Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation

Neurology ◽  
2018 ◽  
Vol 90 (7) ◽  
pp. e575-e582 ◽  
Author(s):  
Nadine Pelzer ◽  
Joost Haan ◽  
Anine H. Stam ◽  
Lisanne S. Vijfhuizen ◽  
Stephany C. Koelewijn ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Characteristics ◽  
Autosomal Dominant ◽  
Mutation Screening ◽  
Dominant Gene ◽  
Hemiplegic Migraine ◽  
Mild Phenotype ◽  
New Genes ◽  
Whole Exome

ObjectiveTo investigate whether the clinical characteristics of patients with hemiplegic migraine with and without autosomal dominant mutations in CACNA1A, ATP1A2, or SCN1A differ, and whether the disease may be caused by mutations in other genes.MethodsWe compared the clinical characteristics of 208 patients with familial (n = 199) or sporadic (n = 9) hemiplegic migraine due to a mutation in CACNA1A, ATP1A2, or SCN1A with those of 73 patients with familial (n = 49) or sporadic (n = 24) hemiplegic migraine without a mutation in these genes. In addition, 47 patients (familial: n = 33; sporadic: n = 14) without mutations in CACNA1A, ATP1A2, or SCN1A were scanned for mutations in novel genes using whole exome sequencing.ResultsPatients with mutations in CACNA1A, ATP1A2, or SCN1A had a lower age at disease onset, larger numbers of affected family members, and more often attacks (1) triggered by mild head trauma, (2) with extensive motor weakness, and (3) with brainstem features, confusion, and brain edema. Mental retardation and progressive ataxia were exclusively found in patients with a mutation. Whole exome sequencing failed to identify pathogenic mutations in new genes.ConclusionsMost patients with hemiplegic migraine without a mutation in CACNA1A, ATP1A2, or SCN1A display a mild phenotype that is more akin to that of common (nonhemiplegic) migraine. A major fourth autosomal dominant gene for hemiplegic migraine remains to be identified. Our observations might guide physicians in selecting patients for mutation screening and in providing adequate genetic counseling.

scholarly journals A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

2021 ◽  
Author(s):  
Qing Li ◽  
Chengfeng Wang ◽  
Wei Li ◽  
Zaiqiang Zhang ◽  
Shanshan Wang ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Skin Biopsy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Collagen Type Iv ◽  
Lacunar Infarcts ◽  
Whole Exome

AbstractPontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

scholarly journals Whole-Exome Sequencing Analysis of Human Semen Quality in Russian Multiethnic Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Semyon Kolmykov ◽  
Gennady Vasiliev ◽  
Ludmila Osadchuk ◽  
Maxim Kleschev ◽  
Alexander Osadchuk
Keyword(s):  
Exome Sequencing ◽  
Ethnic Groups ◽  
Whole Exome Sequencing ◽  
Complex Traits ◽  
Semen Quality ◽  
Population Sample ◽  
Sperm Concentration ◽  
Sequencing Analysis ◽  
New Genes ◽  
Whole Exome

The global trend toward the reduction of human spermatogenic function observed in many countries, including Russia, raised the problem of extensive screening and monitoring of male fertility and elucidation of its genetic and ethnic mechanisms. Recently, whole-exome sequencing (WES) was developed as a powerful tool for genetic analysis of complex traits. We present here the first Russian WES study for identification of new genes associated with semen quality. The experimental 3 × 2 design of the WES study was based on the analysis of 157 samples including three ethnic groups—Slavs (59), Buryats (n = 49), and Yakuts (n = 49), and two different semen quality groups—pathozoospermia (n = 95) and normospermia (n = 62). Additionally, our WES study group was negative for complete AZF microdeletions of the Y-chromosome. The normospermia group included men with normal sperm parameters in accordance with the WHO-recommended reference limit. The pathozoospermia group included men with impaired semen quality, namely, with any combined parameters of sperm concentration <15 × 106/ml, and/or progressive motility <32%, and/or normal morphology <4%. The WES was performed for all 157 samples. Subsequent calling and filtering of variants were carried out according to the GATK Best Practices recommendations. On the genotyping stage, the samples were combined into four cohorts: three sets corresponded to three ethnic groups, and the fourth set contained all the 157 whole-exome samples. Association of the obtained polymorphisms with semen quality parameters was investigated using the χ2 test. To prioritize the obtained variants associated with pathozoospermia, their effects were determined using Ensembl Variant Effect Predictor. Moreover, polymorphisms located in genes expressed in the testis were revealed based on the genomic annotation. As a result, the nine potential SNP markers rs6971091, rs557806, rs610308, rs556052, rs1289658, rs278981, rs1129172, rs12268007, and rs17228441 were selected for subsequent verification on our previously collected population sample (about 1,500 males). The selected variants located in seven genes FAM71F1, PPP1R15A, TRIM45, PRAME, RBM47, WDFY4, and FSIP2 that are expressed in the testis and play an important role in cell proliferation, meiosis, and apoptosis.

