scholarly journals Neuroacanthocytosis diagnózisa új generációs exom-szekvenálással

2017 ◽  
Vol 158 (42) ◽  
pp. 1681-1684 ◽  
Author(s):  
Kinga Hadzsiev ◽  
Mónika Szőts ◽  
Anett Fekete ◽  
László Balikó ◽  
Kim Boycott ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
International Collaboration ◽  
Huntington Disease ◽  
Stop Codon ◽  
Neurological Diseases ◽  
Premature Stop Codon ◽  
Pathogenic Mutation ◽  
Normal Result ◽  
Whole Exome ◽  
Specific Symptoms

Abstract: In a patient with marked symptoms of Huntington disease after the huntingtin testing, which gave normal result, a whole exome sequencing (WES) has been performed based on an international collaboration. A homozygous G>A nucleotid change in the exon 34 of the VPS13A gene has been detected with WES, a mutation resulting in a premature stop codon at the position 1301. This change is a known pathogenic mutation. The aim of this article is to draw attention on the importance of the WES in the diagnosis of rare neurological diseases without any specific symptoms. Orv Hetil. 2017; 158(42): 1681–1684.

scholarly journals AIMP1 Mutation Long-Term Follow-Up, With Decreased Brain N-Acetylaspartic Acid and Secondary Mitochondrial Abnormalities

2019 ◽  
Vol 6 ◽  
pp. 2329048X1982952 ◽  
Author(s):  
Aneal Khan ◽  
Jennifer Bennett ◽  
Morris H. Scantlebury ◽  
Xing-Chang Wei ◽  
Marina Kerr
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Monozygotic Twins ◽  
Trna Synthetase ◽  
Resonance Spectroscopy ◽  
Multifunctional Protein ◽  
Whole Exome ◽  
Long Term Follow Up

Aminoacyl transfer RNA (tRNA) synthetase complex-interacting multifunctional protein I is a noncatalytic component of tRNA multi-synthetase complexes. Although important in joining tRNAs to their cognate amino acids, AIMP1 has several other functions including axonal growth, cytokine activity, and interactions with N-acetylaspartic acid in ribosomal tRNA synthetase complexes. Further, N-acetylaspartic acid donates an aspartate during myelination and is therefore important to axonal integrity. Mutations in AIMP1 can disrupt these functions, as demonstrated in this clinical case study of 2 monozygotic twins, who display congenital opisthotonus, microcephaly, severe developmental delay, and seizures. Whole exome sequencing was used to identify a premature stop codon in the AIMP1 gene (g. 107248613_c.115C>T; p.(Gln39). In the absence of whole exome sequencing, we propose that decreased N-acetylaspartic acid peaks on magnetic resonance spectroscopy could act as a biomarker for AIMP1 mutations.

scholarly journals Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing

2021 ◽  
Author(s):  
Huifang Yan ◽  
Haoran Ji ◽  
Thomas Kubisiak ◽  
Ye Wu ◽  
Jiangxi Xiao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Promising Candidate ◽  
Whole Exome ◽  
First Time ◽  
The Brain ◽  
Rare Group

AbstractHypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.

scholarly journals Exome sequencing in paediatric patients with movement disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Potential Treatment ◽  
Paediatric Patients ◽  
Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

scholarly journals Attenuated Type of Asphyxiating Thoracic Dysplasia due to Mutations in DYNC2H1 Gene

2019 ◽  
Vol 120 (4) ◽  
pp. 124-130
Author(s):  
Anna Čechová ◽  
Alice Baxová ◽  
Jiří Zeman ◽  
Lukáš Lambert ◽  
Tomáš Honzík ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Chest Circumference ◽  
Anthropometric Parameters ◽  
Age Related ◽  
Whole Exome ◽  
Asphyxiating Thoracic Dysplasia ◽  
Health And Disease ◽  
Postnatal Adaptation

Asphyxiating thoracic dysplasia (ATD) represents a heterogeneous group of skeletal dysplasias with short ribs, narrow chest and reduced thoracic capacity. Mutations in several genes including IFT80, DYNC2H1, TTC21B and WDR19 have been found in patients with ATD. Both severe and milder course of the disease were described in correlation with secondary involvement of lung’s function. Two children with attenuated form of ATD are described. Their anthropometric parameters for birth weight, length and head circumference were normal but narrow thorax was observed in both of them in early infancy with chest circumference < –3 SD (standard deviation) in comparison to age related controls. The postnatal adaptation and development of both children was uneventful except for mild tachypnoea in one of them which persisted till the age of 6 months. In both children, radiographs revealed narrow upper half of the chest with shorter ribs and atypical configuration of pelvis with horizontally running acetabula and coarse internal edges typical for ATD. Molecular analyses using whole exome sequencing in one family revealed that the patient is compound heterozygote in DYNC2H1 gene for a frame-shift mutation c.4458delT resulting in premature stop-codon p.Phe1486Leufs*11 and a missense mutation c.9044A>G (p.Asp3015Gly). The second family refused the DNA analysis. Regular monitoring of anthropometric parameters during childhood is of big importance both in health and disease. In addition, measurement of the chest circumference should be included, at least at birth and during infancy.

