Leber congenital amaurosis [27 genes]

Leber congenital amaurosis (LCA) is a spectrum of inherited retinal disorders. The phenotype ranges from severe visual impairment from birth or the first months of life (including erratic eye movements or nystagmus, poor pupillary response to light, oculodigital signs, and severely abnormal full-field electroretinogram (ERG)) to milder forms of visual impairment and later onset. The fundus of the eye may be normal, but has retinal anomalies like pigmentary retinopathy, white deposits at the level of the retinal pigment epithelium, vascular attenuation or pseudopapilledema, and macular atrophy.

It is a disease whose manifestations are limited to the eye and, therefore, the ocular signs and symptoms occur in isolation. When other systemic data are associated, another nomenclature other than LCA may be used to refer to the disease, even though the same gene is responsible.

LCA causes approximately 20% of cases of blindness in children, accounts for 5% of cases of hereditary retinal dystrophies, and has an estimated prevalence of 1/30,000 – 1/80,000 globally.

Molecular characterization is of great importance in this context, as it allows us to confirm the diagnosis, transfer prognostic information known for genes and/or variants, and select patients for new therapies based on gene therapy.

An incidence of 1/30,000 – 1/80,000 newborns is estimated.

This exome service is recommended when there is a high clinical suspicion of having this disease to achieve a response as quickly as possible and thus early deliberating whether or not the patient is a candidate for treatment with new drugs.

The clinical utility of reaching a molecular diagnosis is relevant in this clinical context by allowing the selection of patients who can benefit from new treatments based on gene therapy.

The exome-based service Leber congenital amaurosis is recommended when there is a strong clinical suspicion of this disease. Due to the great relevance of the genetic diagnosis in this context, in the case of a presumptive diagnosis, it is recommended to request a broader panel where differential diagnosis is considered. The generalized retinal dystrophy panel or the retinal dystrophy and differential diagnosis panel may be a better entry alternative when other diagnostic possibilities are also considered.

An exome-based approach allows us to achieve a diagnostic yield of approximately 70% for patients with Leber congenital amaurosis. A small, not well-defined percentage of the remaining 30% that would remain without molecular diagnosis could be attributed to the technical limitations of the technology used.