UNASSIGNED: To clinically and molecularly study a newly found family with North Carolina macular dystrophy (NCMD/MCDR1) from Mexico.
UNASSIGNED: This retrospective study comprised 6 members of a 3-generation Mexican family with NCMD. Clinical ophthalmic examinations, including fundus imaging, spectral-domain optical coherence tomography, electroretinography, and electrooculography, were performed. Genotyping with polymorphic markers in the MCDR1 region was performed to determine haplotypes. Whole-genome sequencing (WGS) was performed followed by variant filtering and copy number variant analysis.
UNASSIGNED: Four subjects from 3 generations were found to have macular abnormalities. The proband presented with lifelong bilateral vision impairment with bilaterally symmetric vitelliform Best disease-like appearing macular lesions. Her 2 children had bilateral large macular coloboma-like malformations, consistent with autosomal dominant NCMD. The 80-year-old mother of the proband had drusen-like lesions consistent with grade 1 NCMD. WGS and subsequent Sanger sequencing found a point mutation at chr6:99593030G>C (hg38) in the noncoding region of the DNase I site thought to be a regulatory element of the retinal transcription factor gene PRDM13. This mutation is the identical site/nucleotide as in the original NCMD family (#765) but is a guanine to cytosine change rather than a guanine to thymine mutation, as found in the original NCMD family.
UNASSIGNED: We report a new noncoding mutation at the same locus (chr6:99593030G>C) involving the same DNase I site regulating the retinal transcription factor gene PRDM13. This suggests that this site, chr6:99593030, is a mutational hotspot.

Macular dystrophies are a heterogeneous group of genetic disorders that often severely threatens the bilateral central vision of the affected patient. While advances in molecular genetics have been instrumental in the understanding and diagnosis of these disorders, there remains significant phenotypical variation among patients within any particular subset of macular dystrophies. Electrophysiological testing remains a vital tool not only to characterize vision loss for differential diagnosis but also to understand the pathophysiology of these disorders and to monitor the treatment effect, potentially leading to therapeutic advances. This review summarizes the application of electrophysiological testing in macular dystrophies, including Stargardt disease, bestrophinopathies, X-linked retinoschisis, Sorsby fundus dystrophy, Doyne honeycomb retina dystrophy, autosomal dominant drusen, occult macular dystrophy, North Carolina macular dystrophy, pattern dystrophy, and central areolar choroidal dystrophy.

BACKGROUND: This study provides a detailed description of a Chinese family with North Carolina macular dystrophy (NCMD) and explores its possible pathogenesis.
METHODS: Five individuals from a three-generation family underwent general ophthalmic examination, multi-imaging examinations and visual electrophysiology examinations when possible. Genetic characterization was carried out by target region sequencing and high-throughput sequencing in affected patients.
RESULTS: Despite severe fundus changes, patients had relatively good visual acuity. Genetic analysis showed that affected patients had PRDM13 gene duplication and heterozygous mutations of the ABCA4 gene. Optical coherence tomography (OCT) showed an abnormal retinal pigment epithelium (RPE) layer in patients with grade 2 lesions, while the neurosensory retina was relatively normal. In grade 3 patients, RPE and choroid atrophy were greater than that of the neurosensory retina, showing concentric atrophy.
CONCLUSIONS: RPE and choroidal atrophy were found to play an important role in the development of macular caldera.

The phenotype of North Carolina macular dystrophy (NCMD) is highly variable and remains poorly appreciated and understood, often causing misdiagnoses in isolated cases. One of the features of NCMD is the general lack of progression despite its original name, \"dominant progressive foveal dystrophy,\" as reported in 1971 by Lefler et al (W.H.L.). The purpose of this study was to report the long-term follow-up of this condition.
Systematic, longitudinal, and detailed documentation along with the imaging of the peripheral retina.
We reexamined 27 of the original family members with NCMD in an office setting 30 to 50 years after they were first reported.
The evaluation of all the affected subjects included best-corrected visual acuity (BCVA), slit-lamp and dilated-fundus examinations, wide-field fundus and autofluorescent photography, and spectral-domain OCT (SD OCT). Blood was collected for DNA extraction, banking, and sequencing.
Best-corrected visual acuity, slit-lamp and dilated-fundus examinations, wide-field fundus and autofluorescent photography, and SD OCT.
The 27 subjects examined were a part of the original family with NCMD that was initially reported in 1971. A point mutation (NC_000006.11:g.100040906G>T) (Hg19) in a noncoding region of a deoxyribonuclease I hypersensitivity binding site was found in all the affected subjects. Nine subjects were the affected children of those originally examined 30 to 50 years ago by Kent W. Small (K.W.S.) and W.H.L., and the remaining 17 subjects (34 eyes) had been examined 30 years previously by K.W.S. Of these 17 subjects (34 eyes), 4 of 34 (11%) eyes showed worsening of vision and evidence of fibrosis due to choroidal neovascular membranes (CNVMs). Fourteen of the 27 (51%) patients showed peripheral retinal drusen, which did not seem to correlate with the severity of the macular disease.
Most patients with NCMD have stable vision and fundus findings throughout their lives. The ones who experienced BCVA decline did so because of the apparent evidence of CNVMs. Patients with grade 2 NCMD seem to be at an increased risk of further or progressive vision loss due to CNVMs. Intravitreal therapy with vascular endothelial growth factor inhibitors may benefit these patients if they are treated in a timely fashion. Peripheral retina drusen of varying degrees of severity were found in slightly more than half of the affected subjects.

