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BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Original publication




Journal article


Ophthalmic Genet

Publication Date





511 - 519


Congenital limb deformities, North Carolina macular dystrophy, genetic linkage, macular dystrophy, retinal 1, human, retinal dysplasia, Adult, Aged, Child, Preschool, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Corneal Dystrophies, Hereditary, Electroretinography, Exome, Eye Proteins, Female, Fluorescein Angiography, Genetic Linkage, Genome-Wide Association Study, Genotyping Techniques, Haplotypes, Humans, Limb Deformities, Congenital, Male, Middle Aged, Pedigree, Polymerase Chain Reaction, Sequence Analysis, DNA, Tomography, Optical Coherence