Genetic testing in patients with retinitis pigmentosa

TY - JOUR

T1 - Genetic testing in patients with retinitis pigmentosa

T2 - Features of unsolved cases

AU - Birtel, Johannes

AU - Gliem, Martin

AU - Oishi, Akio

AU - Müller, Philipp L

AU - Herrmann, Philipp

AU - Holz, Frank G

AU - Mangold, Elisabeth

AU - Knapp, Michael

AU - Bolz, Hanno J

AU - Charbel Issa, Peter

N1 - © 2019 Royal Australian and New Zealand College of Ophthalmologists.

PY - 2019/8

Y1 - 2019/8

N2 - IMPORTANCE: Uncommon characteristics in genetically unsolved retinitis pigmentosa (RP) patients may indicate an incorrect clinical diagnosis or as yet unknown genetic causes resulting in specific retinal phenotypes. The diagnostic yield of targeted next-generation sequencing may be increased by a reasonable preselection of RP-patients.BACKGROUND: To systematically evaluate and compare features of genetically solved and unsolved RP-patients.DESIGN: Retrospective, observational study.PARTICIPANTS: One-hundred and twelve consecutive RP-patients who underwent extensive molecular genetic analysis.METHODS: Characterization of patients based on multimodal imaging and medical history.MAIN OUTCOME MEASURES: Differences between genetically solved and unsolved RP-patients.RESULTS: Compared to genetically solved patients (n = 77), genetically unsolved patients (n = 35) more frequently had an age of disease-onset above 30 years (60% vs 8%; P < 0.0001), showed atypical fundus features (49% vs 8%; P < 0. 0001) and indicators for phenocopies (eg, autoimmune diseases) (17% vs 0%; P < 0. 001). Evidence for a particular inheritance pattern was less common (20% vs 49%; P < 0. 01). The diagnostic yield was 84% (71/85) in patients with first symptoms below 30 years-of-age, compared to 69% (77/112) in the overall cohort. The other selection criteria alone or in combination resulted in limited further increase of the diagnostic yield (up to 89%) while excluding considerably more patients (up to 56%) from genetic testing.CONCLUSIONS AND RELEVANCE: The medical history and retinal phenotype differ between genetically solved and a subgroup of unsolved RP-patients, which may reflect undetected genotypes or retinal conditions mimicking RP. Patient stratification may inform on the individual likelihood of identifying disease-causing mutations and may impact patient counselling.

AB - IMPORTANCE: Uncommon characteristics in genetically unsolved retinitis pigmentosa (RP) patients may indicate an incorrect clinical diagnosis or as yet unknown genetic causes resulting in specific retinal phenotypes. The diagnostic yield of targeted next-generation sequencing may be increased by a reasonable preselection of RP-patients.BACKGROUND: To systematically evaluate and compare features of genetically solved and unsolved RP-patients.DESIGN: Retrospective, observational study.PARTICIPANTS: One-hundred and twelve consecutive RP-patients who underwent extensive molecular genetic analysis.METHODS: Characterization of patients based on multimodal imaging and medical history.MAIN OUTCOME MEASURES: Differences between genetically solved and unsolved RP-patients.RESULTS: Compared to genetically solved patients (n = 77), genetically unsolved patients (n = 35) more frequently had an age of disease-onset above 30 years (60% vs 8%; P < 0.0001), showed atypical fundus features (49% vs 8%; P < 0. 0001) and indicators for phenocopies (eg, autoimmune diseases) (17% vs 0%; P < 0. 001). Evidence for a particular inheritance pattern was less common (20% vs 49%; P < 0. 01). The diagnostic yield was 84% (71/85) in patients with first symptoms below 30 years-of-age, compared to 69% (77/112) in the overall cohort. The other selection criteria alone or in combination resulted in limited further increase of the diagnostic yield (up to 89%) while excluding considerably more patients (up to 56%) from genetic testing.CONCLUSIONS AND RELEVANCE: The medical history and retinal phenotype differ between genetically solved and a subgroup of unsolved RP-patients, which may reflect undetected genotypes or retinal conditions mimicking RP. Patient stratification may inform on the individual likelihood of identifying disease-causing mutations and may impact patient counselling.

KW - Adult

KW - Electroretinography

KW - Female

KW - Genetic Testing

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Male

KW - Middle Aged

KW - Phenotype

KW - Retinitis Pigmentosa/diagnosis

KW - Retrospective Studies

KW - Tomography, Optical Coherence

KW - Visual Acuity/physiology

KW - Visual Fields/physiology

U2 - 10.1111/ceo.13516

DO - 10.1111/ceo.13516

M3 - SCORING: Journal article

C2 - 30977268

VL - 47

SP - 779

EP - 786

JO - CLIN EXP OPHTHALMOL

JF - CLIN EXP OPHTHALMOL

SN - 1442-6404

IS - 6

ER -