Schematic and representative images of measurements in fundus autofluorescence imaging and spectral-domain optical coherence tomography.

<p>Patient 9: area of questionably decreased autofluorescence (QDAF, blue), 1.37 mm²; area of definitely decreased autofluorescence (black), 0.33 mm²; transverse loss of external limiting membrane (ELM-loss, red), 1.75 mm, transverse loss of ellipsoid zone (EZ-loss, blue), 2.24 mm; best-corrected visual acuity, 20/100; <i>ABCA4</i> variants, c.1622T>C;3113C>T:p.[Leu541Pro;Ala1038Val] and c.6316C>T:p.(Arg2106Cys).</p

Highest potential mean-to-standard deviation ratio (MSDR) for each single outcome measure at different weightings with all possible weight combinations of the other metrics.

<p>MSDRs for best-corrected visual acuity (grey) decrease at increasing weight. MSDRs for transition zones of questionably decreased autofluorescence (blue) increase until 25% weight, but gradually decrease at higher weights. MSDRs for transition zones of definitely decreased autofluorescence decrease at weights higher than 5%. MSDRs for loss of the ellipsoid zone (green) are constant, but decrease substantially at weights higher than approximately 70%. MSDRs for loss of the external limiting membrane (black) decrease at weights higher than approximately 80%.</p

Visual acuity as a function of degrees of retinal eccentricity.

<p>Visual acuity as a function of degrees of retinal eccentricity.</p

Characteristics of early-onset Stargardt cohorts from Radboud university medical center (Radboudumc) and Moorfields Eye Hospital (MEH).

<p>Characteristics of early-onset Stargardt cohorts from Radboud university medical center (Radboudumc) and Moorfields Eye Hospital (MEH).</p

Weighted composite score and predicted outcome.

<p>Matching colors represent the right and left eye of the same patient. (A) Results from six early-onset Stargardt patients. (B) The predicted outcome in the replication cohort showed comparable results.</p

<i>ABCA4</i> variants in early-onset Stargardt patients from Radboud university medical center (Radboudumc) and Moorfields Eye Hospital (MEH).

<p><i>ABCA4</i> variants in early-onset Stargardt patients from Radboud university medical center (Radboudumc) and Moorfields Eye Hospital (MEH).</p

Yearly progression rate of changes in retinal eccentricity (<i>ε</i>) by visual function, fundus autofluorescence and optical coherence tomography.

<p>Yearly progression rate of changes in retinal eccentricity (<i>ε</i>) by visual function, fundus autofluorescence and optical coherence tomography.</p

Genome-wide linkage and haplotype sharing analysis implicates the <i>MCDR3</i> locus as a candidate region for a developmental macular disorder in association with digit abnormalities

<p><i>Background</i>: Developmental macular disorders are a heterogeneous group of rare retinal conditions that can cause significant visual impairment from childhood. Among these disorders, autosomal dominant North Carolina macular dystrophy (NCMD) has been mapped to 6q16 (<i>MCDR1</i>) with recent support for a non-coding disease mechanism of <i>PRDM13</i>. A second locus on 5p15-5p13 (<i>MCDR3</i>) has been implicated in a similar phenotype, but the disease-causing mechanism still remains unknown.</p> <p><i>Methods</i>: Two families affected by a dominant developmental macular disorder that closely resembles NCMD in association with digit abnormalities were included in the study. Family members with available DNA were genotyped using the Affymetrix GeneChip Human Mapping 250K Sty array. A parametric multipoint linkage analysis assuming a fully penetrant dominant model was performed using MERLIN. Haplotype sharing analysis was carried out using the non-parametric Homozygosity Haplotype method. Whole-exome sequencing was conducted on selected affected individuals.</p> <p><i>Results</i>: Linkage analysis excluded <i>MCDR1</i> from the candidate regions (LOD < –2). There was suggestive linkage (LOD = 2.7) at two loci, including 9p24.1 and 5p15.32 that overlapped with <i>MCDR3</i>. The haplotype sharing analysis in one of the families revealed a 5 cM shared IBD segment at 5p15.32 (<i>p</i> value = 0.004). Whole-exome sequencing did not provide conclusive evidence for disease-causing alleles.</p> <p><i>Conclusions</i>: These findings do not exclude that this phenotype may be allelic with NCMD <i>MCDR3</i> at 5p15 and leave the possibility of a non-coding disease mechanism, in keeping with recent findings on 6q16. Further studies, including whole-genome sequencing, may help elucidate the underlying genetic cause of this phenotype and shed light on macular development and function.</p

Summary of Clinical Characteristics of Patients with Disease Causing Mutations in <i>AIPL1</i>.

<p>BCVA – best corrected visual acuity; PL - perception of light; BEO – both eyes open; PL - perception of light; XT - exotropia; ET - esotropia; N – no; ND – not done; Am –amaurotic; NS - nuclear sclerosis; OD - right eye; OS - left eye; PAT- photoattraction; PAV - photoaversion; DR- drusen; PS - posterior subcapsular cataract; KC – keratoconus; Y – yes.</p

Scotopic and photopic ERG recordings of patient case 7.

<p>ERGs recorded from case 7 aged 14 months, using skin electrodes to a range of flash strengths (Grass (gr) 1–16) presented scotopically and photopically are shown above age-matched control data in the lower grey panel. These ERGs indicate cone photoreceptor dysfunction; evidenced by markedly reduced photopic cone and 30 Hz flicker ERGs, and a scotopic red flash ERG that shows predominance of the later rod dominated b-wave (arrowed). The scotopic (gr4) mixed rod cone waveform lacks an a-wave and the time to peak is increased. In contrast predominantly rod mediated function is within the normal range; evidenced by the normal a-wave to a maximal scotopic flash and rod driven b-wave to a scotopic dim blue flash.</p