The Clinical Findings, Pathogenic Variants, and Gene Therapy Qualifications Found in a Leber Congenital Amaurosis Phenotypic Spectrum Patient Cohort

Abstract

This retrospective study examines the clinical characteristics and underlying genetic variants that exist in a Leber congenital amaurosis (LCA) patient cohort evaluated at the inherited retinal disease (IRD) clinic at the University of Minnesota (UMN)/M Health System. Our LCA cohort consisted of 33 non-syndromic patients and one patient with Joubert syndrome. We report their relevant history, clinical findings, and genetic testing results. We monitored disease presentation utilizing ocular coherence tomography (OCT) and fundus autofluorescence (FAF). Electroretinogram testing (ERG) was performed in patients when clinically indicated. Next-generation sequencing (NGS) and genetic counseling was offered to all evaluated patients. Advanced photoreceptor loss was noted in 85.7% of the subjects. All patients who underwent FAF had findings of either a ring of macular hypo/hyper AF or peripheral hypo-AF. All patients had abnormal ERG findings. A diagnostic genetic test result was identified in 74.2% of the patients via NGS single-gene testing or panel testing. Two patients in our cohort qualified for Luxturna^® and both received treatment at the time of this study. These data will help IRD specialists to understand the genetic variants and clinical presentations that characterize our patient population in the Midwest region of the United States.

Keywords: Leber congenital amaurosis; early-onset severe retinal dystrophy; fundus autofluorescence; gene therapy; genetic testing; inherited retinal disease; ocular coherence tomography.

Figure 1

Examples of ellipsoid zone (EZ) bandwidth: (a) normal EZ; (b–d) progression of EZ degeneration to (b) EZ 1500–3500 µm, (c) EZ 1500 µm, and (d) complete attenuation of EZ.

Figure 2

Example grading criteria for FAF imaging.

Figure 3

Distribution of causative genes identified in the LCA patient cohort.

Figure 4

Detailed summary of the LCA patients who underwent genetic testing. (a) Nonsyndromic and syndromic patients in our cohort with a diagnostic pathogenic/likely pathogenic variant identified on genetic testing (b) Patients with only variable(s) of uncertain significance on genetic testing but suspicious of the possible diagnostic value based on the clinical presentation (c) Patients that were found to be non-diagnostic on genetic testing.

Figure 5

Prevalence of mutations in LCA-associated genes. The studies included the Midwest US (our cohort), Germany [31], Brazil [32], China [33], Japan [28], and Australia [30].