scholarly journals Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization

2020 ◽  
Vol 6 (2) ◽  
pp. e397 ◽  
Author(s):  
Dong-Hui Chen ◽  
Caitlin Latimer ◽  
Mayumi Yagi ◽  
Mesaki Kenneth Ndugga-Kabuye ◽  
Elyana Heigham ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Autosomal Dominant ◽  
Cerebellar Atrophy ◽  
Dominant Inheritance ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Behavioral Abnormalities ◽  
Significant Pathology ◽  
Autosomal Dominant Ataxia ◽  
Dominant Ataxia

ObjectiveTo identify the genetic cause of autosomal dominant ataxia complicated by behavioral abnormalities, cognitive decline, and autism in 2 families and to characterize brain neuropathologic signatures of dominant STUB1-related ataxia and investigate the effects of pathogenic variants on STUB1 localization.MethodsClinical and research-based exome sequencing was used to identify the causative variants for autosomal dominant ataxia in 2 families. Gross and microscopic neuropathologic evaluations were performed on the brains of 4 affected individuals in these families.ResultsMutations in STUB1 have been primarily associated with childhood-onset autosomal recessive ataxia, but here we report heterozygous missense variants in STUB1 (p.Ile53Thr and p.The37Leu) confirming the recent reports of autosomal dominant inheritance. Cerebellar atrophy on imaging and cognitive deficits often preceded ataxia. Unique neuropathologic examination of the 4 brains showed the marked loss of Purkinje cells (PCs) without microscopic evidence of significant pathology outside the cerebellum. The normal pattern of polarized somatodendritic STUB1 protein expression in PCs was lost, resulting in aberrant STUB1 localization in the distal PC dendritic arbors.ConclusionsThis study confirms a dominant inheritance pattern in STUB1-ataxia in addition to a recessive one and documents its association with cognitive and behavioral disability, including autism. In the most extensive analysis of cerebellar pathology in this disease, we demonstrate disruption of STUB1 protein in PCs as part of the underlying pathogenesis.

scholarly journals A Case of Autosomal Dominant Ataxia with Vocal Cord Palsy Attributed to a Mutation in the PRNP Gene

2020 ◽  
Vol 7 (6) ◽  
pp. 688-692 ◽  
Author(s):  
Prashanth L. Kukkle ◽  
Thenral S. Geetha ◽  
Anita Mahadevan ◽  
Vedam L. Ramprasad
Keyword(s):  
Vocal Cord ◽  
Autosomal Dominant ◽  
Prnp Gene ◽  
Vocal Cord Palsy ◽  
Autosomal Dominant Ataxia ◽  
Dominant Ataxia

Ocular Motility in North Carolina Autosomal Dominant Ataxia

1996 ◽  
Vol 16 (2) ◽  
pp. 91-95 ◽  
Author(s):  
Kent W. Small ◽  
Stephen C. Pollock ◽  
Jeffrey M. Vance ◽  
Jeff M. Stajich ◽  
Margaret Pericak-Vance
Keyword(s):  
North Carolina ◽  
Autosomal Dominant ◽  
Ocular Motility ◽  
Autosomal Dominant Ataxia ◽  
Dominant Ataxia

scholarly journals Spinocerebellar ataxia type 10 in the South of Brazil: the Amerindian-Belgian connection

2015 ◽  
Vol 73 (8) ◽  
pp. 725-727 ◽  
Author(s):  
Hélio Afonso Ghizoni Teive ◽  
Adriana Moro ◽  
Mariana Moscovich ◽  
Walter Oleskho Arruda ◽  
Renato Puppi Munhoz ◽  
...  
Keyword(s):  
Latin America ◽  
Spinocerebellar Ataxia ◽  
Autosomal Dominant ◽  
Spinocerebellar Ataxia Type ◽  
The South ◽  
Rare Form ◽  
History Of ◽  
Autosomal Dominant Ataxia ◽  
South Of Brazil ◽  
Dominant Ataxia

Spinocerebellar ataxia type 10 (SCA10) is a rare form of autosomal dominant ataxia found predominantly in patients from Latin America with Amerindian ancestry. The authors report the history of SCA10 families from the south of Brazil (the states of Paraná and Santa Catarina), emphasizing the Belgian-Amerindian connection.

scholarly journals Two novel missense variants in SPTBN2 likely associated with spinocerebellar ataxia type 5

2021 ◽  
Author(s):  
Xianli Bian ◽  
Shang Wang ◽  
Suqin Jin ◽  
Shunliang Xu ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Cerebellar Atrophy ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxias ◽  
Targeted Next Generation Sequencing ◽  
The Family ◽  
Severe Ataxia ◽  
Autosomal Dominant Ataxia ◽  
Generation Sequencing ◽  
Dominant Ataxia

