scholarly journals P.071 Novel mutations in SPG7 identified from patients with late-onset spasticity

2018 ◽  
Vol 45 (s2) ◽  
pp. S35-S35
Author(s):  
MM Almomen ◽  
KA Martens ◽  
A Hanson ◽  
L Korngut ◽  
G pfeffer
Keyword(s):  
Cerebellar Ataxia ◽  
Late Onset ◽  
Diagnostic Yield ◽  
Genetic Diseases ◽  
Transcript Level ◽  
Progressive External Ophthalmoplegia ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Leg Weakness

Background: Hereditary spastic paraplegia (HSP) is a group of genetic diseases that cause progressive degeneration of the corticospinal tract. Historically, this disease was divided into two types:the classic subtype, with leg weakness and hypertonic bladder, and the complicated subtype, with features such as cerebellar ataxia or optic atrophy.Mutations in SPG7 (encoding paraplegin) leads to complicated HSP causing cerebellar ataxia, progressive external ophthalmoplegia in addition to the classical symptoms. AFG3L2 is a binding partner of paraplegin and mutations in AFG3L2 cause a similar syndrome Methods: From a neurogenetic clinic , we identified 11 patients with late-onset HSP. Sequencing of SPG7 and AFG3L2 was performed using a customised assay, and/or clinical diagnostic sequencing panels.SPG7 transcript level quantification was performed from whole blood RNA on a digital droplet qPCR system. Results: We identified 4 patients with pathogenic variants or variants of unknown significance in SPG7. No AFG3L2 mutations were identified. We provide evidence for pathogenicity for three mutations that were not previously associated with SPG7-related disease, based on their occurrence in context of the correct phenotype, and the reduction of transcript levels measured with RT-qPCR.A curious association of the heterozygous p.Gly349Ser mutation in association with an ALS-like syndrome is reported. Conclusions:SPG7 mutations sequencing has high diagnostic yield in late onset paraparesis

P3567Genetic screening for monogenic hypertension in hypertensive individuals in a clinical setting

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Bao ◽  
J Zhong ◽  
J Cai ◽  
X Yang
Keyword(s):  
Functional Analysis ◽  
Diagnostic Yield ◽  
Basic Research ◽  
Functional Evaluation ◽  
Variants Of Unknown Significance ◽  
Treatment And Prevention ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Monogenic Hypertension ◽  
Number Of Individuals

Abstract Objectives Monogenic hypertension describes a series of hypertension syndromes inherited by Mendelian law and present with complex phenotypes. Methods 1179 cases with monogenic hypertension potential were evaluated by sequencing 37 causative genes. Pathogenic variants were classified by using American College of Medical Genetics guidelines. Additionally, 49 variants of unknown significance were selected to receive functional analysis. The yield of combined genetic and functional analysis was evaluated. Results 21 deleterious variants were identified in 33 of 1179 (2.80%). Functional analysis for 49 unknown significant variants showed 32 variants harbored by 61 individuals led to abnormally expressed protein levels. Overall, combining genetic screening with functional analysis promoted diagnostic yield to 8.73%. The main etiology established was primary aldosteronism, with CACNA1H harboring the greatest mutation burden. Logistic regression analysis showed hypertension complicated with special manifestations had the strongest correlation with disease causing variants detection (p=0.03). Sequencing Results Summary Number of variants Number of individuals* Percentage† Individuals with no variant 0 524 44.44% Individuals with variants identified 592 655 55.56% Individuals with single contributing variant 297 480 40.71% Individuals with two or multiple contributing variants 295 175 14.84% Number of variants identified   Pathogenic and likely pathogenic variants 21 33 2.80%   Variants of unknown significance 570 634 53.77%   Benign or likely benign variants 1 1 0.08% Type of variant   Frameshift deletion 8 15 1.27%   Frameshift insertion 5 5 0.42%   Nonframeshift deletion 10 10 0.85%   Nonframeshift insertion 6 12 1.02%   Nonsynonymous SNV 546 607 51.48%   Stopgain SNV 18 30 2.54% WES, whole-exome sequencing. *The statistics in this table was based on 1179 individuals. †The percentage was calculated by the number of individuals in each category. A flow chart of this study. Conclusion Our findings demonstrate an enhanced diagnostic ability by combining genetic analysis with functional evaluation and enables targeted treatment and prevention of hypertension. Acknowledgement/Funding This work was supported by National Basic Research Program of China (973 Program, 2014CB542300, 2014CB542302).

