Personalized Diagnosis and Management of Congenital Cataract by Next-Generation Sequencing

doi:10.1016/j.ophtha.2014.06.006

Ophthalmology

Volume 121, Issue 11, November 2014, Pages 2124-2137.e2

https://doi.org/10.1016/j.ophtha.2014.06.006 Get rights and content

Purpose

To assess the utility of integrating genomic data from next-generation sequencing and phenotypic data to enhance the diagnosis of bilateral congenital cataract (CC).

Design

Evaluation of diagnostic technology.

Participants

Thirty-six individuals diagnosed with nonsyndromic or syndromic bilateral congenital cataract were selected for investigation through a single ophthalmic genetics clinic.

Methods

Participants underwent a detailed ophthalmic examination, accompanied by dysmorphology assessment where appropriate. Lenticular, ocular, and systemic phenotypes were recorded. Mutations were detected using a custom-designed target enrichment that permitted parallel analysis of 115 genes associated with CC by high-throughput, next-generation DNA sequencing (NGS). Thirty-six patients and a known positive control were tested. Suspected pathogenic variants were confirmed by bidirectional Sanger sequencing in relevant probands and other affected family members.

Main Outcome Measures

Molecular genetic results and details of clinical phenotypes were identified.

Results

Next-generation DNA sequencing technologies are able to determine the precise genetic cause of CC in 75% of individuals, and 85% patients with nonsyndromic CC were found to have likely pathogenic mutations, all of which occurred in highly conserved domains known to be vital for normal protein function. The pick-up rate in patients with syndromic CC also was high, with 63% having potential disease-causing mutations.

Conclusions

This analysis demonstrates the clinical utility of this test, providing examples where it altered clinical management, directed care pathways, and enabled more accurate genetic counseling. This comprehensive screen will extend access to genetic testing and lead to improved diagnostic and management outcomes through a stratified medicine approach. Establishing more robust genotype–phenotype correlations will advance knowledge of cataract-forming mechanisms.

Section snippets

Recruitment and Selection of Patients with Congenital Cataract

Patients with CC were diagnosed through the National Health Service (NHS) ophthalmic genetics clinic at Saint Mary's Hospital (Manchester). A 3-generation family history and a full medical history were obtained from all patients, and all patients underwent a detailed ophthalmic examination. Where additional problems or dysmorphic features were present, a full systemic and dysmorphic assessment was undertaken by a clinical geneticist (Table 1, available at www.aaojournal.org). Informed consent

Patient Profiles

The systemic and ophthalmic features of the 36 patients selected for screening are listed in Table 1 (available at www.aaojournal.org), and a selection of cataract morphologies identified during this study are displayed in Figure 1. Analysis of the patient information revealed that 20 patients with nonsyndromic CC and 16 patients with syndromic CC had been selected for testing. It is also noteworthy that 10 of the probands were of consanguineous parentage.

Next-Generation DNA Sequencing Yields Excellent Coverage of Genes Implicated in Human Cataractogenesis

Results from the sequencing of

Discussion

In this study, we used a custom-designed target enrichment for the capture of all coding exons and flanking intronic sequences of genes associated with CC for subsequent massively parallel sequencing. We tested 36 patients and have shown a high mutation detection rate, proving the efficacy of this method in determining the precise genetic cause of CC and providing further evidence of the utility of NGS in the diagnosis of a genetically heterogeneous condition. The absence of previously

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Citation Excerpt :
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View all citing articles on Scopus

: Supplemental material is available at www.aaojournal.org.

: Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

: Funded by Fight for Sight (grant no. 1831) and supported by the Manchester Academic Health Science Centre and the Manchester National Institute for Health Research Biomedical Research Centre. The funding organization had no role on the design or conduct of this research.

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Original articlePersonalized Diagnosis and Management of Congenital Cataract by Next-Generation Sequencing

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Recruitment and Selection of Patients with Congenital Cataract

Patient Profiles

Next-Generation DNA Sequencing Yields Excellent Coverage of Genes Implicated in Human Cataractogenesis

Discussion

J Cataract Refract Surg

Prog Biophys Mol Biol

Trends Mol Med

Ophthalmology

Ophthalmology

Semin Cell Dev Biol

J Mol Diagn

Genet Med

J Mol Diagn

Mol Genet Metab

Am J Hum Genet

Exp Eye Res

Genet Med

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Measuring and interpreting the incidence of congenital ocular anomalies: lessons from a national study of congenital cataract in the UK

Invest Ophthalmol Vis Sci

Genetics of childhood cataract

Curr Opin Ophthalmol

Biological glass: structural determinants of eye lens transparency

Philos Trans R Soc Lond B Biol Sci

Genetic and segregation analysis of congenital cataract in the Indian population

Clin Genet

Aetiology of congenital and paediatric cataract in an Australian population

Br J Ophthalmol

Congenital and infantile cataract: aetiology and management

Eur J Pediatr

The differential diagnosis of cataracts in infancy and childhood

Am J Dis Child

Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma

Hum Mol Genet

Evaluation of pediatric cataracts and systemic disorders

Curr Opin Ophthalmol

Clinical and experimental advances in congenital and paediatric cataracts

Philos Trans R Soc Lond B Biol Sci

Organic-aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation; a clinical entity

AMA Am J Dis Child

Congenital X-linked cataract, dental anomalies and brachymetacarpalia

Birth Defects Orig Artic Ser

X-linked cataract and Huchinsonian teeth

Paediatr Child Health

Cockayne syndrome: review of 140 cases

Am J Med Genet

Next-generation DNA sequencing

Nat Biotechnol

A sensitive and specific diagnostic test for hearing loss using a microdroplet PCR-based approach and next generation sequencing

Am J Med Genet A

Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease

Eur J Hum Genet

Molecular diagnosis for heterogeneous genetic diseases with targeted high-throughput DNA sequencing applied to retinitis pigmentosa

J Med Genet

Performance evaluation of the next-generation sequencing approach for molecular diagnosis of hereditary hearing loss

Otolaryngol Head Neck Surg

Comprehensive mutation analysis for congenital muscular dystrophy: a clinical PCR-based enrichment and next-generation sequencing panel

PLoS One

A paradigm shift in the delivery of services for diagnosis of inherited retinal disease

J Med Genet

Cat-Map: putting cataract on the map

Mol Vis

Fast and accurate short read alignment with Burrows-Wheeler transform

Oxford, England: Bioinformatics

Original article
Personalized Diagnosis and Management of Congenital Cataract by Next-Generation Sequencing