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Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease
Journal article   Open access   Peer reviewed

Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease

Edwin M Stone, Jeaneen L Andorf, S Scott Whitmore, Adam P DeLuca, Joseph C Giacalone, Luan M Streb, Terry A Braun, Robert F Mullins, Todd E Scheetz, Val C Sheffield, …
Ophthalmology (Rochester, Minn.), Vol.124(9), pp.1314-1331
09/2017
DOI: 10.1016/j.ophtha.2017.04.008
PMCID: PMC5565704
PMID: 28559085
url
https://www.ncbi.nlm.nih.gov/pmc/articles/5565704View
Open Access

Abstract

To devise a comprehensive multiplatform genetic testing strategy for inherited retinal disease and to describe its performance in 1000 consecutive families seen by a single clinician. Retrospective series. One thousand consecutive families seen by a single clinician. The clinical records of all patients seen by a single retina specialist between January 2010 and June 2016 were reviewed, and all patients who met the clinical criteria for a diagnosis of inherited retinal disease were included in the study. Each patient was assigned to 1 of 62 diagnostic categories, and this clinical diagnosis was used to define the scope and order of the molecular investigations that were performed. The number of nucleotides evaluated in a given subject ranged from 2 to nearly 900 000. Sensitivity and false genotype rate. Disease-causing genotypes were identified in 760 families (76%). These genotypes were distributed across 104 different genes. More than 75% of these 104 genes have coding sequences small enough to be packaged efficiently into an adeno-associated virus. Mutations in ABCA4 were the most common cause of disease in this cohort (173 families), whereas mutations in 80 genes caused disease in 5 or fewer families (i.e., 0.5% or less). Disease-causing genotypes were identified in 576 of the families without next-generation sequencing (NGS). This included 23 families with mutations in the repetitive region of RPGR exon 15 that would have been missed by NGS. Whole-exome sequencing of the remaining 424 families revealed mutations in an additional 182 families, and whole-genome sequencing of 4 of the remaining 242 families revealed 2 additional genotypes that were invisible by the other methods. Performing the testing in a clinically focused tiered fashion would be 6.1% more sensitive and 17.7% less expensive and would have a significantly lower average false genotype rate than using whole-exome sequencing to assess more than 300 genes in all patients (7.1% vs. 128%; P < 0.001). Genetic testing for inherited retinal disease is now more than 75% sensitive. A clinically directed tiered testing strategy can increase sensitivity and improve statistical significance without increasing cost.
 Retinal Diseases - genetics Genetic Testing United States Humans Middle Aged Child, Preschool Family Health Infant Male DNA Mutational Analysis Sensitivity and Specificity Aged, 80 and over Adult Female Retrospective Studies Eye Proteins - genetics Child Genotype Sequence Analysis, DNA Eye Diseases, Hereditary - genetics Exome - genetics Pedigree Adolescent Aged High-Throughput Nucleotide Sequencing Mutation

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