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

2019 ◽  
Vol 22 (4) ◽  
pp. 745-751
Author(s):  
Eva Lenassi ◽  
Jill Clayton-Smith ◽  
Sofia Douzgou ◽  
Simon C. Ramsden ◽  
Stuart Ingram ◽  
...  
Keyword(s):  
Preschool Children ◽  
Genetic Testing ◽  
Clinical Utility ◽  
Diagnostic Yield ◽  
Anterior Segment ◽  
Ectopia Lentis ◽  
Anterior Segment Dysgenesis ◽  
Eye Disorders ◽  
Retinal Disorders ◽  
Inherited Retinal Disorders

Abstract 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.

scholarly journals Correction: Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

2020 ◽  
Author(s):  
Eva Lenassi ◽  
Jill Clayton-Smith ◽  
Sofia Douzgou ◽  
Simon C. Ramsden ◽  
Stuart Ingram ◽  
...  
Keyword(s):  
Preschool Children ◽  
Genetic Testing ◽  
Clinical Utility ◽  
Eye Disorders

Expanded yield of multiplex panel testing in fully accrued prospective trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1525-1525
Author(s):  
Gregory Idos ◽  
Allison W. Kurian ◽  
Charite Nicolette Ricker ◽  
Duveen Sturgeon ◽  
Julie Culver ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Genetic Testing ◽  
Cancer Risk ◽  
Clinical Utility ◽  
Diagnostic Yield ◽  
Pathogenic Mutation ◽  
Gene Panel ◽  
Cancer Risk Assessment ◽  
Panel Testing ◽  
Gene Panel Testing

1525 Background: Genetic testing is a powerful tool for stratifying cancer risk. Multiplex gene panel (MGP) testing allows simultaneous analysis of multiple high- and moderate- penetrance genes. However, the diagnostic yield and clinical utility of panels remain to be further delineated. Methods: A report of a fully accrued trial (N = 2000) of patients undergoing cancer-risk assessment. Patients were enrolled in a multicenter prospective cohort study where diagnostic yield and off-target mutation detection was evaluated of a 25 gene MGP comprised of APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were enrolled if they met standard testing guidelines or were predicted to have a ≥2.5% mutation probability by validated models. Differential diagnoses (DDx) were generated after expert clinical genetics assessment, formulating up to 8 inherited cancer syndromes ranked by estimated likelihood. Results: 1998/2000 patients had reported MGP test results. Women constituted 81% of the sample, and 40% were Hispanic; 241 tested positive for at least 1 pathogenic mutation (12.1%) and 689 (34.5%) patients carried at least 1 variant of uncertain significance. The most frequently identified mutations were in BRCA1 (17%, n = 41), BRCA2 (15%, n = 36), APC (8%, n = 19), CHEK2 (7%, n = 17), ATM (7%, n = 16). 39 patients (16%) had at least 1 pathogenic mutation in a mismatch repair (MMR) gene ( MLH1, n = 10; MSH2, n = 10; MSH6, n = 8; PMS2, n = 11). 43 individuals (18%) had MUTYH mutations – 41 were monoallelic. Among 19 patients who had mutations in APC – 16 were APC I1307K. Only 65% (n = 159) of PV results were included in the DDx, with 35% (n = 86) of mutations not clinically suspected. Conclusions: In a diverse cohort, multiplex panel use increased genetic testing yield substantially: 35% carried pathogenic mutations in unsuspected genes, suggesting a significant contribution of expanded multiplex testing to clinical cancer risk assessment. The identification of off-target mutations broadens our understanding of cancer risk and genotype-phenotype correlations. Follow-up is ongoing to assess the clinical utility of multiplex gene panel testing. Clinical trial information: NCT02324062.

scholarly journals The NYCKidSeq project: study protocol for a randomized controlled trial incorporating genomics into the clinical care of diverse New York City children

2020 ◽  
Author(s):  
Jacqueline A. Odgis ◽  
Katie M. Gallagher ◽  
Sabrina A. Suckiel ◽  
Katherine E. Donohue ◽  
Michelle A. Ramos ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Genetic Testing ◽  
Clinical Utility ◽  
Diagnostic Yield ◽  
Controlled Trial ◽  
Genomic Medicine ◽  
Whole Genome ◽  
Diverse Populations ◽  
Randomized Controlled ◽  
Genomic Results

