Abstract
Purpose :
We published the initial findings of 5 mutations in 12 NCMD families with 141 subjects. The purpose of this study is to clinically and molecularly study our entire NCMD database of 372 subjects to determine if our initial findings continue to be substantiated.
Methods :
Ophthalmic examinations and whole genome sequencing (WGS) and/or targeted DNA Sanger sequencing was performed on our entire dataset of 53 families with 372 subjects. Junction PCR and Sanger sequencing was used to confirm point mutations and characterize duplications involving the MCDR1/MCDR3/PRDM13 locus.
Results :
Of the total 372 subjects evaluated to date, 269 were found to be affected having DNA sequence changes consistent with MCDR1 on chromosome 6 or MCDR3 on chromosome 5. Unaffected family member sequenced was 103 subjects. In addition to our 12 initial families, we report the findings of an additional 41 families with 75 subjects affected and 32 unaffected siblings. Eight of these new families, 35 subjects, were found to have the original NCMD “V1” Chr6:99593030G>T mutation, in a non-coding region of the DNASE1 site 12 kb upstream of the retinal transcription factor PRDM13. Fourteen families, 50 subjects, had the “V2” mutation Chr6:99593111G>C in the same DNASE1 site. One Asian family with 2 subjects had our previously reported Asian “V3” Chr6:99593164C>T mutation in the same DNASE1 site. Two new single nucleotide variants (SNVs) have recently been reported by us from our dataset, Ch6:99599064A>G in four members of one Czech family and Chr6:99959303G>C in four members of a Mexican family. A new tandem duplication Chr6:99560265-99616492 involving the same DNASE1 site, was recently reported by us in a Turkish family.
Conclusions :
North Carolina Macular Dystrophy (NCMD/MCDR1/MCDR3) is more prevalent than typically thought with a worldwide distribution making the name of this disease a gross misnomer. Continued identification of subjects and families and their mutations supports our initial discovery of mutations. Our group has found 8 of 13 total NCMD mutations. All of the mutations (SNVs and duplications) appear to involve DNASE1 sites in non-coding regions. The mutations on chromosome 6 continue to appear to alter the expression of the retinal transcription factor PRDM13 while the chromosome 5 mutations may affect the IRX1 expression as we originally reported.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.