scholarly journals A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 362 ◽  
Author(s):  
Anna Letko ◽  
Elisabeth Dietschi ◽  
Marco Nieburg ◽  
Vidhya Jagannathan ◽  
Corinne Gurtner ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Genetic Variant ◽  
Missense Variant ◽  
Whole Genome Sequence ◽  
Cognitive Disability ◽  
Spinocerebellar Ataxias ◽  
Critical Interval ◽  
Spongy Degeneration ◽  
Pathogenic Variants ◽  
Ataxia Syndrome

Spinocerebellar ataxias is an umbrella term for clinically- and neuropathologically-heterogeneous early-onset hereditary neurodegenerative diseases affecting several dog breeds. The purpose of this study is to identify the causative genetic variant associated with ataxia, tremor, and loss of balance in Alpine Dachsbracke dogs. We investigated two related litters in which four cases were reported. Neuropathology of two dogs revealed spongy degeneration associated with axonal degeneration. Combined genetic linkage and autozygosity analyses in four cases and eight related controls showed one critical disease-associated interval on chromosomes 27. Private whole-genome sequence variants of one ataxia case against 600 unrelated controls revealed one protein-changing variant within the critical interval in the SCN8A gene (c.4898G>T; p.Gly1633Val). Perfect segregation with the phenotype was confirmed by genotyping >200 Alpine Dachsbracke dogs. SCN8A encodes a voltage-gated sodium channel and the missense variant was predicted deleterious by three different in silico prediction tools. Pathogenic variants in SCN8A were previously reported in humans with ataxia, pancerebellar atrophy, and cognitive disability. Furthermore, cerebellar ataxia syndrome in the ‘jolting’ mutant mice is caused by a missense variant in Scn8a. Therefore, we considered the SCN8A:c.4898G>T variant to be the most likely cause for recessively inherited spinocerebellar ataxia in Alpine Dachsbracke dogs.

scholarly journals Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Elisabeth A. Rosenthal ◽  
David R. Crosslin ◽  
Adam S. Gordon ◽  
David S. Carrell ◽  
Ian B. Stanaway ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Large Family ◽  
Missense Variant ◽  
Mixed Ancestry ◽  
Limited Sample ◽  
Health Records ◽  
Pathogenic Variants ◽  
Phenotype Data ◽  
Emerge Network ◽  
Using Data

Abstract Background Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample. Methods Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry. Results We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP. Conclusions Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.

scholarly journals A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Giada Moresco ◽  
Jole Costanza ◽  
Carlo Santaniello ◽  
Ornella Rondinone ◽  
Federico Grilli ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Clinical Presentation ◽  
De Novo ◽  
Clinical Signs ◽  
Missense Variant ◽  
Psychomotor Development ◽  
Helicase Domain ◽  
Protein Activity ◽  
Mrna Metabolism ◽  
Pathogenic Variants

Abstract Background De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.625C > G) by whole exome sequencing (WES). The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome. Conclusions This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

scholarly journals A novel nonsense variant of the AGXT identified in a Chinese family: special variant research in the Chinese reference genome

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Chang Bao Xu ◽  
Xu Dong Zhou ◽  
Hong En Xu ◽  
Yong Li Zhao ◽  
Xing Hua Zhao ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Reference Genome ◽  
Genetic Diagnosis ◽  
Primary Hyperoxaluria ◽  
Missense Variant ◽  
Population Heterogeneity ◽  
Chinese Family ◽  
Pathogenic Variants ◽  
Variation Database ◽  
Genetic Level

Abstract Background Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. Case presentation In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband’s mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. Conclusions Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.

scholarly journals Novel SCN5A and GPD1L Variants Identified in Two Unrelated Han-Chinese Patients With Clinically Suspected Brugada Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Meng Yuan ◽  
Yi Guo ◽  
Hong Xia ◽  
Hongbo Xu ◽  
Hao Deng ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Missense Variant ◽  
Han Chinese ◽  
Chinese Patients ◽  
Splicing Variant ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Gated Channel ◽  
Life Threatening ◽  
Glycerol 3 Phosphate Dehydrogenase

