Abstract
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.
Highlights
North Carolina macular dystrophy (NCMD) is a rare autosomal dominant disorder in which there is abnormal development of the macula, a crucial structure of the central retina responsible for central vision and colour perception[1]
Four families were previously reported: suggestive linkage at the MCDR3 locus has been recently described for family 114, family 2 was originally reported to be linked to the MCDR3 locus[11], and families 12 and 13 were linked to MCDR17, 9, with family 13 recently found to carry the single nucleotide variants (SNVs) V2 upstream of PRDM1315
We report two distinct heterozygous tandem duplications at the MCDR3 locus in 30 affected individuals from 10 NCMD families
Summary
North Carolina macular dystrophy (NCMD) is a rare autosomal dominant disorder in which there is abnormal development of the macula, a crucial structure of the central retina responsible for central vision and colour perception[1]. Understanding the genetics of rare developmental macular conditions is key for unravelling the mechanism of development of this structure that is found only in higher primates within mammals[1]. One MCDR3-linked family of Danish origin[3] was found to carry a 900 kb tandem duplication[15] that includes the entire coding sequence of IRX1. In this report we present a combination of genomic investigations in a cohort of 18 NCMD families. The aim of this study was to identify any causative molecular changes and mechanism of disease in these families
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