scholarly journals Diagnostic Yield of Genetic Testing in Sudden Cardiac Death with Autopsy Findings of Uncertain Significance

2021 ◽  
Vol 10 (9) ◽  
pp. 1806
Author(s):  
Mercedes Iglesias ◽  
Tomas Ripoll-Vera ◽  
Consuelo Perez-Luengo ◽  
Ana Belen García ◽  
Susana Moyano ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Ventricular Hypertrophy ◽  
Diagnostic Yield ◽  
Left Ventricular ◽  
Molecular Autopsy ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Uncertain Significance ◽  
Frequent Variant

Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. This study aims to evaluate the diagnostic yield of genetic testing in these cases. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Genetic testing was performed. Results: In a series of 195 SD cases, we selected 31 cases presenting idiopathic LVH (n = 16, 51.61%), nonsignificant CA (n = 17, 54.84%), and/or PMF (n = 24, 77.42%) in the autopsy. Mean age was 41 ± 7.2 years. Diagnostic yield of genetic test was 67.74%, considering variants of unknown significance (VUS), pathogenic variants (PV) and likely pathogenic variants (LPV); 6.45% including only PV and LPV. Structural genes represented 41,93% (n = 13) of cases, while 38,7% (n = 12) were related to channelopathies. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

scholarly journals Targeted next generation sequencing identifies a genetic spectrum of DNA variants in patients with hemiplegic migraine

2019 ◽  
Vol 2 ◽  
pp. 251581631988163 ◽  
Author(s):  
Neven Maksemous ◽  
Robert A Smith ◽  
Heidi G Sutherland ◽  
Bridget H Maher ◽  
Omar Ibrahim ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Diagnostic Yield ◽  
Next Generation ◽  
Hemiplegic Migraine ◽  
Targeted Next Generation Sequencing ◽  
Variants Of Unknown Significance ◽  
High Mutation Frequency ◽  
Unknown Significance ◽  
Atp1a2 Gene ◽  
Generation Sequencing

Objective: Hemiplegic migraine in both familial (FHM) and sporadic (SHM) forms is a rare subtype of migraine with aura that can be traced to mutations in the CACNA1A, ATP1A2 and SCN1A genes. It is characterised by severe attacks of typical migraine accompanied by hemiparesis, as well as episodes of complex aura that vary significantly between individuals. Methods: Using a targeted next generation sequencing (NGS) multigene panel, we have sequenced the genomic DNA of 172 suspected hemiplegic migraine cases, in whom no mutation had previously been found by Sanger sequencing (SS) of a limited number of exons with high mutation frequency in FHM genes. Results: Genetic screening identified 29 variants, 10 of which were novel, in 35 cases in the three FHM genes ( CACNA1A, ATP1A2 and SCN1A). Interestingly, in this suspected HM cohort, the ATP1A2 gene harboured the highest number of variants with 24/35 cases (68.6%), while CACNA1A ranked the second gene, with 5 variants identified in 7/35 cases (20%). All detected variants were confirmed by SS and were absent in 100 non-migraine healthy control individuals. Assessment of variants with the American College of Medical Genetics and Genomics guidelines classified 8 variants as pathogenic, 3 as likely pathogenic and 18 as variants of unknown significance. Targeted NGS gene panel increased the diagnostic yield by fourfold over iterative SS in our diagnostics facility. Conclusion: We have identified 29 potentially causative variants in an Australian and New Zealand cohort of suspected HM cases and found that the ATP1A2 gene was the most commonly mutated gene. Our results suggest that screening using NGS multigene panels to investigate ATP1A2 alongside CACNA1A and SCN1A is a clinically useful and efficient method.

