North Carolina Macular Dystrophy: Haplotype-Based Mutation Age Estimation for Variants V1 (chr6:99593030 G>T) and V2 (chr6:99593111 G>C)

Authors

• Joanna Im
• Kent W. Small
• Emmanuelle Genin
• Nitin Udar
• Fadi Shaya
• Amber Diaz
• Uma Udar
• Monique J. Leys
• Thomas Rice
• Gregory Rognon, Corewell Health East Resident

Document Type

Conference Proceeding

Publication Date

6-2026

Publication Title

Investigative Ophthalmology and Visual Science

Abstract

Purpose : Previous haplotype analysis of 37 North Carolina Macular Dystrophy (NCMD) families indicated that the V1 and V2 variants arose from distinct most recent common ancestors. We performed a haplotype-based mutation age estimation study using short tandem repeat (STR) markers to estimate the ages of V1 and V2 and place these founder mutations on a timescale for NCMD-affected families in populations where they are enriched.

Methods : Subjects with NCMD were identified by clinical examination and/or clinical record review. With IRB-approved written consent, DNA from blood or saliva was genotyped at 19 STR markers across the 5.4 Mb MCDR1 region. 17 V1 subjects and 37 V2 subjects were genotyped and analyzed for mutation age estimation. V1 and V2 ages were estimated using EstiAge applied to shared haplotypes, assuming a constant population size, a 25 year generation time, and a mean STR mutation rate of 0.001 per generation under a random mutation model.

Results : Haplotype-based mutation age estimations place the V1 founder at approximately 150 years old (95% CI, 100-375) and the V2 founder at approximately 700 years old (95% CI, 500-1,000), based on STR haplotypes from 17 V1 and 37 V2 carriers. These point estimates and widely separated confidence intervals support V2 as a substantially older founder than V1, consistent with earlier haplotype and geographic data.

Conclusions : These mutation age estimates demonstrate that the two MCDR1 founder mutations differ by several centuries in genealogical depth, consistent with V2's broader American-European distribution. Placing V1 and V2 on an absolute timescale provides, to our knowledge, the first specific temporal context for these variants and may help distinguish long-standing founders from more recent, private NCMD mutations when counseling affected families.

Volume

67

Issue

7

First Page

5026

Comments

Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, May 3-7, 2026, Denver, CO

Last Page

5026

Recommended Citation

Im J, Small KW, Genin E, Udar N, Shaya F, Diaz A, et al. [Rognon G]. North Carolina macular dystrophy: haplotype-based mutation age estimation for variants V1 (chr6:99593030 G>T) and V2 (chr:99593111 G>C). Invest Ophthalmol Vis Sci. 2026 Jun;67(7):5026.