Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects

Tatour, Yasmin; Ben-Yosef, Tamar

doi:10.3390/diagnostics10100779

Cited by 60 publications

(49 citation statements)

References 79 publications

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“…Mutations in disease genes may affect the retina in isolation, or may have more systemic effects. For example, there are 80 systemic conditions with a retinal phenotype and 200 genes that not only affect retinal health but also the central nervous system, kidneys or heart [ 20 ]. Such complexity makes it near-impossible for a diagnosis to be achieved in most instances solely on the basis of disease phenotype [ 2 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Dockery

Whelan

Humphries

et al. 2021

IJMS

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Inherited retinal diseases (IRDs) represent a collection of phenotypically and genetically diverse conditions. IRDs phenotype(s) can be isolated to the eye or can involve multiple tissues. These conditions are associated with diverse forms of inheritance, and variants within the same gene often can be associated with multiple distinct phenotypes. Such aspects of the IRDs highlight the difficulty met when establishing a genetic diagnosis in patients. Here we provide an overview of cutting-edge next-generation sequencing techniques and strategies currently in use to maximise the effectivity of IRD gene screening. These techniques have helped researchers globally to find elusive causes of IRDs, including copy number variants, structural variants, new IRD genes and deep intronic variants, among others. Resolving a genetic diagnosis with thorough testing enables a more accurate diagnosis and more informed prognosis and should also provide information on inheritance patterns which may be of particular interest to patients of a child-bearing age. Given that IRDs are heritable conditions, genetic counselling may be offered to help inform family planning, carrier testing and prenatal screening. Additionally, a verified genetic diagnosis may enable access to appropriate clinical trials or approved medications that may be available for the condition.

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Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Dockery

Whelan

Humphries

et al. 2021

IJMS

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“…Cilia, as a complex structure, comprises more than 900 genes that are involved in ciliary structure and function 41 , and those genes are called ciliary genes. Because TTLL11 is a ciliary gene, and ciliary genes, such as POC5, were already related to retinal function 42 – 45 , the ciliary retinal tissue was then investigated. Zebrafish ttll11 has been reported to be expressed within the CNS and neural tube 38 .…”

Section: Resultsmentioning

confidence: 99%

Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family

Mathieu

Patten

Aragon-Martin

et al. 2021

Sci Rep

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Idiopathic scoliosis (IS) is a complex 3D deformation of the spine with a strong genetic component, most commonly found in adolescent girls. Adolescent idiopathic scoliosis (AIS) affects around 3% of the general population. In a 5-generation UK family, linkage analysis identified the locus 9q31.2-q34.2 as a candidate region for AIS; however, the causative gene remained unidentified. Here, using exome sequencing we identified a rare insertion c.1569_1570insTT in the tubulin tyrosine ligase like gene, member 11 (TTLL11) within that locus, as the IS causative gene in this British family. Two other TTLL11 mutations were also identified in two additional AIS cases in the same cohort. Analyses of primary cells of individuals carrying the c.1569_1570insTT (NM_194252) mutation reveal a defect at the primary cilia level, which is less present, smaller and less polyglutamylated compared to control. Further, in a zebrafish, the knock down of ttll11, and the mutated ttll11 confirmed its role in spine development and ciliary function in the fish retina. These findings provide evidence that mutations in TTLL11, a ciliary gene, contribute to the pathogenesis of IS.

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“…SRDs are a highly heterogeneous group of ocular diseases characterized by a challenging molecular characterization and clinical management (Shaheen et al 2016 ; Tatour and Ben-Yosef 2020 ). In the literature, it is rather frequent to find studies focused on specific syndromes (Knopp et al 2015 ; Vilboux et al 2017 ) or single panel-based studies (Shaheen et al 2016 ; Jiman et al 2020 ), which provide a biased landscape of SRDs.…”

Section: Discussionmentioning

confidence: 99%

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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Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects

Cited by 60 publications

References 79 publications

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family

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

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