Hereditary spastic paraplegia associated with a novel homozygous intronic noncanonical splice site variant in the AP4B1 gene

2021 ◽  
Author(s):  
Clara Gómez‐González ◽  
Cristina Pizarro‐Sánchez ◽  
Carlos Rodríguez‐Antolín ◽  
Ignacio Pascual‐Pascual ◽  
Mar Garcia‐Romero ◽  
...  
Keyword(s):  
Splice Site ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Splice Site Variant

scholarly journals A case of de novo splice site variant inSLC35A2showing developmental delays, spastic paraplegia, and delayed myelination

2019 ◽  
Vol 7 (8) ◽  
Author(s):  
Sachiko Miyamoto ◽  
Mitsuko Nakashima ◽  
Tsukasa Ohashi ◽  
Takuya Hiraide ◽  
Kenji Kurosawa ◽  
...  
Keyword(s):  
Splice Site ◽  
Developmental Delays ◽  
De Novo ◽  
Spastic Paraplegia ◽  
Splice Site Variant ◽  
Delayed Myelination

scholarly journals A Novel SPAST/SPG4 Splice-Site Variant in a Family with Dominant Hereditary Spastic Paraplegia

2020 ◽  
Vol 2020 ◽  
pp. 1-3
Author(s):  
Nathaniel M. Robbins ◽  
Jillian R. Ozmore ◽  
Thomas L. Winder ◽  
Pedro Gonzalez-Alegre ◽  
Tanya M. Bardakjian
Keyword(s):  
Splice Site ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraparesis ◽  
Spastic Paraplegia ◽  
Novel Variant ◽  
Consensus Splice Site ◽  
Diagnostic Work ◽  
Next Generation Sequencing Ngs ◽  
Work Up

Some causes of spastic paraplegia are treatable and many are not. Diagnostic work-up to determine the etiology can be costly and invasive. Here we report the case of a man with slowly progressive spastic paraparesis. Using a multigene next-generation sequencing (NGS) panel, we identified a novel variant in the consensus splice site of the SPAST gene (exon 13, c.1536G>A, heterozygous), affecting codon 512 of the SPAST mRNA. The observed variant segregated with the disease in four tested family members. In this case, genetic confirmation obviated the need for additional testing such as MRI and lumbar puncture and helped the patient and his family understand his condition and prognosis. We conclude with a brief discussion of the SPG4/SPAST gene and the role of multigene panels in the diagnosis and management of hereditary spastic paraplegia.

A novel splice site mutation in ERLIN2 causes hereditary spastic paraplegia in a Saudi family

2013 ◽  
Vol 56 (1) ◽  
pp. 43-45 ◽  
Author(s):  
Salma M. Wakil ◽  
Saeed Bohlega ◽  
Samya Hagos ◽  
Batoul Baz ◽  
Haya Al Dossari ◽  
...  
Keyword(s):  
Splice Site ◽  
Hereditary Spastic Paraplegia ◽  
Splice Site Mutation ◽  
Spastic Paraplegia ◽  
Site Mutation ◽  
Saudi Family

Novel splice-site variant of UCHL1 in an Indian family with autosomal recessive spastic paraplegia-79

2018 ◽  
Vol 63 (8) ◽  
pp. 927-933 ◽  
Author(s):  
Aneek Das Bhowmik ◽  
Siddaramappa J. Patil ◽  
Dipti Vijayrao Deshpande ◽  
Venkatraman Bhat ◽  
Ashwin Dalal
Keyword(s):  
Splice Site ◽  
Autosomal Recessive ◽  
Spastic Paraplegia ◽  
Indian Family ◽  
Splice Site Variant

scholarly journals Novel Splice-Site and Missense Variant of PNPLA6 in an Austrian Family Causing Spastic Paraplegia-39 with Cerebellar Oculomotor Disorder

2022 ◽  
Author(s):  
Sebastian Viertauer ◽  
Ingo Kurth ◽  
Katja Eggermann ◽  
Christian Eggers
Keyword(s):  
Splice Site ◽  
Lower Limb ◽  
Clinical Symptoms ◽  
Hypogonadotropic Hypogonadism ◽  
Missense Variant ◽  
Compound Heterozygous ◽  
Spastic Paraplegia ◽  
Meaningful Improvement ◽  
Pathogenic Variants ◽  
Splice Site Variant

Abstract Background The term hereditary spastic paraplegia comprises an ever-expanding array of neurological disorders with distinct aetiologies. Spastic paraplegia 39 is one of the many variants with additional features of other organs and neurological systems. We describe a large kindred with two hitherto undescribed mutations of PNPLA6 and a novel clinical phenotype as, in addition to spastic paraplegia, affected subjects suffered from a prominent cerebellar oculomotor dysfunction. Methods Three of five genetically tested family members of a large kindred were affected by spastic gait and cerebellar oculomotor dysfunction. Clinical, imaging, laboratory and electrophysiological data were analyzed. Genetic analysis was done using next-generation sequencing. Segregation analyses were performed by Sanger sequencing. To assess the pathogenicity of genetic variants on the encoded protein, in silico assessments were carried out. Results Two hitherto unknown sequence variants in the PNPLA6 gene, a splice-site variant c.1635+3G>T and a missense variant c.3401A>T, p.(Asp1134Val), were detected. Compound-heterozygous siblings presented with lower limb spasticity and a marked cerebellar oculomotor disorder accompanied by moderate hypogonadotropic hypogonadism in the female. A paternal uncle being homozygous for the splice-site variant of PNPLA6 presented with increased lower limb reflexes, an unstable gait and cerebellar oculomotor dysfunction. Treatment with 4-aminopyridin, a potassium channel blocker, lead to meaningful improvement of clinical symptoms. Conclusion PNPLA6 gene variants are associated with a broad phenotypic spectrum to which we add cerebellar oculomotor dysfunction. In our kindred, the full clinical manifestation only occurred in compound-heterozygous subjects indicating that biallelic pathogenic variants lead to more serious and earlier onset of symptoms. Our findings emphasize the role of PNPLA6 in different neurodegenerative disorders.

scholarly journals In Silico Analysis of Variants of Uncertain Significance in AP4S1 Gene

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Sobia Nazir Chaudry ◽  
Ammara Akhtar ◽  
Ayman Naeem ◽  
Dr. Mureed Husaain
Keyword(s):  
Splice Site ◽  
Protein Function ◽  
Hereditary Spastic Paraplegia ◽  
In Silico ◽  
Low Frequency ◽  
In Silico Analysis ◽  
Neurological Complications ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Silico Analysis

Hereditary spastic paraplegia is a group of heterogeneous neurological disorders with genetic etiologies. It is characterized by spasticity in lower limbs along with neurological complications. Sequencing technologies have identified numerous disease causing variants in AP4S1 gene. However, many very low frequency variations in AP4S1 have the potential to cause hereditary spastic paraplegia in a recessive inheritance manner. This study was designed to identify these potential disease causing variants in AP4S1 gene using in silico tools. These tools predict the effects of deleterious variants on protein function and pre-mRNA splicing. To predict the pathogenicity of missense variants PhD-SNPg, PROVEAN, SNPs&GO, and CADD were used. Splice site variants were analyzed using Spliceman, SPiCE, and Human Splice Finder (HSF). In silico analysis identified six missense and five splice site variants with the potential to cause hereditary spastic paraplegia.

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