The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series
Abstract
Objective: A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss-of-function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders. Methods: Cases with NUS1-related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform. Clinical data were acquired through retrospective case-note review. Results: We identified 41 subjects carrying 38 different pathogenic or likely pathogenic heterozygous NUS1 variants. The majority of cases displayed developmental delays and intellectual disability of variable severity. Epilepsy was present in 68.3% of cases (28/41) with onset typically in early childhood. Strikingly, 87.8% of cases (36/41) presented with movement disorders and for 13 of these cases the movement disorder was not accompanied by epilepsy. The phenomenology of the movement disorders was complex with myoclonus observed in 68.3% of cases (28/41), either in isolation or in combination with dystonia, ataxia, and/or parkinsonism. Seven cases that otherwise did not have prominent movement disorders had mild incoordination and intention tremor, suggestive of cerebellar dysfunction. There was no observed genotype-phenotype correlation, suggesting that other genetic or acquired factors impact the clinical presentation. Interpretation: Heterozygous NUS1 pathogenic variants cause a complex neurological disorder, variably featuring developmental and epileptic encephalopathies and a broad spectrum of movement disorders, which represent the major source of neurological disability for most cases. ANN NEUROL 2025;98:561-572.
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BibTeX
@article{brooker2026spectrum,
title = {{The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series}},
author = {Sarah Brooker and Maria Novelli and Robert Coukos and Neha Prakash and Walaa Kamel and Marta Amengual-Gual and Mathieu Anheim and Giulia Barcia and Tanya Bardakjian and Franciska Baur and Steffen Berweck and Bigna Bölsterli and Melanie Brugger and Thomas Cassini and Nicolas Chatron and Brian Corner and Hormos Salimi Dafsari and Jean-Madeleine de Sainte Agathe and Colin Ellis and Kimberly Ezell and Cendrine Foucard and Steven Frucht and Maria Garcia and Deepak Gill and Anne Guimier and Rizwan Hamid and Damià Heine-Suñer and Peter Herkenrath and Marie Hully and Ioannis Isaias and Louis Januel and Chloe Laurencin and Taylor Laut and Alinoe Lavillaureix and Gaetan Lesca and Marion Lesieur-Sebellin and Luca Magistrelli and Cecilia Marelli and Heather Mefford and Bryce Mendelsohn and Saadet Mercimek-Andrews and Claire Miller and Shekeeb Mohammad and Francesca Morgante and Sirisha Nandipati and Thomas Opladen and Mahesh Padmanaban and Micaela Pauni and Gianni Pezzoli and Amelie Piton and Francis Ramond and Giulietta Riboldi and Christelle Rougeot-Jung and Fernando Santos-Simarro and Ingrid Scheffer and Naoual Serari and Christine Stahl and Ann Stembridge Kung and Susana Tarongí Sanchez and Christel Thauvin-Robinet},
journal = {Annals of Neurology},
year = {2026},
month = oct,
doi = {10.1002/ana.27272},
url = {https://hal.science/hal-05836533v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series
AU - Sarah Brooker
AU - Maria Novelli
AU - Robert Coukos
AU - Neha Prakash
AU - Walaa Kamel
AU - Marta Amengual-Gual
AU - Mathieu Anheim
AU - Giulia Barcia
AU - Tanya Bardakjian
AU - Franciska Baur
AU - Steffen Berweck
AU - Bigna Bölsterli
AU - Melanie Brugger
AU - Thomas Cassini
AU - Nicolas Chatron
AU - Brian Corner
AU - Hormos Salimi Dafsari
AU - Jean-Madeleine de Sainte Agathe
AU - Colin Ellis
AU - Kimberly Ezell
AU - Cendrine Foucard
AU - Steven Frucht
AU - Maria Garcia
AU - Deepak Gill
AU - Anne Guimier
AU - Rizwan Hamid
AU - Damià Heine-Suñer
AU - Peter Herkenrath
AU - Marie Hully
AU - Ioannis Isaias
AU - Louis Januel
AU - Chloe Laurencin
AU - Taylor Laut
AU - Alinoe Lavillaureix
AU - Gaetan Lesca
AU - Marion Lesieur-Sebellin
AU - Luca Magistrelli
AU - Cecilia Marelli
AU - Heather Mefford
AU - Bryce Mendelsohn
AU - Saadet Mercimek-Andrews
AU - Claire Miller
AU - Shekeeb Mohammad
AU - Francesca Morgante
AU - Sirisha Nandipati
AU - Thomas Opladen
AU - Mahesh Padmanaban
AU - Micaela Pauni
AU - Gianni Pezzoli
AU - Amelie Piton
AU - Francis Ramond
AU - Giulietta Riboldi
AU - Christelle Rougeot-Jung
AU - Fernando Santos-Simarro
AU - Ingrid Scheffer
AU - Naoual Serari
AU - Christine Stahl
AU - Ann Stembridge Kung
AU - Susana Tarongí Sanchez
AU - Christel Thauvin-Robinet
PY - 2026
DA - 2026/10/23
JO - Annals of Neurology
DO - 10.1002/ana.27272
UR - https://hal.science/hal-05836533v1
AB - Objective: A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss-of-function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders. Methods: Cases with NUS1-related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform. Clinical data were acquired through retrospective case-note review. Results: We identified 41 subjects carrying 38 different pathogenic or likely pathogenic heterozygous NUS1 variants. The majority of cases displayed developmental delays and intellectual disability of variable severity. Epilepsy was present in 68.3% of cases (28/41) with onset typically in early childhood. Strikingly, 87.8% of cases (36/41) presented with movement disorders and for 13 of these cases the movement disorder was not accompanied by epilepsy. The phenomenology of the movement disorders was complex with myoclonus observed in 68.3% of cases (28/41), either in isolation or in combination with dystonia, ataxia, and/or parkinsonism. Seven cases that otherwise did not have prominent movement disorders had mild incoordination and intention tremor, suggestive of cerebellar dysfunction. There was no observed genotype-phenotype correlation, suggesting that other genetic or acquired factors impact the clinical presentation. Interpretation: Heterozygous NUS1 pathogenic variants cause a complex neurological disorder, variably featuring developmental and epileptic encephalopathies and a broad spectrum of movement disorders, which represent the major source of neurological disability for most cases. ANN NEUROL 2025;98:561-572.
SN - 0364-5134
SN - 1531-8249
ER -