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bioRxiv · 10.1101/107573

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

Cipriani, 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. R.·Moore, A. T.
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Abstract

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, noncoding 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.\n\nAbbreviations list

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Cipriani, 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. R., Moore, A. T.. 2017-02-12. Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus. https://doi.org/10.1101/107573

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