RPE65 c.393T>A, p.(Asn131Lys): Novel Sequence Variant Detected

Abstract

Background: Leber congenital amaurosis (LCA) is a monogenic, but genetically heterogenous disease, and at least 27 genes are implicated. This case report is aimed at providing evidence to link the novel variant RPE65 c.393T>A, p.(Asn131Lys), variant of uncertain significance (VUS), to clinical phenotype and to set the ground for objective assignment of pathogenicity confidence. Case Presentation. A case report of a female patient with LCA who manifested with nystagmus, night blindness, profound visual deficiency, and peripheral involvement of the retina consistent with RPE65 dystrophy. A thorough clinical examination, diagnostic evaluation, and genetic testing were performed. The patient was a compound heterozygote in trans form: RPE65 c.304G>T, p.(Glu102∗) pathogenic, and RPE65 c.393T>A, p.(Asn131Lys), VUS. The latter variant is absent in healthy controls and is considered harmful on in silico prediction.

Conclusions: We conclude that RPE65 c.393T>A, p.(Asn131Lys) contributed to the pathologic phenotype, demonstrating its significance clearly in the case presented, and should be reclassified according to the criteria of evidence as likely pathogenic. This being the case, patients with this specific variant are likely candidates for genetic treatment.

Figure 1

ultra-widefield fundus photos of the (a) right eye and the (b) left eye showing pale and waxy optic nerve head with clear boundaries and area of atrophy peripapillary, paving-stone degeneration, drusen-like retinal deposits, bone spicule-like pigmentary clumping, and attenuated retinal vessels at mid- and far periphery.

Figure 2

Fundus autofluorescence photos of the (a) right eye and the (b) left eye. Pale fundi and absence of RPE autofluorescence. Chorioretinal atrophy reveals the hyperautofluorescent attributes of the sclera.