Abstract Introduction Spinocerebellar ataxias (SCAs) are a heterozygous group of neurodegenerative disorders. Spinocerebellar ataxia type 5 (SCA5) is a rare autosomal-dominant ataxia with pure cerebellum involvement. The clinical characteristics are limb and gait ataxia, trunk ataxia, sensory deficits, abnormal eye movement, dysarthria, and hyperactive tendon reflexes. Spectrin beta nonerythrocytic 2 gene (SPTBN2), coding β-III spectrin protein, was identified to be associated with SCA5. To date, more than 19 variants of SPTBN2 have been reported. Methods A family and an apparently sporadic patient with ataxia and cerebellar atrophy were recruited from Shandong Province (China). To discover the disease-causing variants, capillary electrophoresis and targeted next-generation sequencing were performed in the proband of the family and the sporadic patient. The candidate variants were verified by Sanger sequencing and analyzed by bioinformatics software. Results In our study, we verified two novel heterozygous variants in SPTBN2 in a SCA pedigree and a sporadic patient. The proband of the pedigree and her mother presented with walking instability and progressively getting worse. The sporadic patient suffered from slurred speech, walking instability, and drinking water choking cough. MRI examination of the proband and sporadic patient both displayed moderate cerebellar atrophy. The variants identified were traditionally conserved and predicted probably damaging and disease-causing by bioinformatics analysis. Conclusion We identified two novel heterozygous variants of SPTBN2 resulting in severe ataxia which further delineated the correlation between the genotype and phenotype of SCA5, and pathogenesis of variants in SPTBN2 should be further researched.

scholarly journals Parental segregation study reveals rare benign and likely benign variants in a Brazilian cohort of rare diseases

2021 ◽  
Author(s):  
Caio Robledo Quaio ◽  
Jose Ricardo Magliocco Ceroni ◽  
Murilo Castro Cervato ◽  
Helena Strelow Thurow ◽  
Caroline Monaco Moreira ◽  
...  
Keyword(s):  
Rare Diseases ◽  
Segregation Analysis ◽  
Autosomal Dominant ◽  
Rare Variants ◽  
De Novo ◽  
Molecular Data ◽  
Autosomal Dominant Inheritance ◽  
Dominant Inheritance ◽  
Pathogenic Variants ◽  
Genomic Studies

Genomic studies may generate massive amounts of data, bringing interpretation challenges. Efforts for the differentiation of benign and pathogenic variants gain importance. In this article, we used segregation analysis and other molecular data to reclassify to benign or likely benign several rare clinically curated variants of autosomal dominant inheritance from a cohort of 500 Brazilian patients with rare diseases. This study included only symptomatic patients who had undergone molecular investigation with exome sequencing for suspected diseases of genetic etiology. Variants clinically suspected as the causative etiology and harbored by genes associated with highly-penetrant conditions of autosomal dominant inheritance underwent Sanger confirmation in the proband and inheritance pattern determination because a “de novo” event was expected. Among all 327 variants studied, 321 variants were inherited from asymptomatic parents. Considering segregation analysis, we have reclassified 51 rare variants as benign (n=51) and 211 as likely benign (n=211). In our study, the inheritance of a highly penetrant variant expected to be de novo for pathogenicity assumption was considered as a non-segregation and, therefore, a key step for benign or likely benign classification. Studies like ours may help to identify rare benign variants and improve the correct interpretation of genetic findings.

An autosomal dominant ataxia maps to 19q13: Allelic heterogeneity of SCA13 or novel locus?

Neurology ◽  
2005 ◽  
Vol 65 (7) ◽  
pp. 1111-1113 ◽  
Author(s):  
M. F. Waters ◽  
D. Fee ◽  
K. P. Figueroa ◽  
D. Nolte ◽  
U. Muller ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Allelic Heterogeneity ◽  
Autosomal Dominant Ataxia ◽  
Dominant Ataxia

scholarly journals Parental Segregation Study Reveals Rare Benign and Likely Benign Variants in a Brazilian Cohort of Rare Diseases

2021 ◽  
Author(s):  
Caio Robledo D' Angioli Costa Quaio ◽  
Jose Ricardo Magliocco Ceroni ◽  
Murilo Castro Cervato ◽  
Helena Strelow Thurow ◽  
Caroline Monaco Moreira ◽  
...  
Keyword(s):  
Segregation Analysis ◽  
Autosomal Dominant ◽  
Rare Variants ◽  
De Novo ◽  
Molecular Data ◽  
Autosomal Dominant Inheritance ◽  
Dominant Inheritance ◽  
Pathogenic Variants ◽  
Genomic Studies ◽  
Pattern Determination

Abstract Genomic studies may generate massive amounts of data, bringing interpretation challenges. Efforts for the differentiation of benign and pathogenic variants gain importance.In this article, we used segregation analysis and other molecular data to reclassify to benign or likely benign several rare clinically curated variants of autosomal dominant inheritance from a cohort of 500 Brazilian patients with rare diseases.This study included only symptomatic patients who had undergone molecular investigation with exome sequencing for suspected diseases of genetic etiology. Variants clinically suspected as the causative etiology and harbored by genes associated with highly-penetrant conditions of autosomal dominant inheritance underwent Sanger confirmation in the proband and inheritance pattern determination because a “de novo” event was expected.Among all 327 variants studied, 321 variants were inherited from asymptomatic parents. Considering segregation analysis, we have reclassified 51 rare variants as benign (n=51) and 211 as likely benign (n=211).In our study, the inheritance of a highly penetrant variant expected to be de novo for pathogenicity assumption was considered as a non-segregation and, therefore, a key step for benign or likely benign classification. Studies like ours may help to identify rare benign variants and improve the correct interpretation of genetic findings.

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