New Noncoding Base Pair Mutation at the Identical Locus as the Original NCMD/MCDR1 in a Mexican Family, Suggesting a Mutational Hotspot

Kent W Small; Stijn Van de Sompele; Jessica Avetisjan; Nitin Udar; Steven Agemy; Elfride De Baere; Fadi S Shaya

doi:10.1177/24741264221129432

New Noncoding Base Pair Mutation at the Identical Locus as the Original NCMD/MCDR1 in a Mexican Family, Suggesting a Mutational Hotspot

J Vitreoretin Dis. 2023 Jan 2;7(1):33-42. doi: 10.1177/24741264221129432. eCollection 2023 Jan-Feb.

Authors

Kent W Small^{1

2}, Stijn Van de Sompele³, Jessica Avetisjan^{1

2}, Nitin Udar^{1

2}, Steven Agemy⁴, Elfride De Baere³, Fadi S Shaya^{1

2}

Affiliations

¹ Macula and Retina Institute, Glendale and Los Angeles, CA, USA.
² Molecular Insight Research Foundation, Glendale and Los Angeles, CA, USA.
³ Center for Medical Genetics Ghent (CMGG), Department of Biomolecular Medicine, Ghent University, and Ghent University Hospital, Ghent, Belgium.
⁴ New York Retina Consultants PLLC, New York, NY, USA.

Abstract

Purpose: To clinically and molecularly study a newly found family with North Carolina macular dystrophy (NCMD/MCDR1) from Mexico.

Methods: This retrospective study comprised 6 members of a 3-generation Mexican family with NCMD. Clinical ophthalmic examinations, including fundus imaging, spectral-domain optical coherence tomography, electroretinography, and electrooculography, were performed. Genotyping with polymorphic markers in the MCDR1 region was performed to determine haplotypes. Whole-genome sequencing (WGS) was performed followed by variant filtering and copy number variant analysis.

Results: Four subjects from 3 generations were found to have macular abnormalities. The proband presented with lifelong bilateral vision impairment with bilaterally symmetric vitelliform Best disease-like appearing macular lesions. Her 2 children had bilateral large macular coloboma-like malformations, consistent with autosomal dominant NCMD. The 80-year-old mother of the proband had drusen-like lesions consistent with grade 1 NCMD. WGS and subsequent Sanger sequencing found a point mutation at chr6:99593030G>C (hg38) in the noncoding region of the DNase I site thought to be a regulatory element of the retinal transcription factor gene PRDM13. This mutation is the identical site/nucleotide as in the original NCMD family (#765) but is a guanine to cytosine change rather than a guanine to thymine mutation, as found in the original NCMD family.

Conclusions: We report a new noncoding mutation at the same locus (chr6:99593030G>C) involving the same DNase I site regulating the retinal transcription factor gene PRDM13. This suggests that this site, chr6:99593030, is a mutational hotspot.

Keywords: DNase I site; MCDR1; NCMD; North Carolina macular dystrophy; PRDM13; SV; chromosome 6; copy number variant; inherited retinal diseases; mutational hotspot; single nucleotide variants; whole-genome sequencing.