scholarly journals Sorting Rare ALS Genetic Variants by Targeted Re-Sequencing Panel in Italian Patients: OPTN, VCP, and SQSTM1 Variants Account for 3% of Rare Genetic Forms

2020 ◽  
Vol 9 (2) ◽  
pp. 412 ◽  
Author(s):  
Viviana Pensato ◽  
Stefania Magri ◽  
Eleonora Dalla Bella ◽  
Pierpaola Tannorella ◽  
Enrica Bersano ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Next Generation Sequencing Technology ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Rare Gene ◽  
Motor Neuron Loss ◽  
Generation Sequencing ◽  
Lateral Sclerosis ◽  
Diagnostic Investigations

Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease due to motor neuron loss variably associated with frontotemporal dementia (FTD). Next generation sequencing technology revealed an increasing number of rare and novel genetic variants and interpretation of their pathogenicity represents a major challange in the diagnosis of ALS. We selected 213 consecutive patients with sporadic or familial (16%) ALS, tested negative for SOD1, FUS, TARDBP, and C9orf72 mutations. To reveal rare forms of genetic ALS, we performed a comprehensive multi-gene panel screening including 46 genes associated with ALS, hereditary motor neuronopathies, spastic paraplegia, and FTD. Our study allowed the identification of pathogenic or likely pathogenic variants in 4.2% of patients. The genes with the highest percentage of pathogenic variants were OPTN (1%), VCP (1%) SQSTM1(1%), SETX (0.4%), FIG4 (0.4%), and GARS1 (0.4%) genes. We also found 49 novel or rare gene variants of unknown significance in 30 patients (14%), 44 unlikely pathogenic variants (39%), and 48 variants in ALS susceptibility genes. The results of our study suggest the screening of OPTN, VCP, and SQSTM1 genes in routine diagnostic investigations for both sporadic and familial cases, and confirm the importance of diagnosis and couselling for patients and their relative family members.

Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients

Cardiology ◽  
2020 ◽  
Vol 145 (11) ◽  
pp. 746-756
Author(s):  
Tatiana Vershinina ◽  
Yulia Fomicheva ◽  
Alexey Muravyev ◽  
John Jorholt ◽  
Alexandra Kozyreva ◽  
...  
Keyword(s):  
Ion Channel ◽  
Age Groups ◽  
Left Ventricular ◽  
Barth Syndrome ◽  
Reduced Ejection Fraction ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Paediatric Patients ◽  
Unknown Significance ◽  
Sarcomeric Genes

<b><i>Introduction:</i></b> Left ventricular non-compaction (LVNC) represents a genetically heterogeneous cardiomyopathy which occurs in both children and adults. Its genetic spectrum overlaps with other types of cardiomyopathy. However, LVNC phenotypes in different age groups can have distinct genetic aetiologies. The aim of the study was to decipher the genetic spectrum of LVNC presented in childhood. <b><i>Patient Group and Methods:</i></b> Twenty patients under the age of 18 years diagnosed with LVNC were enrolled in the study. Target sequencing and whole-exome sequencing were performed using a panel of 108 cardiomyopathy-associated genes. Pathogenic, likely pathogenic, and variants of unknown significance found in genes highly expressed in cardiomyocytes were considered as variants of interest for further analysis. <b><i>Results:</i></b> The median age at presentation was 8.0 (0.1–17) years, with 6 patients presenting before 1 year of age. Twelve (60%) patients demonstrated reduced ejection fraction. Right ventricular (RV) dilation was registered in 6 (30%), often in combination with reduced RV contractility (25%). Almost half (45%) of the patients demonstrated biventricular involvement already at disease presentation. For pathogenic and likely pathogenic variants, the positive genotyping rate was 45%, and these variants were found mainly in non-contractile structural sarcomeric genes (<i>ACTN2</i>, <i>MYPN</i>, and <i>TTN</i>) or in metabolic and signal transduction genes (<i>BRAF</i> and <i>TAZ</i>). Likely pathogenic <i>TAZ</i> variants were detected in all 5 patients suspected of having Barth syndrome. No pathogenic or likely pathogenic variants were found in genes encoding for sarcomeric contractile proteins, but variants of unknown significance were detected in 3 out of 20 patients (<i>MYH6</i>, <i>MYH7</i>, and <i>MYLK2</i>). In 4 patients, variants of unknown significance in ion-channel genes were detected. <b><i>Conclusion:</i></b> We detected a low burden of contractile sarcomeric variants in LVNC patients presenting below the age of 18 years, with the major number of variants residing in non-contractile structural sarcomeric genes. The identification of the variants in ion-channel and related genes not previously associated with LVNC in paediatric patients requires further examination of their functional role.

