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Dana Schlegel, Kari E Branham, John R Heckenlively, Abigail T Fahim, Thiran Jayaundera; The journey from clinical to genetic diagnosis in Stargardt disease. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1433.
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A clinical diagnosis of Stargardt doesn't guarantee a genetic diagnosis of ABCA4-related disease. We evaluated how frequently patients with a clinical diagnosis of Stargardt had a genetic diagnosis of ABCA4-related disease, how frequently they had inconclusive or negative test results, and how often they had disease-causing mutations in other genes.
A retrospective chart review was performed on patients seen in the retinal dystrophy clinic of the Kellogg Eye Center who had received an ICD-10 code corresponding to Stargardt disease (H35.52) since the initiation of the Epic system (2012). Patients were selected if “Stargardt” was listed under the impression of a Kellogg retinal dystrophy specialist before genetic testing. As part of routine care, some were tested only for ABCA4, but most had panel testing of 3-250 genes including ABCA4. Test results were reviewed to determine the genetic diagnosis.
Of the 123 patients with a clinical diagnosis of Stargardt before genetic testing, 69 (56%) had a definitive diagnosis of ABCA4 disease (2 pathogenic or likely-pathogenic variants in ABCA4, in trans if segregation status known), 6 (4.8%) had a possible diagnosis of ABCA4 disease (1 pathogenic variant and 1 variant of unknown significance (VUS) in ABCA4), 3 (2.4%) had a genetic diagnosis of RDS disease, 32 (26%) had inconclusive results (only one mutation in a gene with recessive inheritance or a VUS or likely-benign variant in a gene with dominant inheritance), and 10 (8%) had negative genetic testing results. In addition, one patient appeared to have IFT80-related disease (1 pathogenic variant and 1 VUS), one to have CRB1-related disease (a homozygous likely-pathogenic variant), and one WDR19-related disease (a homozygous VUS).
For many patients with a diagnosis of Stargardt, genetic testing is negative or inconclusive, preventing them from enrolling in some clinical trials. Those with mutations in RDS may have different reproductive risks than expected if counseled only on the autosomal recessive inheritance of ABCA4. In some, the disease-causing gene may not normally be associated with macular dystrophy (ie. IFT80, CRB1, WDR19), which may affect prognosis and risks for syndromic disease features. Therefore, it is important to counsel those who order genetic testing that the outcome may be inconclusive or negative and that testing may provide a different genetic diagnosis from what was expected.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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