PMID- 34526759 OWN - NLM STAT- MEDLINE DCOM- 20211231 LR - 20221207 IS - 1090-0535 (Electronic) IS - 1090-0535 (Linking) VI - 27 DP - 2021 TI - A novel duplication involving PRDM13 in a Turkish family supports its role in North Carolina macular dystrophy (NCMD/MCDR1). PG - 518-527 AB - PURPOSE: To clinically and molecularly investigate a new family with North Carolina macular dystrophy (NCMD) from Turkey, a previously unreported geographic origin for this phenotype. METHODS: Clinical ophthalmic examinations, including fundus imaging and spectral domain-optical coherence tomography (SD-OCT), were performed on eight members of a two-generation non-consanguineous family from southern Turkey. Whole genome sequencing (WGS) was performed on two affected subjects, followed by variant filtering and copy number variant (CNV) analysis. Junction PCR and Sanger sequencing were used to confirm and characterize the duplication involving PRDM13 at the nucleotide level. The underlying mechanism was assessed with in silico analyses. RESULTS: The proband presented with lifelong bilateral vision impairment and displayed large grade 3 coloboma-like central macular lesions. Five of her six children showed similar macular malformations, consistent with autosomal dominant NCMD. The severity grades in the six affected individuals from two generations are not evenly distributed. CNV analysis of WGS data of the two affected family members, followed by junction PCR and Sanger sequencing, revealed a novel 56.2 kb tandem duplication involving PRDM13 (chr6:99560265-99616492dup, hg38) at the MCDR1 locus. This duplication cosegregates with the NCMD phenotype in the five affected children. No other (likely) pathogenic variants in known inherited retinal disease genes were found in the WGS data. Bioinformatics analyses of the breakpoints suggest a replicative-based repair mechanism underlying the duplication. CONCLUSIONS: We report a novel tandem duplication involving the PRDM13 gene in a family with NCMD from a previously unreported geographic region. The duplication size is the smallest that has been reported thus far and may correlate with the particular phenotype. CI - Copyright (c) 2021 Molecular Vision. FAU - Small, Kent W AU - Small KW AD - Macula and Retina Institute, Glendale and Los Angeles, CA. AD - Molecular Insight Research Foundation, Glendale and Los Angeles, CA. FAU - Van de Sompele, Stijn AU - Van de Sompele S AD - Center for Medical Genetics Ghent (CMGG), Department of Biomolecular Medicine, Ghent University and Ghent University Hospital, Ghent Belgium. FAU - Nuytemans, Karen AU - Nuytemans K AD - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL. AD - John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL. FAU - Vincent, Andrea AU - Vincent A AD - Ophthalmology, New Zealand National Eye Centre, University of Auckland, New Zealand. FAU - Yuregir, Ozge Ozalp AU - Yuregir OO AD - University of Health Sciences and Adana City Hospital, Adana, Turkey. FAU - Ciloglu, Emine AU - Ciloglu E AD - University of Health Sciences and Adana City Hospital, Adana, Turkey. FAU - Sariyildiz, Cahfer AU - Sariyildiz C AD - University of Health Sciences and Adana City Hospital, Adana, Turkey. FAU - Rosseel, Toon AU - Rosseel T AD - Center for Medical Genetics Ghent (CMGG), Department of Biomolecular Medicine, Ghent University and Ghent University Hospital, Ghent Belgium. FAU - Avetisjan, Jessica AU - Avetisjan J AD - Macula and Retina Institute, Glendale and Los Angeles, CA. AD - Molecular Insight Research Foundation, Glendale and Los Angeles, CA. FAU - Udar, Nitin AU - Udar N AD - Macula and Retina Institute, Glendale and Los Angeles, CA. AD - Molecular Insight Research Foundation, Glendale and Los Angeles, CA. FAU - Vance, Jeffery M AU - Vance JM AD - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL. AD - John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL. FAU - Pericak-Vance, Margaret A AU - Pericak-Vance MA AD - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL. AD - John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL. FAU - De Baere, Elfride AU - De Baere E AD - Center for Medical Genetics Ghent (CMGG), Department of Biomolecular Medicine, Ghent University and Ghent University Hospital, Ghent Belgium. FAU - Shaya, Fadi S AU - Shaya FS AD - Macula and Retina Institute, Glendale and Los Angeles, CA. AD - Molecular Insight Research Foundation, Glendale and Los Angeles, CA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210901 PL - United States TA - Mol Vis JT - Molecular vision JID - 9605351 RN - 0 (Transcription Factors) RN - EC 2.1.1.- (PRDM13 protein, human) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) RN - Macular dystrophy, retinal, 1, North Carolina type SB - IM MH - Adolescent MH - Adult MH - Asian People/*genetics MH - Child MH - Child, Preschool MH - Chromosomes, Human, Pair 6/genetics MH - Corneal Dystrophies, Hereditary/diagnostic imaging/*genetics MH - Female MH - *Gene Duplication MH - Genetic Linkage MH - Histone-Lysine N-Methyltransferase/*genetics MH - Humans MH - Male MH - Pedigree MH - Polymerase Chain Reaction MH - Tomography, Optical Coherence MH - Transcription Factors/*genetics MH - Turkey/epidemiology MH - Whole Genome Sequencing PMC - PMC8410230 EDAT- 2021/09/17 06:00 MHDA- 2022/01/01 06:00 PMCR- 2021/01/01 CRDT- 2021/09/16 07:02 PHST- 2021/03/24 00:00 [received] PHST- 2021/08/30 00:00 [accepted] PHST- 2021/09/16 07:02 [entrez] PHST- 2021/09/17 06:00 [pubmed] PHST- 2022/01/01 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 42 [pii] PST - epublish SO - Mol Vis. 2021 Sep 1;27:518-527. eCollection 2021.