Repetitive Sequences in Neurological Diseases and Health*
Date: October 18, 2026
Time: 10:00 am to 11:30 am
Room: Pacific Jewel Ballroom
Track: Plenary
Session Description
More than 50% of the human genome consists of repetitive DNA, including micro- and macrosatellite repeats that contribute to a range of neurological diseases. This session will highlight recent advances in the biology of repeat expansion disorders, with a focus on somatic repeat instability as a key driver of disease and a potential therapeutic target.
Faculty will also examine emerging data on the unexpectedly high prevalence of microsatellite expansions in the general population and the implications for disease risk. In addition, the session will explore epigenetic and molecular mechanisms underlying facioscapulohumeral muscular dystrophy, including the role of D4Z4 repeat contractions.
Together, these presentations will provide a comprehensive overview of evolving concepts in repeat biology and their relevance to disease pathogenesis and therapeutic development.
Learning Objectives
At the conclusion of this session, attendees will be able to:
- Analyze the contribution of repeat expansion and contraction disorders to both rare and common neurological diseases, including factors leading to underdiagnosis.
- Evaluate the limitations of conventional genetic testing and apply specialized diagnostic strategies to detect repeat expansion and contraction mutations.
- Assess the clinical, therapeutic, and familial implications of accurate diagnosis, including impact on emerging treatment strategies and genetic counseling.
Speakers
- (Chair) Laura Ranum, PhD, FANA
- (Co-Chair, Speaker) Silvère Van der Maarel, PhD
- (Speaker) Steven McCarroll, PhD
- (Speaker) Arianna Tucci, MD, PhD
- (Speaker) Niccolò Mencacci, MD, PhD (2026 Emerging Scholar)
- (Speaker) Mohd Salman, PhD, (2026 Emerging Scholar)
- (Awardee) David Newman-Toker, MD, PhD, FANA
- (Awardee) Neil Shneider, MD, PhD, FANA
The Ticking DNA Clock: Lifelong Somatic Expansion of Repeated DNA As a Cause Of DNA-repeat Disorders
Description
Inherited DNA-repeat disorders such as Huntington’s disease (HD) have long challenged scientific and medical understanding: Why do patients have decades of good health, with no apparent biological sign of trouble, before their symptoms commence? Why do such disorders devastate some brain regions and some types of brain cells but not other brain regions and cell types?
In this presentation I will describe experiments and analyses that revealed a surprising underlying dynamic: the inherited HD-causing CAG-repeat tract (in the HTT gene) undergoes decades of expansion in the vulnerable types of neurons, expanding to many times its inherited length (usually 40-50 CAGs). Only after expanding beyond about 150 CAGs does it become toxic to the neuron it is in. Participants will review how this biological insight has reshaped the focus of HD therapeutics efforts – therapies that might, by interfering with this DNA process, some day prevent disease onset as well as slow or stop progression. We will also review how these dynamics play out at different rates in different patients, shaping age at onset.
Attendees will leave with an understanding of the underlying biological dynamics that propel the onset and progression of HD and that may also underlie other DNA-repeat disorders that manifest in mid-life.
Understanding Repeat Expansion Diseases Using Population-scale Genomic Data
Description
DNA repeat expansions are a common cause of neurological disease, yet their accurate detection using short read genome sequencing has long been considered technically unfeasible. In recent years, the availability of large-scale genomic datasets from patients and population cohorts has enabled the development of bioinformatic tools to address these challenges.
This presentation will provide a framework to study repeat expansion diseases prevalence, penetrance, and germline instability, with the aim of improving disease classification, risk prediction, and the identification of genetic modifiers that shape clinical outcomes.
Attendees will leave with a greater understanding of how repeat expansion diseases may be far more common than previously recognized and how large-scale genomic datasets can reveal disease prevalence and genetic risk.
D4Z4 Macrosatellite Repeat Rearrangements in Facioscapulohumeral Muscular Dystrophy
Description
Repetitive DNA constitutes a substantial fraction of the human genome but remains poorly characterized, particularly large tandem repeat structures known as microsatellite repeats. Facioscapulohumeral dystrophy (FSHD) is a genetic muscle disorder caused by epigenetic dysregulation of the D4Z4 macrosatellite repeat, leading to inappropriate expression of the DUX4 transcription factor in skeletal muscle and initiating a cascade of pathogenic downstream effects.
This presentation will examine the biology of the D4Z4 macrosatellite repeat and its central role in FSHD pathogenesis. Participants will review the genetic and epigenetic mechanisms that regulate DUX4 expression, explore the global variation and modifying factors within the FSHD locus, and discuss how these factors influence disease susceptibility and severity. The presentation will also address the molecular and cellular consequences of DUX4 expression and provide an overview of emerging therapeutic strategies aimed at preventing or reversing DUX4-mediated pathology.
Attendees will leave with a deeper understanding of macrosatellite biology, the mechanisms underlying DUX4 activation in FSHD, and the opportunities and challenges associated with current therapeutic approaches targeting this disease pathway.
VPS39 Variants Cause a Spectrum of Neurological Disorders Through Impaired Lysosomal Function and Autophagy
Description
Lysosomal dysfunction and impaired autophagy are increasingly recognized as key mechanisms underlying neurodevelopmental and neurodegenerative disorders. Advances in genomic and functional studies continue to uncover novel disease-causing genes that provide important insights into these cellular pathways and their role in neurological disease.
This presentation will describe the identification and characterization of a novel neurological disorder caused by biallelic variants in VPS39, a core subunit of the HOPS complex that mediates the fusion of autophagosomes and late endosomes with lysosomes. Participants will examine clinical, genetic, and functional data from 14 affected individuals across 10 families, defining two distinct phenotypes: a severe neonatal-onset disorder resembling a lysosomal storage disease and a milder form characterized by developmental delay and progressive cerebellar ataxia. The discussion will highlight how VPS39 variants impair protein stability, disrupt critical structural interactions, and compromise lysosomal function and autophagic flux, expanding the spectrum of HOPS complex disorders and providing new insights into the molecular mechanisms linking lysosomal dysfunction to neurological disease. Broader implications for understanding other neurodevelopmental and neurodegenerative disorders associated with defects in lysosomal and autophagic pathways will also be explored.
Attendees will leave with a greater understanding of the clinical spectrum and molecular mechanisms of VPS39-related disease and the emerging role of lysosomal and autophagic dysfunction in the pathogenesis of neurological disorders.
Speakers
Plasma-derived Extracellular Vesicles from Humans with Silent Stroke and a Mouse Model of Silent Stroke Stimulate a Senescence-associated Secretory Phenotype at the Blood-brain Barrier
Description
Silent stroke, or silent brain infarction, is associated with an increased risk of cognitive decline and future neurological disorders. However, the mechanisms underlying these effects remain unclear. Emerging evidence suggests that circulating extracellular vesicles (EVs) may influence blood-brain barrier (BBB) function and promote cellular senescence.
In this presentation, I will discuss findings from human plasma-derived EVs from stroke patients and from a mouse model of chronic cerebral hypoperfusion, focusing on their ability to activate a senescence-associated secretory phenotype in brain endothelial cells. I will highlight potential links between EV signaling, cellular senescence, and neurovascular dysfunction.
Attendees will gain insight into how disease-associated, plasma-derived EVs may contribute to persistent BBB dysfunction following stroke, and how senescence-associated signaling may affect long-term neurological outcomes. These findings may highlight novel biomarkers and therapeutic targets for stroke and cerebrovascular disease.
Awardee Remarks
