Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia

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Abstract

Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.

Original languageEnglish
JournalClinical Genetics
DOIs
Publication statusE-pub ahead of print - May 8 2019

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Cerebellar Ataxia
Spinocerebellar Degenerations
Spectrin
Ataxia
Spinocerebellar Ataxias
Neurodegenerative Diseases
Phenotype
Mutation
Genes

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@article{858ff94a08ce4bf1b8b208dd87db93c4,
title = "Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia",
abstract = "Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5{\%} in our cohort of unrelated patients screened by targeted next generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.",
author = "Francesco Nicita and Marta Nardella and Emanuele Bellacchio and Paolo Alfieri and Gaetano Terrone and Giorgia Piccini and Federica Graziola and Claudio Pignata and Alessandro Capuano and Enrico Bertini and Ginevra Zanni",
note = "This article is protected by copyright. All rights reserved.",
year = "2019",
month = "5",
day = "8",
doi = "10.1111/cge.13562",
language = "English",
journal = "Clinical Genetics",
issn = "0009-9163",
publisher = "Wiley-Blackwell Publishing Ltd",

}

TY - JOUR

T1 - Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia

AU - Nicita, Francesco

AU - Nardella, Marta

AU - Bellacchio, Emanuele

AU - Alfieri, Paolo

AU - Terrone, Gaetano

AU - Piccini, Giorgia

AU - Graziola, Federica

AU - Pignata, Claudio

AU - Capuano, Alessandro

AU - Bertini, Enrico

AU - Zanni, Ginevra

N1 - This article is protected by copyright. All rights reserved.

PY - 2019/5/8

Y1 - 2019/5/8

N2 - Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.

AB - Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.

U2 - 10.1111/cge.13562

DO - 10.1111/cge.13562

M3 - Article

C2 - 31066025

JO - Clinical Genetics

JF - Clinical Genetics

SN - 0009-9163

ER -