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.
- aCGH
- array comparative genomic hybridization
- CNV
- Copy number variant
- IBD
- Identical-by-descent
- iPSC
- Induced pluripotent stem cell
- DHS
- DNase hypersensitive site
- HH
- Homozygosity Haplotype
- MCDR
- Macular dystrophy region
- NCMD
- North Carolina macular dystrophy
- PCR
- Polymerase chain reaction
- RCHH
- Region with a Conserved Homozygosity Haplotype
- SNP
- Single-nucleotide polymorphism
- SNV
- Single nucleotide variant
- SV
- Structural variant
- WGS
- Whole-genome sequencing