PMC5360453_01
Novel disease-causing variants in TTLL5 in cone dystrophy: Pedigree of the index patient with disease-causing variants in TTLL5 and cosegregation analysis. The index patient, the proband, is the individual II-3, marked with an arrow. Square symbol=male, round symbol=female, filled symbol=affected, unfilled symbol=unaffected, double line=consanguinity. Underneath the symbols, the sequence electropherograms of the disease-causing variant in TTLL5 is found homozygously in the proband and heterozygously in the parents. The underlined letters correspond to the modifications of the sequence induced by this disease-causing variant.
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The index patient was a 9-year-old boy (Figure 2, II-3), corrected for myopia since 3 years of age, who always had difficulty watching television and reading. This c.182-3_182-1delinsAA mutation in TTLL5 was validated in the index patient and the unaffected parents with direct Sanger sequencing (Figure 2).
Clinical investigations of the patient with a homozygous mutation in TTLL5. A: Fundus photographs of the right (left side) and left (right side). There is no macular atrophy or pigment deposits. B, C: The infrared reflectance images (B) and fundus autofluorescence (C) show a moderate increase in perifoveal autofluorescence. D: Optical coherence tomography of the right (up) and left (down) eyes with a selection of peripheral (left) and macular (right) slices for each side show that the periphery is normal while there are subtle changes in the perifoveal area with attenuation of the ellipsoid zone. E: The kinetic (peripheral isopter) and static visual field shows a normal peripheral visual field with a general decrease in retinal sensitivity in the central 30  in accordance with cone dysfunction. F: The International Society for Clinical Electrophysiology of Vision (ISCEV) electroretinogram (ERG) indicates a normal rod function (dark-adapted ERG) while the amplitude values of the cone function (light-adapted ERG) corresponded to 30% of the normal values.
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The index patient was a 9-year-old boy (Figure 2, II-3), corrected for myopia since 3 years of age, who always had difficulty watching television and reading. The fundus showed a moderate overall depigmentation, absence of the foveal reflex with a slight narrowing of the retinal vessels, and moderate pallor of the optic disc but no atrophy or pigment deposits, which was also confirmed with infrared reflectance images (Figure 3A,B). The retinal autofluorescence images were almost normal except a moderate perifoveal hyperautofluorescence (Figure 3C). Optical coherence tomography (OCT) showed a normal peripheral retina, but we noted bilaterally moderate macular thinning with the ellipsoid zone moderately decreased in the thickness in the temporal part of the fovea (Figure 3D). In mixed kinetic and static perimetry, the peripheral isopter IIIc was normal on each side, 90  in temporal and 45  in nasal, but there was a medium decrease in the retinal sensitivity of the central 30 , including in the macular area (Figure 3E). On the ISCEV ERG, the amplitude of the scotopic responses was normal (Figure 3F).