Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy

Optical genome mapping and revisiting short-read genome sequencing data reveal previously overlooked structural variants disrupting retinal disease−associated genes

“…It is clearly established that both SNVs and SVs can also have pathogenic consequences via noncoding mechanisms by affecting regulatory elements, topologically associated domain organization, splicing mechanisms, or untranslated region disruption. 2,35,36 It is likely that more pathogenic SVs are present in our data set, and follow-up analyses are warranted. This study highlights that SVs are an underestimated cause of IRDs and demand a sophisticated approach and more attention to facilitate detection during genome analyses.…”

Multi-omics analysis in human retina uncovers ultraconservedcis-regulatory elements at rare eye disease loci

“…This variant was exclusively found within the studied family, displaying isolated foveal abnormalities, and initially solved with an ultrarare missense variant in CFH, which could not fully explain the clinical presentation (Raychaudhuri et al, 2011;Taylor et al, 2019). As no other likely pathogenic variants were found within relevant loci (Ehrenberg et al, 2021;Kuht et al, 2020Kuht et al, , 2022Small et al, 2016;Van de Sompele et al, 2022), and the observed phenotypes of the affected individuals match within the PAX6 disease spectrum, mis-regulation of PAX6 expression cannot be excluded as a pathogenetic mechanism.…”

“…A major obstacle hampering their identification is the need to define the search space of the CREs they affect in a tissue- and even cell-type specific manner. Here we set out to address this challenge in human retina, of which the cis -regulatory architecture has been well-studied (Cherry et al, 2020; Marchal et al, 2022; Thomas et al, 2022) and for which there is emerging cis -regulatory variation implicated in disease (Bhatia et al, 2013; Ghiasvand et al, 2011; Plaisancié et al, 2018; Van de Sompele et al, 2022).…”

“…Interestingly, coding variants in these genes lead in most cases to syndromic developmental phenotypes with other manifestations apart from the ocular ones as collated in the G2P database 23 . As it has been shown before, the phenotype caused by a coding mutation of a developmental gene can be different from the phenotype caused by a mutation in a CRE controlling spatiotemporal expression of this gene; this is exemplified by the PRDM13 locus, for which bi-allelic coding PRDM13 variants result in hypogonadotropic hypogonadism and perinatal brainstem dysfunction in combination with cerebellar hypoplasia (Whittaker et al, 2021) while cis -regulatory variants in retinal CREs leads to NCMD, a developmental macular disease (Van de Sompele et al, 2022). From our analyses we could identify a cCRE for PRDM13 ( PRDM13_Blooklyn ) that displays an open chromatin context in early RPCs and developing amacrine cells, which are precisely the retinal cell types in which PRDM13 is expressed (Goodson et al, 2018; Watanabe et al, 2015).…”

“…A first example is a de novo single nucleotide variant (SNV) in an ultraconserved enhancer (SIMO element) 150 kb downstream of an intact PAX6 transcriptional unit, found in a case with aniridia (Bhatia et al, 2013). Second, tandem duplications within a gene desert downstream the IRXA cluster (Cipriani et al, 2017; Small et al, 2016) have been found in patients affected by North Carolina Macular Dystrophy (NCMD); the shared duplicated region harbors an enhancer element defined as UCNE that could act as a cis -regulator during retinal development (Van de Sompele et al, 2022).…”