Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease.
To assess the clinical usefulness of genetic testing in a pediatric population with inherited retinal disease (IRD).



Single-center retrospective case series.



Eighty-five unrelated children with a diagnosis of isolated or syndromic IRD who were referred for clinical genetic testing between January 2014 and July 2016.



Participants underwent a detailed ophthalmic examination, accompanied by electrodiagnostic testing (EDT) and dysmorphologic assessment where appropriate. Ocular and extraocular features were recorded using Human Phenotype Ontology terms. Subsequently, multigene panel testing (105 or 177 IRD-associated genes) was performed in an accredited diagnostic laboratory, followed by clinical variant interpretation.



Diagnostic yield and clinical usefulness of genetic testing.



Overall, 78.8% of patients (n = 67) received a probable molecular diagnosis; 7.5% (n = 5) of these had autosomal dominant disease, 25.4% (n = 17) had X-linked disease, and 67.2% (n = 45) had autosomal recessive disease. In a further 5.9% of patients (n = 5), a single heterozygous ABCA4 variant was identified; all these participants had a spectrum of clinical features consistent with ABCA4 retinopathy. Most participants (84.7%; n = 72) had undergone EDT and 81.9% (n = 59) of these patients received a probable molecular diagnosis. The genes most frequently mutated in the present cohort were CACNA1F and ABCA4, accounting for 14.9% (n = 10) and 11.9% (n = 8) of diagnoses respectively. Notably, in many cases, genetic testing helped to distinguish stationary from progressive IRD subtypes and to establish a precise diagnosis in a timely fashion.



Multigene panel testing pointed to a molecular diagnosis in 84.7% of children with IRD. The diagnostic yield in the study population was significantly higher compared with that in previously reported unselected IRD cohorts. Approaches similar to the one described herein are expected to become a standard component of care in pediatric ophthalmology. We propose the introduction of genetic testing early in the diagnostic pathway in children with clinical and/or electrophysiologic findings, suggestive of IRD.
Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Rachel L
RL
Taylor
Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom; Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom.
Neil R A
NRA
Parry
Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Stephanie J
SJ
Barton
Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Christopher
C
Campbell
Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom; Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom.
Claire M
CM
Delaney
Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Jamie M
JM
Ellingford
Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Georgina
G
Hall
Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Claire
C
Hardcastle
Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Jiten
J
Morarji
Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Elisabeth J
EJ
Nichol
Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Lindsi C
LC
Williams
Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Sofia
S
Douzgou
Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Jill
J
Clayton-Smith
Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Simon C
SC
Ramsden
Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Vinod
V
Sharma
Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Susmito
S
Biswas
Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom; Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
I Chris
IC
Lloyd
Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom; Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Jane L
JL
Ashworth
Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. Electronic address: graeme.black@manchester.ac.uk.
Graeme C
GC
Black
Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom; Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Panagiotis I
PI
Sergouniotis
D000293:Adolescent; D002648:Child; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D010375:Pedigree; D010641:Phenotype; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies
D005136:Eye Proteins