Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss

Abstract

Purpose: To analyze the genetic test results of probands referred to eyeGENE with a diagnosis of hereditary maculopathy.

Methods: Patients with Best macular dystrophy (BMD), Doyne honeycomb retinal dystrophy (DHRD), Sorsby fundus dystrophy (SFD), or late-onset retinal degeneration (LORD) were screened for mutations in BEST1, EFEMP1, TIMP3, and CTRP5, respectively. Patients with pattern dystrophy (PD) were screened for mutations in PRPH2, BEST1, ELOVL4, CTRP5, and ABCA4; patients with cone-rod dystrophy (CRD) were screened for mutations in CRX, ABCA4, PRPH2, ELOVL4, and the c.2513G>A p.Arg838His variant in GUCY2D. Mutation analysis was performed by dideoxy sequencing. Impact of novel variants was evaluated using the computational tool PolyPhen.

Results: Among the 213 unrelated patients, 38 had BMD, 26 DHRD, 74 PD, 8 SFD, 6 LORD, and 54 CRD; six had both PD and BMD, and one had no specific clinical diagnosis. BEST1 variants were identified in 25 BMD patients, five with novel variants of unknown significance (VUS). Among the five patients with VUS, one was diagnosed with both BMD and PD. A novel EFEMP1 variant was identified in one DHRD patient. TIMP3 novel variants were found in two SFD patients, PRPH2 variants in 14 PD patients, ABCA4 variants in four PD patients, and p.Arg838His GUCY2D mutation in six patients diagnosed with dominant CRD; one patient additionally had a CRX VUS. ABCA4 mutations were identified in 15 patients with recessive CRD.

Conclusions: Of the 213 samples, 55 patients (26%) had known causative mutations, and 13 (6%) patients had a VUS that was possibly pathogenic. Overall, selective screening for mutations in BEST1, PRPH2, and ABCA4 would likely yield the highest success rate in identifying the genetic basis for macular dystrophy phenotypes. Because of the overlap in phenotypes between BMD and PD, it would be beneficial to screen genes associated with both diseases.

Trial registration: ClinicalTrials.gov NCT00378742.

Keywords: eyeGENE; genetic testing; macular dystrophy.

Figure 1

Clinical phenotype of case 1. A 44-year-old female with visual acuities of 20/25 OD and 20/60 OS became symptomatic at the age of 35. Submacular yellow deposits are circumscribed and measure approximately 120 μm; some have aggregated and form a pigmented center. Outer retinal atrophy of the foveal region is more prominent in the right eye than the left eye. On fluorescein angiography, these deposits stained with fluorescein, and there was no suggestion of a dark choroid.

Figure 2

Clinical phenotype of case 2. A 39-year-old female with visual acuities of 20/25 OD and 20/200 OS and central scotomas in both eyes became symptomatic at the age of 35. Her OCT showed predominant outer retinal atrophy at the fovea with sub-RPE drusenoid-like deposits. The retinal atrophy is worse in the left eye than the right eye. The yellow circumscribed sub-RPE deposits aggregate as a ring in the parafoveal region. These stained on fluorescein angiography, and there was no suggestion of a dark choroid.

Figure 3

Pedigree of case 5. Segregation of the PRPH2 mutation at c.514C>T (p.Arg172Trp) with disease.

Figure 4

Pedigree of case 6. Segregation of the PRPH2 mutation at c.422A>G (p.Tyr141Cys) with disease. Striped background designates family members afflicted with hearing loss, and solid black designates family members affected by retinal degeneration. Question mark designates status unknown.