Stargardt misdiagnosis: How ocular genetics helps

Abstract

Ocular Genetics at Wills Eye Hospital sees a wide range of rare disorders for accurate diagnosis. To demonstrate how focused consultation and genetic testing results in precise diagnoses, we investigated false diagnosis rates for patients referred with a diagnosis of Stargardt disease. This is a retrospective review of patients over a 3 year period referred to our Ocular Genetics clinic for possible Stargardt disease, or already holding a diagnosis of Stargardt disease. Results of diagnostic and genetic testing were compared to standard definition of Stargardt. Of 40 patients, 14 (35%) had been misdiagnosed. Four had non‐Stargardt phenotype of which three had ABCA4 pathogenic variants with phenotypes inconsistent with Stargardt disease. Two of those with pathogenic ABCA4 variants were related. Nine had pathogenic variants in other different genes with overlapping features of Stargardt disease. One had Thioridazine maculopathy. Our study highlights the essential role of the subspecialty field of ocular genetics in obtaining accurate diagnoses for the delivery of correct counseling and interventional trial eligibility assessment.

The Role of the Choroid in Stargardt Disease

“…It has been thought that NIR-AF can better delineate the degree of RPE atrophy [ 12 ] ( Figure 1 and Figure 2 ). The full-field electroretinogram is usually normal or minimally abnormal, whereas multifocal electroretinogram (mf-ERG) may show a more demonstrable reduction of central retina responses [ 6 ].…”

“…testing, is warranted for appropriate genetic counselling, prognostic information, and clinical trials due to the fact of emergent gene therapies [6].…”

“…The classical phenotype is due to biallelic pathogenic variants in the ABCA4 gene. Phenocopies can be caused by heterozygous pathogenic variant in PROM1 or ELOVL4, which can have a clinical profile indistinguishable from classic STGD1 [ 5 , 6 ]. Other types of macular dystrophy can also mimic STGD.…”

“…The term "Stargardt" is often used to describe a wide variety of maculopathies with and without lipofuscin deposits. However, precise diagnosis, aided by genetic testing, 2 of 10 is warranted for appropriate genetic counselling, prognostic information, and clinical trials due to the fact of emergent gene therapies [6].…”

An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

“…For ABCA4R, the commonest phenocopy is the pattern dystrophy caused by variants in PRPH2 inherited in an autosomal dominant manner [70]. Indeed, Ibanez et al recently found that a PRPH2 variant was identified in 10% of their misdiagnosed STGD1 patients [71]. The typical phenotype linked to PRPH2 is a late-onset pattern dystrophy with variable penetrance within families.…”