditary disease, which is caused by variants of the VPS13B gene. The clinical manifestations include characteristic facial features, microcephaly, trunk obesity and mental retardation. The SLC26A4 gene encodes an anion transporter called Pendrin, the variants of SLC26A4 lead to deafness, Pendred syndrome and enlarged vestibular aqueduct. We presence a case of multiple genetic homozygous variants of SLC26A4 and VPS13B.Case presentationIn this study, we described a case of a 65-day-old female infant presenting with hearing loss and poor feeding. The deafness gene screening before admission showed that the patient carried homozygous c.919-2A>G variation of SLC26A4 gene. The symptoms of the patient did not improve significantly after a period of targeted treatment, then the possibility of genetic diseases was considered after consultation with the different departments. Whole exome sequencing was performed, and homozygous splicing variants in intron 38 (c.6940+1G>T) of VPS13B and that in intron 7 (c.919-2A>G) of SLC26A4 were identified. Later, the parent was proved as the carriers of VPS13B and SLC26A4 heterozygous variations by Sanger sequencing.ConclusionsPresence of multiple genetic homozygous variants of SLC26A4 and VPS13B, it is difficult to make an early diagnosis due to early atypical symptoms. Final diagnosis depends on whole exome sequencing which plays an important role in early diagnosis of intractable neonatal cases.

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“…Mutations in greater than 300 genes and mapped loci are now known to be associated with specific retinal disorders (RetNet; https: //sph.uth.edu/retnet/) [2]. Whole exome and next generation sequencing studies are currently on the rise to identify additional IRD-associated genes across different populations [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Technologies and Strategies for the Management of Retinoblastoma

Gudiseva

Berry

Tummina

et al. 2019

Genes

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Retinoblastoma (RB) is an inherited retinal disorder (IRD) caused by the mutation in the RB1 gene or, rarely, by alterations in the MYCN gene. In recent years, new treatment advances have increased ocular and visual preservation in the developed world. The management of RB has improved significantly in recent decades, from the use of external beam radiation to recently, more localized treatments. Determining the underlying genetic cause of RB is critical for timely management decisions. The advent of next-generation sequencing technologies have assisted in understanding the molecular pathology of RB. Liquid biopsy of the aqueous humor has also had significant potential implications for tumor management. Currently, patients' genotypic information, along with RB phenotypic presentation, are considered carefully when making treatment decisions aimed at globe preservation. Advances in molecular testing that improve our understanding of the molecular pathology of RB, together with multiple directed treatment options, are critical for developing precision medicine strategies to treat this disease. Author Contributions: Conceptualization, J.L.B., S.J.T. and J.M.O.; investigation, H.V.G., J.L.B., A.P.; Data curation H.V.G., J.L.B., A.P.; writing-original draft preparation H.V.G., J.L.B.; writing-review and editing A.P., J.L.B., S.J.T. and J.M.O.; Visualization J.L.B. and J.M.O.; supervision, J.M.O.; funding acquisition, J.L.B. and J.M.O.

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The combination of whole‐exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies

Abstract: Purpose: To identify the accurate clinical diagnosis of rare syndromic inherited retinal diseases (IRDs) based on the combination of clinical and genetic analyses.

Cited by 17 publications

References 61 publications

NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases

NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases

Co-existence of Cohen Syndrome and Pendred Syndrome? Diagnostic Challenges Associated With Presence of Multiple Genomic Variants in the Newborn: A Case Report

Next-Generation Technologies and Strategies for the Management of Retinoblastoma

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