2022
DOI: 10.1101/2022.03.08.481329
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Multi-omics profiling, in vitro and in vivo enhancer assays dissect the cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy

Abstract: North Carolina macular dystrophy (NCMD) is a rare autosomal dominant disease affecting macular development. With the identification of non-coding single nucleotide variants (SNVs) near PRDM13 and duplications overlapping a DNase I hypersensitive site (DHS) near PRDM13 or IRX1 as its underlying genetic cause, we hypothesize that NCMD is a retinal enhanceropathy. Here we aim to provide insight into the cis-regulatory mechanisms of NCMD by integrating multi-omics profiling of human retina with in vitro and in viv… Show more

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Cited by 3 publications
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“…Both laboratories found the SNV chr6:99593030 G>C rather than the G>T. Therefore, this noncoding DNase I hypersensitivity site, chr6:99593030 (MCDR1), can have 2 different mutations (first one G>T and herein G>C), suggesting this is a mutational hotspot. 50…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…Both laboratories found the SNV chr6:99593030 G>C rather than the G>T. Therefore, this noncoding DNase I hypersensitivity site, chr6:99593030 (MCDR1), can have 2 different mutations (first one G>T and herein G>C), suggesting this is a mutational hotspot. 50…”
Section: Discussionmentioning
confidence: 99%
“…Both laboratories found the SNV chr6:99593030 G>C rather than the G>T. Therefore, this noncoding DNase I hypersensitivity site, chr6:99593030 (MCDR1), can have 2 different mutations (first one G>T and herein G>C), suggesting this is a mutational hotspot. 50 Reviewing the known mutations along with this newly found mutation might provide insight into common underlying mechanisms causing NCMD and possibly related diseases such as PBRCA. 13,[35][36][37][38][39] This brings the total number of distinct pathogenic variants to 11 for PRDM13 (MCDR1) (Table 1).…”
Section: Discussionmentioning
confidence: 99%
“…Bioinformatic, in silico and in vitro studies also indicate that this DNASE1 site is functional in the macula and peripheral retina and does act as a regulatory element of PRDM13 (Figure 5). 18,22 North Carolina macular dystrophy (NCMD/MCDR1) and PBCRA seem to represent the two ends of a clinical and genetic spectrum of diseases of DNASE1 hypersensitivity binding site mutations affecting the dysregulation of PRDM13 .…”
Section: Discussionmentioning
confidence: 99%