Dataset Information

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

SUBMITTER: Lenassi E

PROVIDER: S-EPMC7118019 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Lenassi Eva E Clayton-Smith Jill J Douzgou Sofia S Ramsden Simon C SC Ingram Stuart S Hall Georgina G Hardcastle Claire L CL Fletcher Tracy A TA Taylor Rachel L RL Ellingford Jamie M JM Newman William D WD Fenerty Cecilia C Sharma Vinod V Lloyd I Chris IC Biswas Susmito S Ashworth Jane L JL Black Graeme C GC Sergouniotis Panagiotis I PI

Genetics in medicine : official journal of the American College of Medical Genetics 20191218 4

<h4>Purpose</h4>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).<h4>Methods</h4>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 (201 ...[more]

PMID: 31848469

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Project description:Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

Project description:IntroductionThe purpose of this study is to assess the prevalence of comprehensive eye examinations in multiethnic preschool children, including children with visually significant eye conditions, and identify factors associated with comprehensive eye examinations.MethodsA sample of 9,197 African American, Hispanic, Asian American, and non-Hispanic White children aged 6-72 months was recruited for the Multi-Ethnic Pediatric Eye Disease Study from 2003 to 2011. Logistic regression performed in 2022 identified independent factors associated with parent-reported history of comprehensive eye examinations. The proportion of children with previous comprehensive eye examinations and the proportion with undetected amblyopia or strabismus were measured.ResultsThe prevalence of comprehensive eye examinations was 6.3% overall and 38.3%, 24.8%, 19.1%, 15.1%, and 9.8% among children with strabismus, amblyopia, significant anisometropia, hyperopia, and astigmatism, respectively. Children without prior comprehensive eye examinations were more likely to have undetected amblyopia or strabismus than those with comprehensive eye examination history (ps<0.001). The prevalence of comprehensive eye examinations was higher among older children. Prevalence varied by race/ethnicity, with 8.1%, 7.9%, 6.3%, and 4.9% of non-Hispanic White, Asian American, African American, and Hispanic children having had prior comprehensive eye examinations, respectively; however, the differences did not remain after adjusting for other associated factors. Older age, a primary caregiver with a college/university degree or higher, having vision insurance, gestational age <33 weeks, neurodevelopmental disorder diagnosis, strabismus, and ocular disease history were all statistically significantly associated with a relatively higher prevalence of comprehensive eye examinations in multivariable analyses.ConclusionsComprehensive eye examinations were uncommon among preschool children, including those with treatable vision disorders. Interventions, such as parent education and vision insurance, are needed to imaprove comprehensive eye examination access and utilization for at-risk preschool children.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

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