A Novel Variant in <scp><i>SQSTM1</i></scp> Gene Causing Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy in a Peruvian Family

Chacaltana‐Vinas, Cesar; Ramirez‐Pajares, Patricia; Manrique‐Palomino, Alid; Clause, Amanda R.; Chawla, Aditi; Thorpe, Erin; Taft, Ryan; Rivera‐Valdivia, Andrea; Sarapura‐Castro, Elison; Bazalar‐Montoya, Jeny; Cornejo‐Olivas, Mario

doi:10.1002/mdc3.14025

Movement Disord Clin Pract

2024

DOI: 10.1002/mdc3.14025

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A Novel Variant in SQSTM1 Gene Causing Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy in a Peruvian Family

Cesar Chacaltana‐Vinas,

Patricia Ramirez‐Pajares,

Alid Manrique‐Palomino

et al.

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2024

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A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis

Masuko,

Sato,

Nakamura

et al. 2024

Molec Gen & Gen Med

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BackgroundHeterozygous variants of sequestosome‐1 gene (SQSTM1) have been reported in patients with various neurological disorders, whereas biallelic pathogenic variants of SQSTM1 can cause child‐onset and multisystem neurodegeneration, including cerebellar ataxia, dystonia, and vertical gaze palsy (NADGP). Here, we describe two cases of NADGP in a Japanese family.MethodsWe performed clinical and genetic laboratory evaluations of the two patients and their healthy parents.ResultsBy whole‐exome sequencing, we identified compound heterozygous variants in SQSTM1(NM_003900.5): c.1A>G p.(Met1?) in the initial codon, and c.969G>A, located at the 3′ end of exon 6, which is novel and seemingly a synonymous but is actually a truncating variant causing aberrant splicing. An SQSTM1 protein expression assay using urine‐derived cells (UDCs) demonstrated that both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of premessenger RNA. Cerebellar ataxia is a characteristic manifestation of this disorder; however, brain magnetic resonance imaging studies have not shown significant cerebellar atrophy. Our patients experienced chorea during adolescence.ConclusionsOnly a few reports have highlighted the presence of chorea; however, our findings suggest that NADGP should be considered as a differential diagnosis of hereditary chorea. This study also demonstrates the utility of UDCs, obtained using noninvasive approaches, in functionally analyzing genetic diseases.

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A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis

Masuko,

Sato,

Nakamura

et al. 2024

Molec Gen & Gen Med

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A Novel Variant in SQSTM1 Gene Causing Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy in a Peruvian Family

Cited by 1 publication

References 11 publications

A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis

A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine‐Derived Cells‐Based Functional Analysis

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