TY - JOUR T1 - Duplication events downstream of <em>IRX1</em> cause North Carolina macular dystrophy at the MCDR3 locus JF - bioRxiv DO - 10.1101/107573 SP - 107573 AU - Valentina Cipriani AU - Raquel S Silva AU - Gavin Arno AU - Nikolas Pontikos AU - Ambreen Kalhoro AU - Sandra Valeina AU - Inna Inashkina AU - Mareta Audere AU - Katrina Rutka AU - Bernard Puech AU - Michel Michaelides AU - Veronica van Heyningen AU - Baiba Lace AU - Andrew R Webster AU - Anthony T Moore Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/02/12/107573.abstract N2 - Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been assigned by linkage to two loci, MCDR1 on chromosome 6q16 and MCDR3 on chromosome 5p15-p13. Recently, non-coding variants upstream of PRDM13 and a large duplication including IRX1 have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies, 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 NCMD families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. 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 at the MCDR3 locus and provide insights into the genetic pathways involved in human macular development.aCGHarray comparative genomic hybridizationCNVCopy number variantIBDIdentical-by-descentiPSCInduced pluripotent stem cellDHSDNase hypersensitive siteHHHomozygosity HaplotypeMCDRMacular dystrophy regionNCMDNorth Carolina macular dystrophyPCRPolymerase chain reactionRCHHRegion with a Conserved Homozygosity HaplotypeSNPSingle-nucleotide polymorphismSNVSingle nucleotide variantSVStructural variantWGSWhole-genome sequencingaCGHarray comparative genomic hybridizationCNVCopy number variantIBDIdentical-by-descentiPSCInduced pluripotent stem cellDHSDNase hypersensitive siteHHHomozygosity HaplotypeMCDRMacular dystrophy regionNCMDNorth Carolina macular dystrophyPCRPolymerase chain reactionRCHHRegion with a Conserved Homozygosity HaplotypeSNPSingle-nucleotide polymorphismSNVSingle nucleotide variantSVStructural variantWGSWhole-genome sequencing ER -