Background: Increasingly, genomics is informing clinical practice, but challenges remain for medical professionals lacking genetics expertise, and in access to and clinical utility of genomic testing for minority and underrepresented populations. The latter is a particularly pernicious problem due to the historical lack of inclusion of racially and ethnically diverse populations in genomic research and genomic medicine. A further challenge is the rapidly changing landscape of genetic tests, and considerations of cost, interpretation and diagnostic yield for emerging modalities like whole genome sequencing. Methods: The NYCKidSeq project is a randomized controlled trial recruiting 1,130 children and young adults predominantly from Harlem and the Bronx with suspected genetic disorders in three disease categories: neurologic, cardiovascular, and immunologic. Two clinical genetic tests will be performed for each participant, either proband, duo or trio whole-genome sequencing (depending on sample availability) and proband targeted gene panels. Clinical utility, cost and diagnostic yield of both testing modalities will be assessed. This study will evaluate the use of a novel, digital platform (GUÍA) to digitize the return of genomic results experience and improve participant understanding for English- and Spanish-speaking families. Surveys will collect data at three study visits; baseline (0 months), results disclosure visit (ROR1, +3 months), and follow up visit (ROR2, +9 months). Outcomes will assess parental understanding of and attitudes towards receiving genomic results for their child and behavioral, psychological and social impact of results. We will also conduct a pilot study to assess a digital tool called GenomeDiver designed to enhance communication between clinicians and genetic testing labs. We will evaluate GenomeDiver's ability to increase the diagnostic yield compared to standard practices, to improve clinician's ability to perform targeted reverse phenotyping, and to increase the efficiency of genetic testing lab personnel. Discussion: The NYCKidSeq project will contribute to the innovations and best practices in communicating genomic test results to diverse populations. This work will inform strategies for implementing genomic medicine in health systems serving diverse populations using methods that are clinically useful, technologically savvy, culturally sensitive, and ethically sound.

scholarly journals Clinical Utility of Exome Sequencing and Reinterpreting Genetic Test Results in Children and Adults With Epilepsy

2020 ◽  
Vol 11 ◽  
Author(s):  
Yong-li Jiang ◽  
Changgeng Song ◽  
Yuanyuan Wang ◽  
Jingjing Zhao ◽  
Fang Yang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Utility ◽  
Genetic Test ◽  
Diagnostic Yield ◽  
Clinical Information ◽  
Test Results ◽  
Diagnostic Potential ◽  
Genetic Test Results ◽  
Diagnosis Rate ◽  
Clinically Significant

The clinical utility of genetic testing for epilepsy has been enhanced with the advancement of next-generation sequencing (NGS) technology along with the rapid updating of publicly available databases. The aim of this study was to evaluate the diagnostic yield of NGS and assess the value of reinterpreting genetic test results in children and adults with epilepsy. We performed genetic testing on 200 patients, including 82 children and 118 adults. The results were classified into three categories: positive, inconclusive, or negative. The reinterpretation of inconclusive results was conducted in April 2020. Overall, we identified disease-causing variants in 12% of the patients in the original analysis, and 14.5% at reinterpretation. The diagnostic yield for adults with epilepsy was similar to that for children (11 vs. 19.5%, p = 0.145). After reinterpretation, 9 of the 86 patients who initially had inconclusive results obtained a clinically significant change in diagnosis. Among these nine revised cases, five obtained positive diagnoses, representing a diagnosis rate of 5.8% (5/86). Manual searches for additional evidence of pathogenicity for candidate variants and updated patient clinical information were the main reasons for diagnostic reclassification. This study emphasizes the diagnostic potential of combining NGS and reinterpretation of inconclusive genetic test reports in children and adults with epilepsy.