Brugada syndrome (BrS) is a complexly genetically patterned, rare, malignant, life-threatening arrhythmia disorder. It is autosomal dominant in most cases and characterized by identifiable electrocardiographic patterns, recurrent syncope, nocturnal agonal respiration, and other symptoms, including sudden cardiac death. Over the last 2 decades, a great number of variants have been identified in more than 36 pathogenic or susceptibility genes associated with BrS. The present study used the combined method of whole exome sequencing and Sanger sequencing to identify pathogenic variants in two unrelated Han-Chinese patients with clinically suspected BrS. Minigene splicing assay was used to evaluate the effects of the splicing variant. A novel heterozygous splicing variant c.2437-2A>C in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) and a novel heterozygous missense variant c.161A>T [p.(Asp54Val)] in the glycerol-3-phosphate dehydrogenase 1 like gene (GPD1L) were identified in these two patients with BrS-1 and possible BrS-2, respectively. Minigene splicing assay indicated the deletion of 15 and 141 nucleotides in exon 16, resulting in critical amino acid deletions. These findings expand the variant spectrum of SCN5A and GPD1L, which can be beneficial to genetic counseling and prenatal diagnosis.

scholarly journals A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Lulu Yan ◽  
Ru Shen ◽  
Zongfu Cao ◽  
Chunxiao Han ◽  
Yuxin Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Dimensional Structure ◽  
Chinese Family ◽  
Speech Impairment ◽  
Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

scholarly journals Phenotype variability and early onset ataxia symptoms in spinocerebellar ataxia type 7: comparison and correlation with other spinocerebellar ataxias

2015 ◽  
Vol 73 (1) ◽  
pp. 18-21 ◽  
Author(s):  
Marcus Vinicius Cristino de Albuquerque ◽  
José Luiz Pedroso ◽  
Pedro Braga Neto ◽  
Orlando Graziani Povoas Barsottini
Keyword(s):  
Spinocerebellar Ataxia ◽  
Early Onset ◽  
Clinical Presentation ◽  
Age Of Onset ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxias ◽  
Phenotype Variability ◽  
Spinocerebellar Ataxia Type 7 ◽  
Early Onset Ataxia

The spinocerebellar ataxias (SCA) are a group of neurodegenerative disorders characterized by heterogeneous clinical presentation. Spinocerebellar ataxia type 7 (SCA7) is caused by an abnormal CAG repeat expansion and includes cerebellar signs associated with visual loss and ophthalmoplegia. Marked anticipation and dynamic mutation is observed in SCA7. Moreover, phenotype variability and very early onset of symptoms may occur. In this article, a large series of Brazilian patients with different SCA subtypes was evaluated, and we compared the age of onset of SCA7 with other SCA. From the 26 patients with SCA7, 4 manifested their symptoms before 10-year-old. Also, occasionally the parents may have the onset of symptoms after their children. In conclusion, our study highlights the genetic anticipation phenomenon that occurs in SCA7 families. Patients with very early onset ataxia in the context of a remarkable family history, must be considered and tested for SCA7.

scholarly journals Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family

2020 ◽  
Vol 10 (4) ◽  
pp. 262
Author(s):  
Giovanna Morello ◽  
Giulia Gentile ◽  
Rossella Spataro ◽  
Antonio Gianmaria Spampinato ◽  
Maria Guarnaccia ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Spinocerebellar Ataxia ◽  
Complex Disease ◽  
Spinocerebellar Ataxia Type ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Spinocerebellar Ataxia Type 1 ◽  
Pathogenic Variants ◽  
Lateral Sclerosis

Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members. Results: Our analysis identified common and distinctive candidate genes/variants and related biological processes that, in addition to or in combination with ATXN1, may contribute to motor neuron degeneration phenotype. Among these, we distinguished ALS-specific likely pathogenic variants in TAF15 and C9ORF72, two ALS-linked genes involved in the regulation of RNA metabolism, similarly to ATXN1, suggesting a selective role for this pathway in ALS pathogenesis. Conclusions: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes.

scholarly journals Hemizygous FLNA variant in West syndrome without periventricular nodular heterotopia

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Yoshitaka Hiromoto ◽  
Yoshiteru Azuma ◽  
Yuichi Suzuki ◽  
Megumi Hoshina ◽  
Yuri Uchiyama ◽  
...  
Keyword(s):  
De Novo ◽  
Missense Variant ◽  
West Syndrome ◽  
Periventricular Nodular Heterotopia ◽  
Psychomotor Delay ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Epileptic Patients ◽  
Nodular Heterotopia ◽  
Refractory Seizures

AbstractPathogenic FLNA variants can be identified in patients with seizures accompanied by periventricular nodular heterotopia (PVNH). It is unusual to find FLNA aberrations in epileptic patients without PVNH on brain imaging. We report a boy with cryptogenic West syndrome followed by refractory seizures and psychomotor delay. We performed whole-exome sequencing and identified a de novo missense variant in FLNA. It is noteworthy that this patient showed no PVNH. As no other pathogenic variants were found in epilepsy-related genes, this FLNA variant likely caused West syndrome but with no PVNH.

