Novel truncating mutation in CACNA1F in a young male patient diagnosed with optic atrophy

Background: Low vision in children can be accompanied by pallor of the optic disc with little or no characteristic morphologic changes of the retina. A variety of diseases can be the underlying cause, including hereditary optic atrophy, Leber's congenital amaurosis (LCA), achromatopsia, and calcium channel, voltage-dependent, L-type, alpha-1F subunit gene (CACNA1F)-associated retinopathy (most widely known as incomplete congenital stationary night blindness: iCSNB). Differentiation at early age is desirable due to large differences in prognosis, but may be difficult because phenotypes overlap and electrophysiological testing is challenging in young patients. We present the case of a 6-year-old boy with unexplained low vision and pallor of the optic disc who originally had been diagnosed with hereditary optic atrophy in the absence of recordable full-field electroretinography (ERG) due to poor patient cooperation. Materials and Methods: Standard Sanger sequencing excluded mutations in the OPA1 gene (autosomal-dominant optic atrophy). To identify the underlying genetic cause, whole-exome sequencing was performed on patient's DNA. Recording of the full-field ERG was successfully performed 6 months later. Results: We identified a novel truncating mutation in CACNA1F gene (NM_001256789: c.3895C > T in exon 33) which led to the correct diagnosis of CACNA1F-associated retinopathy in the young boy. ERG recordings showed a negative scotopic mixed response with preserved oscillatory potentials and a flicker ERG with reduced amplitude and biphasic waveform, compatible with a CACNA1F-asssociated phenotype. Conclusions: We show that genetic testing may help to differentiate between optic atrophy, LCA, and CACNA1F-associated retinopathy at a much earlier age, in absence of electrophysiological examination and by widely overlapping phenotypes.