title: Personalized diagnosis and management of congenital cataract by next-generation sequencing.
abstract: OBJECTIVE
  To assess the utility of integrating genomic data from next-generation sequencing and phenotypic data to enhance the diagnosis of bilateral congenital cataract (CC).
  
  
  METHODS
  Evaluation of diagnostic technology.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Gillespie
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom; Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester Foundation Trust, Manchester, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Ashworth
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Bhaskar
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Williams
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom; Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester Foundation Trust, Manchester, United Kingdom.
authors.forename: Susmito
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester Foundation Trust, Manchester, United Kingdom.
authors.forename: Elias
authors.initials: E
authors.lastname: Kehdi
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Ramsden
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom. Electronic address: graeme.black@manchester.ac.uk.
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Black
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Saint Mary's Hospital, Manchester, United Kingdom; Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester Foundation Trust, Manchester, United Kingdom.
authors.forename: I Christopher
authors.initials: IC
authors.lastname: Lloyd
mesh_terms: D000293:Adolescent; D002386:Cataract / Q000151:congenital / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D008297:Male; D009154:Mutation; D010375:Pedigree; D057285:Precision Medicine
chemical_list: D005136:Eye Proteins; D004247:DNA