The phenotypic features in this NCMD pedigree continue to support the concept that this disorder is a congenital macular malformation rather than a progressive dystrophic entity. Unlike most NCMD families, there was no variable expressivity found in this study, possibly due to the relatively small size of the family. The other hypothesis is that the duplication involves genomic segments that are more consistently or tightly bound to other regulatory regions of PRDM13. The identification of a novel causative tandem duplication involving the DNASE1 site and the PRDM13 gene in this family allows for the expansion of the mutational spectrum of the disease.

Seven affected subjects from a Mexican family underwent a complete ophthalmic assessment that included dilated indirect ophthalmoscopy, fundus photography, optical coherence tomography (OCT), fundus autofluorescence (FAF), kinetic and chromatic perimetry, and electroretinography (ERG). Next-generation sequencing (NGS), followed by array-based comparative genomic hybridization (array-CGH) and quantitative polymerase chain reaction (qPCR) analyzes, were employed to demonstrate the causative molecular defect.

North Carolina macular dystrophy (NCMD) is a rare autosomal dominantly inherited congenital maculopathy caused by either non-coding point mutations or tandem duplications in the DNase I hypersensitivity site DHS6S1, at chromosome 6q16 (MCDR1), or at chromosome 5 (MCDR3). To date, at least 30 NCMD pedigrees from different ethnicities have been genetically identified worldwide. Herein, we report the clinical and genetic features of a newly found NCMD family in Mexico with a novel tandem duplication involving both the DNASE1 site and the PRDM13 gene.

All seven affected patients had a severe appearing phenotype characterized by symmetric excavated atrophic coloboma-like chorioretinal macular lesions. In addition, using OCT, lacunae in the inner retinal layers and inner retinal loss were observed in all patients. NGS identified a heterozygous tandem duplication of the entire coding sequence of the PRDM13 gene in all seven affected individuals, whereas subsequent array CGH, NGS, and Sanger sequencing allowed for the identification of the precise boundaries of a ~148 kb MCDR1 duplication containing the whole PRMD13 gene and the DNASE1 site. Conclusions: The phenotypic features in this NCMD pedigree continue to support the concept that this disorder is a congenital macular malformation rather than a progressive dystrophic entity. Unlike most NCMD families, there was no variable expressivity found in this study, possibly due to the relatively small size of the family. The other hypothesis is that the duplication involves genomic segments that are more consistently or tightly bound to other regulatory regions of PRDM13. The identification of a novel causative tandem duplication involving the DNASE1 site and the PRDM13 gene in this family allows for the expansion of the mutational spectrum of the disease.