P1392Next generation sequencing in lone atrial fibrillation patients

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
I Rudaka ◽  
D Rots ◽  
O Kalejs ◽  
L Gailite
Keyword(s):  
Atrial Fibrillation ◽  
Sudden Cardiac Death ◽  
Genetic Variants ◽  
Cardiac Death ◽  
Structural Heart Disease ◽  
Missense Variant ◽  
Lone Atrial Fibrillation ◽  
Excessive Alcohol Consumption ◽  
Pathogenic Variants ◽  
Rare Genetic Variants

Abstract Background. Minor part of atrial fibrillation (AF) patients develops the disease without any well-known risk factors, which is a particular form of the disease, known as a lone AF. Rare genetic variants were described as causative for lone AF. The aim of this study was to investigate occurrence of rare genetic variants in lone AF patients. Material and Methods. We performed Mendeliome sequencing for 21 lone AF patients. Lone AF was defined as AF in individuals younger than 65 years in the absence of cardiovascular or structural heart disease, endocrinologic or pulmonary disease, chronic kidney disease, obesity and excessive alcohol consumption. Data analysis was performed by current laboratory pipeline. We analyzed 453 cardiomyopathy, arrhythmias and sudden cardiac death related genes. Results. In eight out of 21 (38%) lone AF patients rare likely pathogenic variants were found (Table 1.). Seven rare truncating TTN variants and one LMNA missense variant were observed. Four unrelated patients were positive for the same TTN variant c.13696 C > T; p.(Gln4566Ter). The same variant was previously found in ARVC patient in our laboratory. Segregation analysis and phenotyping of relatives is ongoing. Conclusions. Rare genetic variants are common causes of the lone atrial fibrillation. TTN gene variant c.13696C > T; p.(Gln4566Ter) is a potential founder variant in the Baltic population. Table 1. Genetic variants in lone AF Gender Age of AF onset Genetic variant Family history Male 53 LMNA: p.(Ser326Thr) AF in mother Male 11 TTN: p.(Trp31854Ter) AF in father Male 30 TTN: p.(GLn4566Ter) AF in uncle Female 45 TTN: p.(GLn4566Ter) Negative Male 37 TTN: p.(GLn4566Ter) AF in father Male 25 TTN: p.(GLn4566Ter) AF in father, maternal and paternal grandmother Female 60 TTN: p.(Arg27414Ter) Sudden cardiac death at the age of 50 in grand father Female 52 TTN: p.(Arg1012Ter) AF in mother

scholarly journals MRI Signal Abnormalities of the Inferior Olivary Nuclei in Spinocerebellar Ataxia Type 2

2017 ◽  
Vol 9 (3) ◽  
pp. 267-271 ◽  
Author(s):  
Fumihito Yoshii ◽  
Hitoshi Tomiyasu ◽  
Ryo Watanabe ◽  
Masafuchi Ryo
Keyword(s):  
Spinocerebellar Ataxia ◽  
Autosomal Dominant ◽  
Spinocerebellar Ataxia Type ◽  
Proton Density ◽  
Spinocerebellar Ataxias ◽  
Spinocerebellar Ataxia Type 2 ◽  
Cerebellar Peduncles ◽  
Magnetic Resonance Imaging Mri ◽  
Inferior Olivary

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant spinocerebellar degeneration, associated with extended repeats of the trinucleotide CAG in the ATXN2 gene on the long arm of chromosome 12. Magnetic resonance imaging (MRI) of SCA2 showed significant atrophies of the brainstem, middle cerebellar peduncles, and cerebellum. We report two genetically proven SCA2 patients who showed hypertrophy of the inferior olivary nuclei on proton density- and T2-weighted MRI. This pattern has never been reported in patients with SCA1, SCA3, or SCA6, and may make it possible to differentiate SCA2 from other hereditary spinocerebellar ataxias.

Sign in / Sign up

Export Citation Format

Share Document