scholarly journals Identification of a novel pathogenic missense mutation in PRPF31 using whole exome sequencing: a case report

2018 ◽  
Vol 103 (6) ◽  
pp. 761-767 ◽  
Author(s):  
Laura Bryant ◽  
Olga Lozynska ◽  
Anson Marsh ◽  
Tyler E Papp ◽  
Lucas van Gorder ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Protein Trafficking ◽  
Protein Misfolding ◽  
Autosomal Dominant ◽  
Null Alleles ◽  
Incomplete Penetrance ◽  
Missense Mutations ◽  
Whole Exome

BackgroundVariants in PRPF31, which encodes pre-mRNA processing factor 31 homolog, are known to cause autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance. However, the majority of mutations cause null alleles, with only two proven pathogenic missense mutations. We identified a novel missense mutation in PRPF31 in a family with adRP.MethodsWe performed whole exome sequencing to identify possible pathogenic mutations in the proband of a family with adRP. Available affected family members had a full ophthalmological evaluation including kinetic and two-colour dark adapted static perimetry, electroretinography and multimodal imaging of the retina. Two patients had evaluations covering nearly 20 years. We carried out segregation analysis of the probable mutation, PRPF31 c.590T>C. We evaluated the cellular localisation of the PRPF31 variant (p.Leu197Pro) compared with the wildtype PRPF31 protein.ResultsPRPF31 c.590T>C segregated with the disease in this four-generation autosomal dominant pedigree. There was intrafamilial variability in disease severity. Nyctalopia and mid-peripheral scotomas presented from the second to the fourth decade of life. There was severe rod >cone dysfunction. Visual acuity (VA) was relatively intact and was maintained until later in life, although with marked interocular asymmetries. Laboratory studies showed that the mutant PRPF31 protein (p.Leu197Pro) does not localise to the nucleus, unlike the wildtype PRPF31 protein. Instead, mutant protein resulted in punctate localisation to the cytoplasm.Conclusionsc.590T>C is a novel pathogenic variant in PRPF31 causing adRP with incomplete penetrance. Disease may be due to protein misfolding and associated abnormal protein trafficking to the nucleus.

Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness

2018 ◽  
Vol 94 (5) ◽  
pp. 419-428 ◽  
Author(s):  
X. Lu ◽  
Q. Wang ◽  
H. Gu ◽  
X. Zhang ◽  
Y. Qi ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Pathogenic Variant ◽  
Whole Exome

Whole Exome Sequencing for Mutation Screening in Hemophagocytic Lymphohistiocytosis

2020 ◽  
Author(s):  
Edris Sharif Rahmani ◽  
Majid Fathi ◽  
Mohammad Foad Abazari ◽  
Hojat Shahraki ◽  
Vahid Ziaee Fellow ◽  
...  
Keyword(s):  
Immune System ◽  
Data Analysis ◽  
Exome Sequencing ◽  
Molecular Characterization ◽  
Whole Exome Sequencing ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Mutation Screening ◽  
Positive Family History ◽  
Whole Exome

Background: Hemophagocytic lymphohistiocytosis (HLH) is an immune system disorder characterized by uncontrolled hyper-inflammation owing to hypercytokinemia from the activated but ineffective cytotoxic cells. Establishing a correct diagnosis for HLH patients due to the similarity of this disease with other conditions like malignant lymphoma and leukemia and similarity among its two forms is difficult and not always a successful procedure. Besides, the molecular characterization of HLH due to the locus and allelic heterogeneity is a challenging issue. Materials and Methods: In this experimental study, whole exome sequencing (WES) was used for mutation detection in a four-member Iranian family with children suffering from signs and symptoms of HLH disease. Data analysis was performed by using a multi-step in-house WES approach on Linux OS. Result: In this study, a homozygous nucleotide substitution mutation (c.551G>A:p.W184*) was detected in exon number six of the UNC13D gene. W184* drives to a premature stop codon, so produce a truncated protein. This mutation inherited from parents to a four-month female infant with an autosomal recessive pattern. Parents were carrying out the heterozygous form of W184* without any symptoms. The patient showed clinical signs such as fever, diarrhea, hepatosplenomegaly, high level of ferritin, and a positive family history of HLH disease. W184* has a damaging effect on cytotoxic T lymphocytes, and natural killer cells. These two types of immune system cells without a healthy product of the UNC13D gene will be unable to discharge toxic granules into the synaptic space, so the inflammation in the immune response does not disappear. Conclusion: According to this study, WES can be a reliable, fast, and cost-effective approach for the molecular characterization of HLH patients. Plus, WES specific data analysis platform introduced by this study potentially offers a high-speed analysis step. This cost-free platform doesn't require online data submission.

