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Maria Carolina Ortube, Samuel P Strom, Ariadna Martinez, Michael Gorin; The Challenges, limitations and uncertainties of whole exome sequencing (WES) for hereditary ocular disorders.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6393.
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© ARVO (1962-2015); The Authors (2016-present)
To describe three pediatric genetic cases with heterogeneous retinal phenotypes.
Case 1 was a five months old boy with infantile nystagmus, light perception and nondetectable electroretinogram (ERG), macular atrophy, optic nerve pallor and diffuse retinal pigment epithelium (RPE) changes. WES identified a De novo heterozygous c.124 G>A variant in CRX gene (19q13.33). Variants in the CRX gene are associated with autosomal dominant (AD) cone-rod dystrophy-2 (OMIM 120970) and Leber Congenital Amaurosis (LCA- type 7, OMIM 613829). This variant has previously been reported in a patient with LCA. Additionally a heterozygous c.244 C>T variant of uncertain clinical significance was detected in the AIPL1 gene. Variants in the AIPL1 gene are associated with autosomal recessive (AR) LCA 4, AD juvenile retinitis pigmentosa (OMIM 604392) and AD cone-rod dystrophy (OMIM 604393). This case shows 2 heterozygous mutations in disease-causing genes with an uncertain clinical significance. Case 2 was a 2.5 years old male born to consanguineous parents with myopia, intermittent exotropia, retinal background pigmentation, foveal atrophy and proliferative optic nerve gliosis. He developed visual acuities of counting fingers, severe iritis, nystagmus, cataracts and atypical coalescent areas of macular retinal atrophy with unusual paravenous sheathing. ERG was nondetectable for cones and moderately depressed for rod photoreceptors. WES detected a homozygous c.458 C>T variant in the KCNJ13 gene. KCNJ13 gene mutations have been described in AD snowflake vitreoretinal degeneration (OMIM 193230) and AR LCA cases (OMIM 614186). This KCNJ13 gene variant (c.458 C>T) has not been previously reported and is predicted to be possibly damaging/deleterious (SIFT/PolyPhen). Case 3 was a 13 years old female with congenital nystagmus, photophobia, 20/200 vision and normal fundus exam. ERG showed absence of cone responses and preserved rod responses. A homozygous c.1958T variant in PDE6C was identified by WES. Variants in PDE6C are known to cause AR achromatopsia and cone dystrophy type 4. (OMIM 613093).
Molecular genetics has opened a new path to understand the complexity of retinal diseases. However, in cases with heterogeneous retinal phenotypes, molecular genetics by WES can challenge the clinician to understand which gene is responsible for the ocular condition.
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