Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy

Abstract

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 Human Mutation. 2019;40:578-587. wileyonlinelibrary.com/journal/humu 578 |

North Carolina macular dystrophy: phenotypic variability and computational analysis of disease-implicated non-coding variants

“…This change has been identified in a single family with two affected individuals, a mother and her child; while the mother had typical findings of NCMD, the child had broader retinal involvement in keeping with a related developmental disorder, progressive bifocal chorioretinal atrophy (PBCRA). 2 Notably, an adjacent variant, chr6:100,046,804T>C…”

“…(orange line in the variant row of the Figure), has been reported to cause PBCRA in six affected individuals from two families. 2 The fact that the candidate enhancer encompassing these two PBCRA-implicated variants appears to have a role in both macular and retinal tissue may explain why individuals carrying these changes often develop a phenotype that is more severe than NCMD and is associated with generalized retinal dysfunction. The CADD score ranges from 1 to 99; a higher score indicates greater pathogenicity.…”

“…The phenotype ranges from visually inconsequential subtle retinal spots to macular coloboma-like lesions associated with significant visual impairment. [1][2][3][4][5][6] NCMD was first described in the 1970s in a large pedigree of more than 500 individuals spanning seven generations. This kindred represented a portion of the descendants of two brothers who emigrated from Ireland to the mountains of North Carolina in the early 19 th century.…”

“…Although both these disorders affect the macula from birth, the latter is typically associated with disease progression and electrophysiological evidence of widespread retinal dysfunction. 2 It is also noteworthy that a number of individuals with a phenotype indistinguishable from NCMD have been found to have copy number variants in a different locus in chromosome 5. 1,2 NCMD is part of an expanding group of Mendelian conditions caused by non-coding genetic variants that have an effect on gene expression (e.g., aniridia, 18 limb malformations 19 ).…”

“…2 It is also noteworthy that a number of individuals with a phenotype indistinguishable from NCMD have been found to have copy number variants in a different locus in chromosome 5. 1,2 NCMD is part of an expanding group of Mendelian conditions caused by non-coding genetic variants that have an effect on gene expression (e.g., aniridia, 18 limb malformations 19 ). These variants often alter the sequence of regulatory elements, including transcriptional promoters and enhancers.…”