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North Carolina macular dystrophy (NCMD) is an autosomal dominant congenital maculopathy characterized by distinctive macular changes that range from subtle drusen‐like deposits to coloboma‑like excavations. Multiple independent studies have identified noncoding point mutations and tandem duplications in regulatory regions of PRDM13, establishing a critical link between PRDM13 dysregulation and NCMD (PMID:26507665).
Genetic evidence supporting this association comes from several case reports and multi‐patient studies demonstrating pathogenic variants segregating in affected families. In one multi‐family study, over 102 affected individuals across 12 families exhibited variants in the DNase I hypersensitivity region upstream of PRDM13, thereby firmly establishing autosomal dominant inheritance (PMID:26507665). Other studies, including a Mexican family report and additional East Asian studies, have identified recurrent mutations at the identical nucleotide hotspot, which further corroborates the genetic basis of NCMD (PMID:37008391).
A representative variant, reported as a deletion in PRDM13, is described using HGVS nomenclature as: c.398-2_408del (p.Val133SerfsTer15). This variant, among others, underlines the mutational spectrum that perturbs normal gene regulation during retinal development. In these families, the aberrant regulation of PRDM13 has been linked with variable expressivity of the macular phenotype, ranging from mild visual impairment to severe central excavation (PMID:27777503).
Functional studies have reinforced these findings; enhancer assays, in vivo reporter experiments, and expression analyses in fetal retinal tissues have all demonstrated that disruption of cis‐regulatory elements near PRDM13 leads to its developmental misexpression. These data suggest that the pathogenic mechanism is likely due to a gain of function through inappropriate overexpression of PRDM13 during macular development (PMID:36243009).
It is noteworthy that while duplications involving adjacent genes such as CCNC or IRX1 have been reported, the preponderance of evidence clearly indicates that dysregulation of PRDM13 is the primary driver of the NCMD phenotype. The consistency of the genotype–phenotype correlation across diverse ethnicities and study designs further strengthens this association.
In summary, the convergence of robust genetic and functional evidence establishes a definitive association between PRDM13 and North Carolina macular dystrophy. For clinical diagnostic decision‑making, the identification of PRDM13 regulatory variants offers high specificity and direct implications for patient management and genetic counseling.
Key Take‑home: Detection of PRDM13 regulatory mutations should be integrated into clinical evaluations for NCMD as it provides a definitive molecular diagnosis that informs prognosis and guides management decisions.
Gene–Disease AssociationDefinitiveOver 102 affected individuals across 12 families exhibit autosomal dominant segregation with recurrent noncoding and duplication variants affecting PRDM13 regulatory elements, supported by robust functional data (PMID:26507665, PMID:36243009). Genetic EvidenceStrongMultiple independent case reports and multi‑patient studies have identified diverse pathogenic variants—including noncoding point mutations and tandem duplications—in PRDM13, with confirmed segregation in affected families (PMID:37008391, PMID:27777503). Functional EvidenceModerateIn vitro and in vivo functional assays demonstrate that disruption of cis‑regulatory elements near PRDM13 leads to its misexpression in retinal development, consistent with the NCMD phenotype (PMID:36243009). |