Which Leber congenital amaurosis patients are eligible for gene therapy trials?
BACKGROUND
In 2007, clinical trials began for gene-replacement therapy for RPE65-associated Leber congenital amaurosis. To enroll, subjects must have both disease-causing RPE65 alleles identified. Determining which patients have true disease-causing mutations requires a multistep approach.


METHODS
This study is a retrospective case series using the estimate of pathogenic probability (EPP) algorithm and genotyping of family members to establish phase.


RESULTS
Five probands and their families were studied. Patient 1 had genetic testing elsewhere and was reported to have 2 disease-causing AIPL1 mutations. The family received incorrect prenatal counseling based on this result. We found both variations to be benign ethnic polymorphisms (EPP = 0). Case 2 had possible disease-causing mutations in RPE65, RPGRIP1, and CRB1; however, screening of family members revealed that only CRB1 variations were disease causing and the RPE65 change was a polymorphism found in 11% of African Americans. Case 3 had a diagnosis of CRB1-associated Leber congenital amaurosis, but this mutation had an EPP = 0; a true homozygous disease-causing mutation was later found in RDH12. Patient 4 had 3 mutations found in RPE65, but only 2 were disease causing. Patient 5 had a homozygous mutation in RPE65. Only Patients 4 and 5 would be eligible for clinical trials of RPE65 gene replacement.


CONCLUSIONS
To be eligible for participation in current RPE65 gene therapy trials, patients' DNA must contain 2 correctly segregating alleles with an EPP = 2 or 3. Interpretation of DNA variants is complex; genetic misdiagnosis may lead to ineffective treatment in some patients and lack of treatment in others.
Drack
Arlene V
AV
University of Iowa Hospitals and Clinics, Iowa City, 52242, USA. arlene-drack@uiowa.edu
Johnston
Rebecca
R
Stone
Edwin M
EM
D000465:Algorithms; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D005136:Eye Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D015316:Genetic Therapy; D005838:Genotype; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000628:therapy*; D008297:Male; D009154:Mutation; D018579:Patient Selection; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D002352:Carrier Proteins; D005136:Eye Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase