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

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 P.123 Severe DNM1 Encephalopathy with Dysmyelination due to Recurrent Splice Site Pathogenic Variant

2021 ◽  
Vol 48 (s3) ◽  
pp. S54-S54
Author(s):  
AN Sahly ◽  
E Krochmalnek ◽  
J St-Onge ◽  
M Srour ◽  
KA Myers
Keyword(s):  
Splice Site ◽  
De Novo ◽  
Subcortical White Matter ◽  
Pathogenic Variant ◽  
Pcr Analysis ◽  
Global Developmental Delay ◽  
Missense Mutations ◽  
Central Domain ◽  
Splice Site Variant ◽  
T2 Hyperintensity

Background: Patients with DNM1-encephalopathy almost exclusively have missense variants, mostly in the GTPase domain of DNM1. Delayed myelination has been reported in at least three patients with DNM1-encephalopathy, all with missense mutations in the DNM1 central domain. Only one DNM1 splice-site variant has previously been reported, and the authors questioned whether the variant accounted for all aspects of the patient’s phenotype. Methods: Case-Report. Results: Our patient had hypotonia and brief multifocal tonic seizures from age-1-month. He still has profound global developmental delay, daily seizures and microcephaly. MRI-Brain at age-21-months showed T2 hyperintensity in the bilateral periventricular and subcortical white matter; spectroscopy showed a questionable lactate peak and an elevated choline peak relative to N-acetylaspartate. Clinical gene-panel identified a heterozygous de novo pathogenic variant in intron 9 of DNM1 (c.1197-8G > A; IVS9- 8G>A). In-silico tools categorized this variant as deleterious secondary to a splicing defect. RT-PCR analysis on peripheral blood was unsuccessful as DNM1 expression is extremely low outside of the brain. Conclusions: Our patient carried the same DNM1 variant previously reported, indicating this is a recurrent pathogenic splice-site variant. The spectroscopic abnormalities suggest a possible element of demyelination in DNM1 variants of the central domain, though the mechanism remains unclear.

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 Lethal chondrodysplasia in a family of Holstein cattle is associated with a de novo splice site variant of COL2A1

2016 ◽  
Vol 12 (1) ◽  
Author(s):  
Jørgen S. Agerholm ◽  
Fiona Menzi ◽  
Fintan J. McEvoy ◽  
Vidhya Jagannathan ◽  
Cord Drögemüller
Keyword(s):  
Splice Site ◽  
De Novo ◽  
Holstein Cattle ◽  
Splice Site Variant

scholarly journals De novo splice site variant of ARID1B associated with pathogenesis of Coffin–Siris syndrome

2019 ◽  
Vol 7 (12) ◽  
Author(s):  
Laura Pranckėnienė ◽  
Evelina Siavrienė ◽  
Lucie Gueneau ◽  
Eglė Preikšaitienė ◽  
Violeta Mikštienė ◽  
...  
Keyword(s):  
Splice Site ◽  
De Novo ◽  
Splice Site Variant

scholarly journals A rare large duplication of MLH1 identified in Lynch syndrome

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhishek Kumar ◽  
Nagarajan Paramasivam ◽  
Obul Reddy Bandapalli ◽  
Matthias Schlesner ◽  
Tianhui Chen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Lynch Syndrome ◽  
Splice Site ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Splice Donor Site ◽  
Laboratory Diagnostics ◽  
Mmr Genes ◽  
Base Pair Deletion ◽  
Splice Site Variant

Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.

scholarly journals Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

2020 ◽  
Vol 28 (12) ◽  
pp. 1763-1768
Author(s):  
Thomas Bourinaris ◽  
◽  
Damian Smedley ◽  
Valentina Cipriani ◽  
Isabella Sheikh ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
De Novo ◽  
Age At Onset ◽  
Genetic Diagnosis ◽  
Spastic Paraplegia ◽  
Sequencing Data ◽  
Juvenile Form ◽  
Pathogenic Variants ◽  
Degenerative Disorders ◽  
Significant Gene

AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

A novel BTK gene mutation creates a de-novo splice site in an X-linked agammaglobulinemia patient

Gene ◽  
2015 ◽  
Vol 560 (2) ◽  
pp. 245-248 ◽  
Author(s):  
Chai Teng Chear ◽  
Adiratna Mat Ripen ◽  
Sharifah Adlena Syed Mohamed ◽  
Jasbir Singh Dhaliwal
Keyword(s):  
Gene Mutation ◽  
Splice Site ◽  
De Novo
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