OBJECTIVE: North Carolina macular dystrophy (NCMD) is a rare autosomal dominant inherited disorder characterized by macular impairment with a variety of phenotypic manifestations. The aims of this study were to assess the clinical features of a Chinese family with NCMD and to identify the underlying genetic cause of the disease.
METHODS: Three patients from a Chinese family were included in this study. Detailed ophthalmological examinations were performed, including best corrected visual acuity (BCVA), slit lamp, dilated indirect ophthalmoscopy, fundus photography, optical coherence tomography (OCT), fundus autofluorescence, full-field electroretinography (ERG), and electrooculography (EOG). Genomic DNA was extracted from peripheral blood samples. Whole-genome sequencing and long-read genome sequencing were applied to detect the pathogenic variants. Sanger sequencing was performed to confirm the breakpoints.
RESULTS: All three patients had macular involvement ranging from patchy yellowish-white lesions to big-area thinning, which are typical for NCMD. The BCVA ranged from 20/50 to 20/20. OCT revealed varying degrees of macular structure disorganization. The ERG responses were normal, and the Arden ration of the EOG was reduced. A novel 134.6 kb (g.99932464-100067110dup) tandem duplication on chromosome 6 (NC_000006.11) encompassing the entire CCNC and PRDM13 genes and a DNase 1 hypersensitivity site in the MCDR1 locus was identified.
CONCLUSIONS: A novel large tandem duplication in MCDR1 locus was confirmed in a Chinese family with NCMD with a variety of macular phenotypes.

OBJECTIVE: We present a familial hereditary macular dystrophy, resembling North Carolina Macular Dystrophy. In members of a family, we describe the development of diagnostic-therapeutic approaches and their impact on the prognosis of those whose vision was affected.
METHODS: The macular dystrophy of varying degrees of severity was diagnosed in 3 consecutive generations in different family members, both men and women. Modern therapeutic tools were used for the diagnostics. In one patient of the youngest generation, the development of secondary choroidal neovascularization (CNV) was identified and treated with an anti-VEGF (vascular endothelial growth factor) agent. DNA was isolated from venous blood and genome sequencing was performed in a proband.
RESULTS: We analysed the data of 13 members of one family of three consecutive generations. Six of them had macular dystrophy. The first were two of three siblings, a woman (73 years old) and a man (67). The offspring of the afflicted man, a female (36) and a male (80), had maculopathy. The first daughter of the woman (12) revealed findings of maculopathy but with normal electrical activity of the retina. The second girl (18), developed secondary CNV which responded well to intravitreal anti-VEGF treatment. Genetic analysis excluded mutations previously reported to be pathogenic for NCMD.
CONCLUSIONS: If there is a maculopathy of unclear etiology in younger patients or in patients with unclear development or appearance, it is advisable to focus carefully on the family history and trace the occurrence of impaired vision in other family members.

Fundus autofluorescence (FAF) is a non-invasive retinal imaging modality used in clinical practice to non-invasively map changes at the level of the retinal pigment epithelium (RPE)/photoreceptor complex and alterations of macular pigment distribution. This imaging method is based on the visualization of intrinsic fluorophores and may be easily and rapidly used in routine patient care. Excessive accumulation of lipofuscin granules in the lysosomal compartment of RPE cells represents a common downstream pathogenic pathway in various hereditary and complex retinal diseases. The clinical applications of FAF continue to expand. It is now an essential tool for evaluating macular dystrophies and various hereditary retinal disorders. Fundus autofluorescence (FAF) may detect abnormalities beyond those detected on funduscopic examination, fluorescein angiography (FA) or optical coherence tomography (OCT). Fundus autofluorescence (FAF) imaging is particularly helpful for differential diagnosis, detection and extent delineation of involved retinal areas, genotype-phenotype correlations and monitoring of changes overtime. Given its ease of use, non-invasive nature and value in characterizing retinal disease, FAF enjoys increasing clinical relevance. This review summarizes basic principles and FAF findings in various hereditary retinal diseases.

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 (MCDR1) with recent support for a non-coding disease mechanism of PRDM13. A second locus on 5p15-5p13 (MCDR3) has been implicated in a similar phenotype, but the disease-causing mechanism still remains unknown.
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.
Linkage analysis excluded MCDR1 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 MCDR3. The haplotype sharing analysis in one of the families revealed a 5 cM shared IBD segment at 5p15.32 (p value = 0.004). Whole-exome sequencing did not provide conclusive evidence for disease-causing alleles.
These findings do not exclude that this phenotype may be allelic with NCMD MCDR3 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.

OBJECTIVE: North Carolina macular dystrophy (NCMD) is a very rare autosomal dominant hereditary disease. Up to date there are three types of NCMD described and consequently named macular dystrophy, retinal: MCDR1, MCDR2 and MCDR3. The aim of this study was to perform linkage and copy number variation analysis for the family affected by NCMD followed by the selected candidate gene sequencing.
METHODS: This study concerned a 3-generation, non-consanguineous Latvian family with NCMD. Genome-wide scan, copy number variation and non-parametric linkage analysis was performed. Analysis resolved the locus of interest to the 5p15.33 region. Two of the genes, iroquois homeobox 2 (IRX2) and iroquois homeobox 4 (IRX4), were selected and sanger sequencing was performed.
RESULTS: Linkage analysis indicated a region on chromosome 5 for the analyzed family, corresponding to a genetic locus previously described for MCDR3 (5p15-p13). Chromosomal aberrations were not identified in the affected family members. An upstream intron variant (NM_001278634: c.-139G > A (rs6876836)) in IRX4 gene segregated with NCMD phenotype in the analyzed family.
CONCLUSIONS: It is unlikely to be the causative mutation of NCMD due to its high minor allele frequency 0.3532. Therefore, the role of IRX2 and IRX4 genes in the pathogenesis of NCMD has not been proved. Considerable variability in visual acuity between individuals of the same age group in all the families examined was noted. No overlap between NCMD grade and family generation was seen in the family described in the present study.