Oral Presentation International Congress on Neuronal Ceroid Lipofuscinoses 2025

Genotype-Phenotype Relationships in CLN3 Disease: Insights from a Natural History Study (126448)

Jamison Seabury 1 , Jonathan W. Mink 2 , Erika F. Augustine 3 , Heather R. Adams 1 , Amy Vierhile 1 , Marianna Pereira-Freitas 1 , Jennifer Vermilion 1
  1. University of Rochester Batten Center, Rochester, NY, United States
  2. Consultant , Pittsford, New York, United States
  3. Kennedy Krieger Institute, Baltimore, MD, USA

Background

CLN3 disease is a lysosomal storage disorder caused by biallelic mutations to the CLN3 gene. The most common pathogenic variant is a 966-base-pair deletion known as the “common deletion”. Most patients are homozygous for the common deletion, but ~26% of patients possess another type of pathogenic variant across one or both alleles. While select genetic variants are reportedly associated with atypical disease course, genotype phenotype relationships remain largely misunderstood. We used our natural history database to characterize symptom onset and severity among genetic subgroups of CLN3.   

Methods

We analyzed data from n=99 individuals with genetically confirmed CLN3 disease enrolled in an ongoing natural history study. We classified participants as homozygous (CD/CD) or compound heterozygous for the common deletion, and further categorized compound heterozygotes based on their non-common-deletion variant (missense: CD/M) or nonsense or frameshift: CD/NF). We conducted a one-way ANOVA to analyze symptom onset as reported at most recent assessment and used linear mixed-effects (LME) models to characterize disease progression using Unified Batten Disease Rating Scale (UBDRS) assessments.

Results

Participants with a CD/NF genotype reported the earliest onset of motor symptoms (mean 7.9 years, sd 4.0), significantly younger than those in the CD/M (mean 16.4 years sd 2.7, p=0.005) or CD/CD (mean 12.2 years sd 3.7, p=0.03) cohorts. Mean age of onset for other symptoms did not differ among cohorts. LME modeling of UBDRS scores revealed significant differences in symptom severity among genotype groups after controlling for age. CD/NF (β=12.5, p = 0.03) and CD/CD (β=9.8 p = 0.04) genotypes had higher UBDRS scores than the CD/M cohort.

Discussion

The type of non-common deletion genetic variant impacts CLN3 disease course, pointing to lower disease severity in CD/M participants. These findings contribute to our understanding of the natural history of this disease and have implications for optimizing clinical trial design.