Cipriani, ValentinaSilva, Raquel S.Arno, GavinPontikos, NikolasKalhoro, AmbreenValeina, SandraInashkina, InnaAudere, MaretaRutka, KatrinaPuech, BernardMichaelides, MichelVan Heyningen, VeronicaLace, BaibaWebster, Andrew R.Moore, Anthony T.2021-09-142021-09-142017-12-01Cipriani, V, Silva, R S, Arno, G, Pontikos, N, Kalhoro, A, Valeina, S, Inashkina, I, Audere, M, Rutka, K, Puech, B, Michaelides, M, Van Heyningen, V, Lace, B, Webster, A R & Moore, A T 2017, 'Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus', Scientific Reports, vol. 7, no. 1, 7512. https://doi.org/10.1038/s41598-017-06387-62045-2322https://dspace.rsu.lv/jspui/handle/123456789/6339Publisher Copyright: © 2017 The Author(s).Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been linked to two loci, MCDR1 (chromosome 6q16) and MCDR3 (chromosome 5p15-p13). Recently, non-coding variants upstream of PRDM13 (MCDR1) and a duplication including IRX1 (MCDR3) have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies on eighteen NCMD families, we report two novel overlapping duplications at the MCDR3 locus, in a gene desert downstream of IRX1 and upstream of ADAMTS16. One duplication of 43 kb was identified in nine families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. Three families carry the previously reported V2 variant (MCDR1), while five remain unsolved. The MCDR3 locus is thus refined to a shared region of 39 kb that contains DNAse hypersensitive sites active at a restricted time window during retinal development. Publicly available data confirmed expression of IRX1 and ADAMTS16 in human fetal retina, with IRX1 preferentially expressed in fetal macula. These findings represent a major advance in our understanding of the molecular genetics of NCMD and provide insights into the genetic pathways involved in human macular development.91671496enginfo:eu-repo/semantics/openAccess3.2 Clinical medicine1.1. Scientific article indexed in Web of Science and/or Scopus databaseGeneralSDG 3 - Good Health and Well-being/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article10.1038/s41598-017-06387-6http://www.scopus.com/inward/record.url?scp=85027037545&partnerID=8YFLogxK