Objective: To report a case harboring two different heterozygous

SYNE1 variants whose combined effect is suspected to

underlie a complex neurogenetic phenotype

Background: SYNE1 encodes nesprin-1, one of the largest gene sin human genome. Pathogenic variants are most commonly associated with autosomal recessive cerebellar ataxia, though phenotypic presentations are heterogeneous and complex. In rare cases, SYNE1-related ataxia may result from compound heterozygous mutations, while heterozygous carriers are typically asymptomatic.

Method: A 55-year-old woman, presented with generalized choreiform movements of the extremities since 30 years of age. Her symptoms remained relatively stable until the age of 52, when progressive lower-limb weakness developed. Neurological examination revealed persistent generalized chorea, intention tremor, cerebellar ataxia, dysarthria, spastic paraparese, and upper motor neuron signs including brisk lower-extremity reflexes, ankle clonus, and bilateral extensor plantar responses. Gait was spastic-paraparetic. Due to the complex and progressive phenotype, whole-genome sequencing was performed.

Results: Whole genome sequencing was performed. Two heterozygous missense variants were identified in the SYNE1: rs762050668 (p.Glu7498Lys), predicted to affect splicing, and rs772432833 (p.Glu3782Lys). Both are currently classified as variants of uncertain significance. Additionally, a heterozygous rs1800562 (p.Cys282Tyr) variant was detected in the HFE gene, typically associated with autosomal recessive type 1 hemochromatosis in the homozygous state.

Conclusion: case highlights a complex, lifelong neurogenetic phenotype with extrapyramidal, pyramidal, and cerebellar involvement and late progression. The clinical relevance of heterozygous SYNE1 variants remains uncertain, emphasizing the importance of careful genotype-phenotype correlation and long-term follow-up in atypical movement disorders syndromes.

References: Serag M, Plutino M, Charles P, Azulay JP, Chaussenot A, Paquis-Flucklinger V, Ait-El-Mkadem Saadi S, Rouzier C. A Case Report of SYNE1 Deficiency-Mimicking Mitochondrial Disease and the Value of Pangenomic Investigations. Genes (Basel). 2023 Nov 29;14(12):2154. doi: 10.3390/genes14122154.

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/progressive-lifelong-chorea-with-spastic-paraparese-and-cerebellar-ataxia-associated-with-two-heterozygous-variants-in-the-syne1-gene-a-case-report/