scholarly journals Exome Sequencing Identifies A Nonsense Variant in DAO Associated With Reduced Energy Expenditure in American Indians

2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Paolo Piaggi ◽  
Çiğdem Köroğlu ◽  
Anup K Nair ◽  
Jeff Sutherland ◽  
Yunhua L Muller ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Exome Sequencing ◽  
American Indians ◽  
Genetic Variants ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Dopamine Synthesis ◽  
Acid Oxidase ◽  
Pima Indians ◽  
Amino Acid Oxidase

Abstract Background Obesity and energy expenditure (EE) are heritable and genetic variants influencing EE may contribute to the development of obesity. We sought to identify genetic variants that affect EE in American Indians, an ethnic group with high prevalence of obesity. Methods Whole-exome sequencing was performed in 373 healthy Pima Indians informative for 24-hour EE during energy balance. Genetic association analyses of all high-quality exonic variants (≥5 carriers) was performed, and those predicted to be damaging were prioritized. Results Rs752074397 introduces a premature stop codon (Cys264Ter) in DAO and demonstrated the strongest association for 24-hour EE, where the Ter allele associated with substantially lower 24-hour EE (mean lower by 268 kcal/d) and sleeping EE (by 135 kcal/d). The Ter allele has a frequency = 0.5% in Pima Indians, whereas is extremely rare in most other ethnic groups (frequency &lt; 0.01%). In vitro functional analysis showed reduced protein levels for the truncated form of DAO consistent with increased protein degradation. DAO encodes D-amino acid oxidase, which is involved in dopamine synthesis which might explain its role in modulating EE. Conclusion Our results indicate that a nonsense mutation in DAO may influence EE in American Indians. Identification of variants that influence energy metabolism may lead to new pathways to treat human obesity. Clinical Trial Registration Number NCT00340132.

Whole-Exome Sequencing Identifies Novel Risk Variant for Thrombotic Storm

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1229-1229
Author(s):  
Thomas L. Ortel ◽  
Gary Beecham ◽  
Dale Hedges ◽  
Patrice Whitehead ◽  
Ashley Beecham ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
De Novo ◽  
Stop Codon ◽  
Response To Therapy ◽  
High Quality ◽  
Whole Exome ◽  
Short Period

Abstract Abstract 1229 Background: Thrombotic storm (TS) is an extremely severe clinical phenotype that occurs in a very small subset of patients with venous thromboembolic disease. It is characterized by patients who exhibit two or more of the following in a short period of time; 1) > 2 acute arterial/venous thromboemboli, and/or thrombotic microangiopathy, 2) unusual location, 3) progressive/recent unexplained recurrence, and/or 4) refractory to and/or atypical response to therapy (Kitchens et al., Am J Med, 2011). We hypothesize these patients possess an underlying prothrombotic risk factor that results in an accelerated form of thrombosis following an initial event that provokes the attack in the relevant clinical context. Methods: To identify potential genetic risk variants we performed whole-exome sequencing on a TS participant and his unaffected parents and sibling. The proband was a 14 year old male who presented with thrombosis of the sagittal, right transverse and sigmoid sinuses following a sports-related knee injury. There was no personal or family history of venous thromboembolism, and a hypercoagulable workup, including testing for antiphospholipid antibodies, was negative. His course was complicated by the development of disseminated intravascular coagulation, delaying early initiation of anticoagulant therapy. Despite aggressive supportive care, which included anticoagulation therapy, the proband did not improve and expired after severe cerebral edema with herniation was diagnosed by clinical exam and CT imaging. At autopsy, bilateral pulmonary emboli and extensive pelvic vein thrombosis were also identified. DNA was extracted from whole blood and the relevant regions were captured using the Agilent Sure Select 50mb kit. Sequencing was performed on the Illumina HiSeq2000 under the manufacturer's recommended protocol. Alignment of reads to the reference was performed using BWA, and genotype calls were made with GATK. Variants were initially filtered based on quality (depth ≥ 8, phred-like quality ≥ 30), function (nonsense, missense, splicing), and novelty. Additional filters include inheritance mode (autosomal recessive or de novo heterozygote), conservation (phastcons score > 0.5, GERP score > 2), and damage prediction (SIFT or Polyphen). Potential variants were validated using Sanger sequencing. Results: Whole-exome sequencing identified over 127,000 variants in the nuclear family with at least one member having a high quality variant at the position. Filtering these variants based on function, novelty, and high quality in parents and affected proband reduced the list to 2,735 variants. Of these, 7 variants fit an autosomal recessive model (homozygous in the proband, heterozygous in both parents, not homozygous in the unaffected sibling); of these 7, two were at conserved sites, predicted to be damaging, and also called using SAMTOOLS. The first of the recessive variants is a nonsense variation in the EGFL8 gene (tyrosine to stop codon, at the 74th amino acid; tyr74stop), and the second is in HLA-E (gln276pro). Of the initial list of 2,735 variants there were 138 that fit a de novo heterozygous model (present in the affected proband, but not parents); of these 138, two were at a conserved site, predicted to be damaging, and were also called with SAMTOOLS. The first de novo heterozygote is in SLC26A2 (arg178stop), and the second variant is in PRMT7 (arg531trp). These four variants were resequenced using Sanger sequencing within the family. Three of the variants (EGFL8, SLC26A2, and PRMT7) were confirmed using Sanger; the fourth (HLA-E) is still being resequenced. Discussion: These variants represent excellent candidate loci for thrombotic storm risk. In particular, the EGFL8 variant is a homozygous change to a stop codon less than one quarter of the way through the open reading frame – a change that likely severely damages protein function. Additionally, EGFL8 (epidermal growth factor-like domain-containing protein 8) has two EGF domains, a common motif identified in hemostatic and fibrinolytic proteins, and is therefore potentially involved in coagulation. These variants will be further analyzed for frequency in controls and tested in animal models for functional significance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical and Molecular Characterization of Qatari Patients with Inherited Dysfibrinogenemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1037-1037
Author(s):  
Amna Gameil ◽  
Hajer Al-Mulla ◽  
Aliaa Amer ◽  
Tawfeg Ben-Omran ◽  
Mohamed A Yassin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Clinical Phenotype ◽  
Pathogenic Mutation ◽  
Functional Assay ◽  
Sequencing Analysis ◽  
Thrombin Time ◽  
Whole Exome ◽  
Antigen Assay

