Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus

• Published in: bioRxiv
• Main Authors: Cipriani, Valentina, Silva, Raquel S, Gavin, Arno, Pontikos, Nikolas, Kalhoro, Ambreen, Valeina, Sandra, Inashkina, Inna, Audere, Mareta, Rutka, Katrina, Puech, Bernard, Michaelides, Michel, Veronica Van Heyningen, Lace, Baiba, Webster, Andrew R, Moore, Anthony T
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 13.02.2017
• Subjects: Chromosome 5; Chromosome 6; Deoxyribonuclease; Fetuses; Haplotypes; Retina; North Carolina
• DOI: 10.1101/107573

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.