Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

Lenassi, Eva; Clayton‐Smith, Jill; Douzgou, Sofia; Ramsden, Simon; Ingram, Stuart; Hall, Georgina; Hardcastle, Claire; Fletcher, Tracy; Taylor, Rachel L.; Ellingford, Jamie M; Newman, William; Fenerty, Cecilia; Sharma, Vinod; Lloyd, Iva; Biswas, Susmito; Ashworth, Jane; Black, Graeme C M; Sergouniotis, Panagiotis I.

doi:10.1038/s41436-019-0722-8

Cited by 47 publications

(48 citation statements)

References 38 publications

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“…For RED, a significant number of patients have an underlying genetic etiology. Effective and individualized approaches to clinical management are consequently dependent upon a comprehensive means of delivering genetic or genomic testing [ 8 ]. Genomic testing allows a precise diagnosis of highly heterogeneous disorders, improves counselling (e.g.…”

Section: Main Textmentioning

confidence: 99%

The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

Black

Sergouniotis

Sodi

et al. 2021

Orphanet J Rare Dis

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Background Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN–EYE) is to facilitate improvement in diagnosis of RED in European member states. Main body Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. Short conclusion Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED.

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Section: Main Textmentioning

confidence: 99%

The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

Black

Sergouniotis

Sodi

et al. 2021

Orphanet J Rare Dis

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“…The clinical exome (Oculome) does not search for CNVs nor have they yet been analyzed by the Genomics England analysis pipeline. Molecular diagnostic rates for albinism are highly variable, ranging from 56–91% in the literature [ 32 , 53 , 54 ]. Lasseaux et al (2018) reported a diagnostic yield of 72% from a large French study of 990 probands with albinism [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Lenassi et al solved 29 out of 32 (91%) preschool children with suspected albinism using a targeted panel of 18 ( n = 30) or 26 ( n = 1) or 40 ( n = 1) genes with confirmed mutations in TYR ( n = 18), OCA2 ( n = 7), TYRP1 ( n = 2), HPS5 ( n = 1), and GPR143 ( n = 1). The authors did not specify the reason for selecting different gene-specific panels and the patient demographic details (aside from age) were not presented [ 54 ]. The probands who underwent expanded gene panel testing harbored OCA2 and TYR variants.…”

Section: Discussionmentioning

confidence: 99%

Prospective Study of the Phenotypic and Mutational Spectrum of Ocular Albinism and Oculocutaneous Albinism

Chan

Schiff

Tailor

et al. 2021

Genes

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Albinism encompasses a group of hereditary disorders characterized by reduced or absent ocular pigment and variable skin and/or hair involvement, with syndromic forms such as Hermansky–Pudlak syndrome and Chédiak–Higashi syndrome. Autosomal recessive oculocutaneous albinism (OCA) is phenotypically and genetically heterogenous (associated with seven genes). X-linked ocular albinism (OA) is associated with only one gene, GPR143. We report the clinical and genetic outcomes of 44 patients, from 40 unrelated families of diverse ethnicities, with query albinism presenting to the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between November 2017 and October 2019. Thirty-six were children (≤ 16 years) with a median age of 31 months (range 2–186), and eight adults with a median age of 33 years (range 17–39); 52.3% (n = 23) were male. Genetic testing using whole genome sequencing (WGS, n = 9) or a targeted gene panel (n = 31) gave an overall diagnostic rate of 42.5% (44.4% (4/9) with WGS and 41.9% (13/31) with panel testing). Seventeen families had confirmed mutations in TYR (n = 9), OCA2, (n = 4), HPS1 (n = 1), HPS3 (n = 1), HPS6 (n = 1), and GPR143 (n = 1). Molecular diagnosis of albinism remains challenging due to factors such as missing heritability. Differential diagnoses must include SLC38A8-associated foveal hypoplasia and syndromic forms of albinism.

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“…These included gathering further phenotypic details from the family and initiating additional clinical work-up to further investigate the patient's phenotype. In a cohort of 201 preschoolers with inherited eye disorders, medical records were reviewed to identify that unnecessary diagnostic tests were avoided in 21% of patients, as a result of genetic or genomic testing 33 .…”

Section: The Fryback and Thornbury Model Applied To Evidence Collectimentioning

confidence: 99%

Clinical utility of genomic sequencing: a measurement toolkit

Hayeems

Dimmock²,

Bick

et al. 2020

npj Genom. Med.

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Whole-genome sequencing (WGS) is positioned to become one of the most robust strategies for achieving timely diagnosis of rare genomic diseases. Despite its favorable diagnostic performance compared to conventional testing strategies, routine use and reimbursement of WGS are hampered by inconsistencies in the definition and measurement of clinical utility. For example, what constitutes clinical utility for WGS varies by stakeholder’s perspective (physicians, patients, families, insurance companies, health-care organizations, and society), clinical context (prenatal, pediatric, critical care, adult medicine), and test purpose (diagnosis, screening, treatment selection). A rapidly evolving technology landscape and challenges associated with robust comparative study design in the context of rare disease further impede progress in this area of empiric research. To address this challenge, an expert working group of the Medical Genome Initiative was formed. Following a consensus-based process, we align with a broad definition of clinical utility and propose a conceptually-grounded and empirically-guided measurement toolkit focused on four domains of utility: diagnostic thinking efficacy, therapeutic efficacy, patient outcome efficacy, and societal efficacy. For each domain of utility, we offer specific indicators and measurement strategies. While we focus on diagnostic applications of WGS for rare germline diseases, this toolkit offers a flexible framework for best practices around measuring clinical utility for a range of WGS applications. While we expect this toolkit to evolve over time, it provides a resource for laboratories, clinicians, and researchers looking to characterize the value of WGS beyond the laboratory.

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Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

Cited by 47 publications

References 38 publications

The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

Prospective Study of the Phenotypic and Mutational Spectrum of Ocular Albinism and Oculocutaneous Albinism

Clinical utility of genomic sequencing: a measurement toolkit

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