Gene mutation screening using whole exome sequencing in lipid storage myopathy

2015 ◽  
Vol 25 ◽  
pp. S204
Author(s):  
K. Takayama ◽  
S. Mitsuhashi ◽  
I. Nonaka ◽  
S. Noguchi ◽  
I. Nishino
Keyword(s):  
Exome Sequencing ◽  
Gene Mutation ◽  
Whole Exome Sequencing ◽  
Mutation Screening ◽  
Lipid Storage ◽  
Lipid Storage Myopathy ◽  
Whole Exome

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>CAT): c.104 G>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.

scholarly journals Mutation-Specific Dominant Negative Effects Determine the Phenotype in SRP54 Deficiency

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 437-437
Author(s):  
Christoph Schuerch ◽  
Thorsten Schaefer ◽  
Joelle S. Müller ◽  
Pauline Hanns ◽  
Jonas Schärer ◽  
...  
Keyword(s):  
Protein Expression ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Conflicts Of Interest ◽  
Dominant Negative ◽  
Severe Neutropenia ◽  
Negative Effects ◽  
Mild Phenotype ◽  
Whole Exome ◽  
Neutrophil Differentiation

Whole exome sequencing analyses are increasingly performed on patients presenting with suspected inherited disease but lacking classical mutations linked to presented phenotypes. Using whole-exome sequencing in SBDS-negative Shwachman-Diamond Syndrome (SDS) families, we recently identified three independent patients, each of whom carried a heterozygous de novo missense variant of SRP54 (encoding signal recognition particle 54 kDa). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). Whilst two of the identified patients were carrying nucleotide transversion in SRP54 (p.T115A and p.G226E), which manifested in typical SDS features like neutropenia and exocrine pancreatic insufficiency, the third patient was carrying a nucleotide deletion (p.T117Δ), which only manifested in mild neutropenia without additional SDS features (Carapito et al. 2017, JCI). Here, we describe a zebrafish knock-out (KO) mutant as the very first transgenic in vivo model of SRP54 deficiency, translate our previous findings into living organisms and propose disease-driving mechanisms. We show that homozygous srp54 mutant zebrafish are suffering not only from severe neutropenia as shown by flow cytometry and Whole-Mount-In-Situ Hybridization (WISH), but also from gross developmental defects leading to early embryonic lethality. In fact, srp54-/- zebrafish did not survive more than 72 hours post fertilization, indicating that complete loss of Srp54 is not compatible with life. Injection with wild-type human SRP54 mRNA induced transient restoration of SRP54 protein expression and slightly enhanced the survival of the homozygous mutants. However, long-term viability could not be restored, revealing that srp54 is not only critically required during early embryogenesis but also at later stages of development. Heterozygous siblings on the other hand are viable and display only mild neutropenia but no pancreas defects. Interestingly however, injection of mutant mRNAs of human SRP54 (p.T115A, p.T117Δ, p.226E) into heterozygous srp54 KO mutants aggravated the phenotype inducing more profound neutropenia and pancreas changes similar to those observed in classical SDS patients. Of note, these effects were more severe for the transversions p.T115A and p.G226E. Mutation p.T117Δ only caused a minor reduction in the number of neutrophils, without affecting the pancreas. To further investigate SRP54 driven neutrophil defects, we used lentiviral transduction to exogenously express human SRP54 mutant variants in promyelocytic HL-60 cells. When stimulating these cells to differentiate by ATRA treatment, we found significantly impaired morphologic differentiation and CD11b surface induction compared to control cells. The severity of these effects was again specific to the three different identified mutations, with p.T115A and p.G226E being more severe than p.T117Δ. These findings confirm the type-specific effects of SRP54 mutations and indicate that SRP54 defects interfere with neutrophil differentiation and thus ultimately lead to neutropenia. Collectively, we here describe a novel zebrafish disease model of SDS and congenital neutropenia founding on SRP54 as molecular driver. Our model demonstrates that at least one healthy allele of srp54 is pivotal for survival, which is in line with the findings in humans, where homozygous mutations in SRP54 have never been detected. We reveal that the phenotypic manifestation of heterozygous SRP54 mutations strongly depends on the type of mutation: while mutations likely causing a simple SRP54 loss of function (e.g. p.T117Δ) induce a rather mild phenotype characterized by moderate neutropenia only (analogous to the heterozygous fish mutant), more severe SDS-like phenotypes involve SRP54 mutations that exert dominant negative effects (e.g. p.T115A and p.G226E). Ultimately, we make use of the promyelocytic cell line HL-60 to propose neutrophil differentiation defects as the underlying cause of SRP54 driven neutropenia. At the time being, RNA sequencing and protein expression analyses are performed in our laboratory, which will add to the understanding of the mechanistical background of the neutrophilic differentiation blockage and eventually uncover novel treatment strategies for SRP54 deficiency. Disclosures No relevant conflicts of interest to declare.

Whole exome sequencing identifies SCD5 as a novel causative gene for autosomal dominant nonsyndromic deafness

2020 ◽  
Vol 63 (5) ◽  
pp. 103855 ◽  
Author(s):  
Xingxing Lu ◽  
Yanmei Zhang ◽  
Li Chen ◽  
Qi Wang ◽  
Zhen'gang Zeng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Nonsyndromic Deafness ◽  
Causative Gene ◽  
Whole Exome
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