Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease

Taylor, Rachel L.; Parry, Neil R. A.; Barton, Stephanie; Campbell, Christopher; Delaney, Claire; Ellingford, Jamie M; Hall, Georgina; Hardcastle, Claire; Morarji, Jiten; Nichol, Elisabeth J.; Williams, Lindsi C.; Douzgou, Sofia; Clayton‐Smith, Jill; Ramsden, Simon; Sharma, Vinod; Biswas, Susmito; Lloyd, Iva; Ashworth, Jane; Black, Graeme C M; Sergouniotis, Panagiotis I.

doi:10.1016/j.ophtha.2017.02.005

Cited by 50 publications

(37 citation statements)

References 38 publications

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“…In addition to highlighting the possibility of extraocular involvement, genetic testing can help differentiate progressive from stationary IRD subtypes. 2 Here, we found that genetic testing helped reduce prognostic uncertainty in 25% (15/59) of study participants. Interestingly, approximately 1 in 4 children in whom a progressive disorder was strongly considered were shown to have a stationary condition ( Supplementary Table 1).…”

Section: Discussionmentioning

confidence: 75%

“…A subset of participants underwent fundus imaging, and electrodiagnostic testing was performed in most children with a suspected diagnosis of albinism or IRD using previously described methods. 2 Where extraocular features were present or suspected, a full systemic assessment was undertaken by a consultant clinical geneticist.…”

Section: Phenotypic Data Collectionmentioning

confidence: 99%

“…In the latter scenario, ocular manifestations are often one of the first presenting features of a syndrome (e.g., individuals with Marfan syndrome often present with ectopia lentis). [2][3][4][5][6] In the past three decades, over 400 genes have been found to be associated with inherited eye disorders. Such advances in delineating the molecular pathology of these conditions, together with breakthroughs in DNA sequencing technologies, catalyzed the development of powerful genomic tests.…”

Section: Introductionmentioning

confidence: 99%

“…A subset of the cases included in this study has been previously reported (see Supplementary Table 1 for more information). 2,3 Ethics committee approval for the study was obtained from the North West Research Ethics Committee (11/NW/0421 and 15/YH/0365) and all investigations were conducted in accordance to the tenets of the Declaration of Helsinki.…”

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confidence: 99%

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

Lenassi

Clayton‐Smith

Douzgou

et al. 2020

Genetics in Medicine

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Purpose A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). Methods Two hundred one unrelated children (0–5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011–2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. Results The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). Conclusion Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.

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Section: Discussionmentioning

confidence: 75%

Section: Phenotypic Data Collectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Lenassi

Clayton‐Smith

Douzgou

et al. 2020

Genetics in Medicine

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“…In 2002, we reported five families with patients affected by ACHM caused by mutations in GNAT2 (Kohl et al, ; Rosenberg et al, ). Since then only few reports of single families have been published (Aligianis et al, ; Piña, Baumert, Loyer, & Koenekoop, ; Ouechtati et al, ; Langlo et al, , Taylor et al, ; Carss et al, ; Ueno et al, ). Herein we report the results of our genetic investigation of our complete ACHM cohort over a period of 16 years, in total identifying 23 affected individuals from 19 independent families carrying likely disease‐causing mutations in GNAT2 , of which 12 mutations have never been reported before.…”

Section: Introductionmentioning

confidence: 99%

Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene

et al. 2019

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Achromatopsia (ACHM) is a hereditary cone photoreceptor disorder characterized by the inability to discriminate colors, nystagmus, photophobia, and low‐visual acuity. Six genes have been associated with this rare autosomal recessively inherited disease, including the GNAT2 gene encoding the catalytic α‐subunit of the G‐protein transducin which is expressed in the cone photoreceptor outer segment. Out of a cohort of 1,116 independent families diagnosed with a primary clinical diagnosis of ACHM, we identified 23 patients with ACHM from 19 independent families with likely causative mutations in GNAT2, representing 1.7% of our large ACHM cohort. In total 22 different potentially disease‐causing variants, of which 12 are novel, were identified. The mutation spectrum also includes a novel copy number variation, a heterozygous duplication of exon 4, of which the breakpoint matches exactly that of the previously reported exon 4 deletion. Two patients carry just a single heterozygous variant. In addition to our previous study on GNAT2‐ACHM, we also present detailed clinical data of these patients.

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Accuracy of Next-Generation Sequencing for Molecular Diagnosis in Patients With Infantile Nystagmus Syndrome

et al. 2017

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syndrome (INS) is a group of disorders presenting with genetic and clinical heterogeneities that have challenged the genetic and clinical diagnoses of INS. Precise molecular diagnosis in early infancy may result in more accurate genetic counseling and improved patient management. OBJECTIVE To assess the accuracy of genomic data from next-generation sequencing (NGS) and phenotypic data to enhance the definitive diagnosis of INS. DESIGN, SETTING, AND PARTICIPANTS A single-center retrospective case series was conducted in 48 unrelated, consecutive patients with INS, with or without associated ocular or systemic conditions, who underwent genetic testing between June 1, 2015, and January 31, 2017. Next-generation sequencing analysis was performed using a target panel that included 113 genes associated with INS (n = 47) or a TruSight One sequencing panel that included 4813 genes associated with known human phenotypes (n = 1). Variants were filtered and prioritized by in-depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Patients underwent a detailed ophthalmic examination, including electroretinography and optical coherence tomography, if feasible. MAIN OUTCOMES AND MEASURES Diagnostic yield of targeted NGS testing. RESULTS Among the 48 patients (21 female and 27 male; mean [SD] age at genetic testing, 9.2 [10.3] years), 8 had a family history of nystagmus and 40 were simplex. All patients were of a single ethnicity (Korean). Genetic variants that were highly likely to be causative were identified in 28 of the 48 patients, corresponding to a molecular diagnostic yield of 58.3% (95% CI, 44.4%-72.2%). FRMD7, GPR143, and PAX6 mutations appeared to be the major genetic causes of familial INS. A total of 10 patients (21%) were reclassified to a different diagnosis based on results of NGS testing, enabling accurate clinical management. CONCLUSIONS AND RELEVANCE These findings suggest that NGS is an accurate diagnostic tool to differentiate causes of INS because diagnostic tests, such as electroretinography and optical coherence tomography, are not easily applicable in young infants. Accurate application of NGS using a standardized, stepwise, team-based approach in early childhood not only facilitated early molecular diagnosis but also led to improved personalized management in patients with INS.

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Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease

Cited by 50 publications

References 38 publications

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

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

Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene

Accuracy of Next-Generation Sequencing for Molecular Diagnosis in Patients With Infantile Nystagmus Syndrome

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