scholarly journals Poor Yield of Routine Transthyretin Screening in Patients with Idiopathic Neuropathy

2020 ◽  
Vol 47 (6) ◽  
pp. 816-819
Author(s):  
Dina Namiranian ◽  
Colin Chalk ◽  
Rami Massie
Keyword(s):  
Genetic Screening ◽  
Diagnostic Yield ◽  
Familial Amyloid Polyneuropathy ◽  
North American Population ◽  
Rare Entity ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Life Threatening ◽  
Amyloid Polyneuropathy ◽  
Transthyretin Familial Amyloid Polyneuropathy

ABSTRACT:Background and objectives:Transthyretin familial amyloid polyneuropathy (TTR-FAP) is caused by a mutation in the transthyretin (TTR) gene. Although classically described as rapidly progressive and life-threatening, recent studies on TTR-FAP show significant genetic and phenotypic heterogeneity depending on geographic localization. In light of new therapeutic advances and their implication for patient management, the aim of our study was to determine the prevalence of TTR-FAP within patients with idiopathic neuropathy in a North American population.Methods:We sequenced the TTR gene in a cohort of patients with idiopathic neuropathy. Genetic screening was performed in 110 patients from two neuromuscular clinics in Montreal, Canada.Results:No variants of unknown significance or pathogenic mutations were detected in the TTR gene.Conclusion:Our study confirms that TTR-FAP is a rare entity in our patient population, and that diagnostic yield of screening all patients with idiopathic neuropathy is very low.

scholarly journals Designing Myeloid Gene Panels

2021 ◽  
Author(s):  
Fang Zhao ◽  
David S. Bosler ◽  
James R. Cook
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Pathology ◽  
Diagnostic Yield ◽  
Gene Panel ◽  
Next Generation ◽  
Gene Set ◽  
Variants Of Unknown Significance ◽  
The Core ◽  
Unknown Significance ◽  
Generation Sequencing

Context.— Next-generation sequencing studies are increasingly used in the evaluation of suspected chronic myeloid neoplasms (CMNs), but there is wide variability among laboratories in the genes analyzed for this purpose. Recently, the Association for Molecular Pathology CMN working group recommended a core 34-gene set as a minimum target list for evaluation of CMNs. This list was recommended based on literature review, and its diagnostic yield in clinical practice is unknown. Objective.— To determine the diagnostic yield of the core 34 genes and assess the potential impact of including selected additional genes. Design.— We retrospectively reviewed 185 patients with known or suspected CMNs tested using a 62-gene next-generation sequencing panel that included all 34 core genes. Results.— The Association for Molecular Pathology's core 34 genes had a diagnostic yield of 158 of 185 (85.4%) to detect at least 1 variant with strong/potential clinical significance and 107 of 185 (57.8%) to detect at least 2 such variants. The 62-gene panel had a diagnostic yield of 160 of 185 (86.5%) and 112 of 185 (60.5%), respectively. Variants of unknown significance were identified in 49 of 185 (26.5%) using the core 34 genes versus 76 of 185 (41.1%) using the 62-gene panel. Conclusions.— This study demonstrates that the Association for Molecular Pathology–recommended core 34-gene set has a high diagnostic yield in CMNs. Inclusion of selected additional genes slightly increases the rate of abnormal results, while also increasing the detection of variants of unknown significance. We recommend inclusion of CUX1, DDX41, ETNK1, RIT1, and SUZ12 in addition to the Association for Molecular Pathology's 34-gene core set for routine evaluation of CMNs.

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