Diagnostic yield and clinical utility of genetic testing in children with seizure onset after 2 years of age: an update

2021 ◽  
Vol 132 ◽  
pp. S59
Author(s):  
Khalida Liaquat ◽  
Kim Gall ◽  
Emmanuela Izzo ◽  
Akashdeep Singh ◽  
Kirsi Alakurtti ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Utility ◽  
Diagnostic Yield ◽  
Seizure Onset

scholarly journals Congenital glaucoma with anterior segment dysgenesis in individuals with biallelic CPAMD8 variants

2018 ◽  
Author(s):  
Owen M Siggs ◽  
Emmanuelle Souzeau ◽  
Deepa A Taranath ◽  
Tiger Zhou ◽  
Andrew Dubowsky ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Genome Sequencing ◽  
Anterior Segment ◽  
Congenital Glaucoma ◽  
Compound Heterozygous ◽  
Ectopia Lentis ◽  
Developmental Abnormalities ◽  
Anterior Segment Dysgenesis ◽  
Phenotypic Spectrum ◽  
Compound Heterozygous Variants

AbstractPurposeCongenital glaucoma is a significant cause of irreversible blindness. In some instances glaucoma is associated with developmental abnormalities of the ocular anterior segment, which can impair drainage of aqueous humor, leading to an increase in intraocular pressure.MethodsGenome sequencing was performed on a parent-proband congenital glaucoma trio, with exome sequencing of 79 additional individuals with suspected primary congenital glaucoma.ResultsWe describe a unique ocular anterior segment dysgenesis associated with congenital glaucoma in four individuals from three unrelated families. In each case, disease was associated with compound heterozygous variants in CPAMD8, a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. CPAMD8 expression was highest in neural crest-derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation of key drainage structures and the development of high intraocular pressure and glaucoma.ConclusionsThis study reveals a unique genetic cause of childhood glaucoma, and expands the phenotypic spectrum of CPAMD8-associated ocular disease.

scholarly journals Precision Medicine through Next-Generation Sequencing in Inherited Eye Diseases in a Korean Cohort

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 27
Author(s):  
Dabin Moon ◽  
Hye Won Park ◽  
Dongheon Surl ◽  
Dongju Won ◽  
Seung-Tae Lee ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Retinal Dystrophy ◽  
Anterior Segment ◽  
Case Series ◽  
Eye Diseases ◽  
Eye Disease ◽  
Gene Deletions ◽  
Anterior Segment Dysgenesis ◽  
Infantile Nystagmus Syndrome ◽  
Individualized Management

In this study, we investigated medically or surgically actionable genes in inherited eye disease, based on clinical phenotype and genomic data. This retrospective consecutive case series included 149 patients with inherited eye diseases, seen by a single pediatric ophthalmologist, who underwent genetic testing between 1 March 2017 and 28 February 2018. Variants were detected using a target enrichment panel of 429 genes and known deep intronic variants associated with inherited eye disease. Among 149 patients, 38 (25.5%) had a family history, and this cohort includes heterogeneous phenotype including anterior segment dysgenesis, congenital cataract, infantile nystagmus syndrome, optic atrophy, and retinal dystrophy. Overall, 90 patients (60.4%) received a definite molecular diagnosis. Overall, NGS-guided precision care was provided to 8 patients (5.4%). The precision care included cryotherapy to prevent retinal detachment in COL2A1 Stickler syndrome, osteoporosis management in patients with LRP5-associated familial exudative vitreoretinopathy, and avoidance of unnecessary phlebotomy in hyperferritinemia-cataract syndrome. A revision of the initial clinical diagnosis was made in 22 patients (14.8%). Unexpected multi-gene deletions and dual diagnosis were noted in 4 patients (2.7%). We found that precision medical or surgical managements were provided for 8 of 149 patients (5.4%), and multiple locus variants were found in 2.7% of cases. These findings are important because individualized management of inherited eye diseases can be achieved through genetic testing.

Diagnostic yield and clinical utility of genetic testing in children with seizure onset after two years of age: Update over 2 1/2-year program in Europe and the Middle East

2021 ◽  
Vol 132 (2) ◽  
pp. S100-S101
Author(s):  
Akashdeep Singh ◽  
Kimberly Gall ◽  
Emanuela Izzo ◽  
Kirsi Alakurtti ◽  
Eija H. Seppala ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Middle East ◽  
Clinical Utility ◽  
Diagnostic Yield ◽  
Seizure Onset
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