Pathogenic variants in North Carolina macular dystrophy (NCMD) have rarely been reported in the East Asian population. Herein, we reported novel variants of NCMD in 2 Korean families. The regions associated with NCMD were analyzed with genome sequencing, and variants were filtered based on the minor allele frequency (0.5%) and heterozygosity. Non-coding variants were functionally annotated using multiple computational tools. We identified two rare novel variants, chr6:g.99,598,914T>C (hg38; V17) and chr6:g.99,598,926G>A (hg38; V18) upstream of PRDM13 in families A and B, respectively. In Family 1, Grade 2 NCMD and a best-corrected visual acuity of 20/25 and 20/200 in the right and left eyes, respectively, were observed. In Family B, all affected individuals had Grade 1 NCMD with characteristic confluent drusen at the fovea and a best-corrected visual acuity of 20/20 in both eyes. These two variants are 10-22 bp downstream of the reported V10 variant within the DNase1 hypersensitivity site. This site is associated with progressive bifocal chorioretinal atrophy and congenital posterior polar chorioretinal hypertrophy and lies in the putative enhancer site of PRDM13. We identified two novel NCMD variants in the Korean population and further validated the regulatory role of the DNase1 hypersensitivity site upstream of PRDM13.

To describe a new ocular phenotype in a single Egyptian family associated with a heterozygous noncoding mutation in the North Carolina macular dystrophy (NCMD/MCDR1) locus, likely affecting the PRDM13 gene. A retrospective, clinical chart review of 11 members of a four-generation family. Comprehensive ophthalmic examinations included visual acuity, refraction, fundus imaging, spectral-domain optical coherence tomography, and full-field electroretinography. Molecular genetic analysis of the MCDR1 region was performed using whole genome and targeted sequencing. The main outcome measures were DNA sequence variants, clinical, retinal imaging, and electroretinography findings. The five affected adult family members tested carried a single heterozygous mutation in a noncoding region (Chr6:100,046,783A>C) located 7.8 kb upstream of PRDM13. Visual acuity ranged from 20/200 to 20/400. All members had extensive chorioretinal absence/thinning extending outside of the maculae with extensive posterior bowing of the choroid and sclera centered in the macula giving a large macular coloboma-like appearance. Two additional members had cystoid fluid, and one had macular detachment. Full-field electroretinography revealed reduced cone and rod responses in all affected members. The phenotype of this disease falls between the spectrum of progressive bifocal chorioretinal atrophy and NCMD. The findings are most consistent with progressive bifocal chorioretinal atrophy with the exception that there is no bifocal nature to the appearance nor is it progressive. Another view is that the phenotype seems to be an extremely severe form of NCMD. Given that this disease falls in between progressive bifocal chorioretinal atrophy and NCMD, we propose calling it congenital posterior polar chorioretinal hypoplasia.

The autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA) disease locus has been mapped to chromosome 6q14-16.2 that overlaps the North Carolina macular dystrophy (NCMD) locus MCDR1. NCMD is a nonprogressive developmental macular dystrophy, in which variants upstream of PRDM13 have been implicated. Whole genome sequencing was performed to interrogate structural variants (SVs) and single nucleotide variants (SNVs) in eight individuals, six affected individuals from two families with PBCRA, and two individuals from an additional family with a related developmental macular dystrophy. A SNV (chr6:100,046,804T>C), located 7.8 kb upstream of the PRDM13 gene, was shared by all PBCRA-affected individuals in the disease locus. Haplotype analysis suggested that the variant arose independently in the two families. The two affected individuals from Family 3 were screened for rare variants in the PBCRA and NCMD loci. This revealed a de novo variant in the proband, 21 bp from the first SNV (chr6:100,046,783A>C). This study expands the noncoding variant spectrum upstream of PRDM13 and suggests altered spatio-temporal expression of PRDM13 as a candidate disease mechanism in the phenotypically distinct but related conditions, NCMD and PBCRA.