Abstract Background and Objectives: Inherited Dysfibrinogenemia is a rare functional fibrinogen disorder in which the fibrinogen protein is present but with a reduced function. Fibrinogen is a 340-kDa glycoprotein that is encoded by three genes namely: Fibrinogen Bb (FGB), Aa (FGA), and g (FGG). The disorder is characterized by a wide spectrum of clinical phenotypes, ranging from asymptomatic to mild- to-severe bleeding or thrombotic manifestations and recurrent miscarriages. The mode of inheritance is mostly autosomal dominant manner and frequently as a result of a point mutation in FGA (Arg35) and FGG (Arg301). The laboratory diagnosis is based on discrepancy between fibrinogen antigen (detected by immunoassay or by immuno-turbidimetric assay) and functional assay (detected by Clauss method or other clot-based assays). The disorder is often associated with prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT).Fibrinogen activity is reduced by Clauss method while the antigen assay remains normal. The management is directed towards prevention of bleeding with prophylactic fibrinogen concentrates or cryoprecipitate prior to invasive procedures, surgeries or delivery. Dysfibrinogenemia is a rare disorder yet it is very prevalent in Qatar as a result of high rate of consanguineous marriages. The aim of our study is to describe the clinical phenotype in relation to genotype in this cohort. Methods We conducted a retrospective analysis of 23 patients with Inherited Dysfibrinogenemia reported by our center from 2015 to 2020 . Patients with a positive family of history fibrinogen disorder and abnormal coagulation screen, low functional fibrinogen assay (by Clauss method) or normal antigen level by turbidimetry were included. Whole exome sequencing (WES) was performed on the proband case which detected a likely pathogenic mutation that was tested on subsequent cases. We diagnosed our patients with Inherited Dysfibrinogenemia based on both coagulation-based assays and molecular tests. Probable Inherited Dysfibrinogenemia was considered in patients where the molecular test or antigen assay were not performed. To assess the clinical phenotype, data was collected that included; age at diagnosis, gender, bleeding and thrombotic events as well as coagulation screening. (Table 1) Results 23 patients who were described in this cohort belong to the same tribe. 74% (17 o/23) were female and only 41% (7/17) reported an obstetric bleeding (postpartum or post abortion) and one reported mild bleeding that occurred in the postmenopausal period and no previous bleeding (case#19). The median age of diagnosis was 28.8 years (5-69) for the females. All male cases in the cohort were detected either during routine screening or prior to surgery with no previous history of bleeding. No thrombotic events were observed in this cohort. Genetic Analysis Following proper genetic counseling and informed consent, whole exome sequencing analysis (WES) was performed on the index case which included testing of the fibrinogen genes FGA, FGB and FGG. WES revealed a likely pathogenic mutation in the FGA gene (p. Arg35His (R35H) (CGT&gt;CAT): c.104 G&gt;A in exon 2)-Located within the cleavage site of fibrinopeptide A by thrombin (The UniProt Consortium, 2017), which is a mutational hotspot. This result is likely consistent with the diagnosis of Dysfibrinogenemia. Conclusion The FGA R35H mutation is considered a probable recurrent variant in a large tribe in the Qatari population and is associated with late onset mild bleeding manifestations in minority of cases . Despite the fact that the reported tribe is highly consanguineous, the R35H mutation behaved in an autosomal dominant manner rather than recessive in this cohort.Further studies to assess phenotype - genotype correlation of Dysfibrinogenemia is warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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