scholarly journals Characterization of a novel CSF1R mutation causing hereditary diffuse leukoencephalopathy with spheroids in a case presenting with young-onset dementia

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S118-S118
Author(s):  
Walid Nasr ◽  
Mahmoud Gad ◽  
Tareq Qassem
Keyword(s):  
Novel Mutation ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Insertion Mutation ◽  
Heterozygous Deletion ◽  
Young Onset ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Young Onset Dementia ◽  
Rapid Cognitive Decline

ObjectiveThis poster aims to report an unregistered mutation CSF1R gene in a patient presenting young-onset dementia.Hypothesis: Novel heterozygous deletion–insertion mutation in the Colony-Stimulating Factor 1 Receptor (CSF1R) gene is linked to a case of hereditary diffuse leukoencephalopathy with spheroids (HDLS), presenting with young-onset dementia.BackgroundCSF1R mediates proliferation, differentiation, and survival of monocytes/ macrophages and microglia. Pathogenic variants in the CSF1R gene cause autosomal dominant diffuse hereditary leukoencephalopathy with spheroids characterized by variable behavioural, cognitive, and motor changes, usually presenting with young-onset dementia. The average lifespan after the start of the symptoms is often 6 years.Case reportMolecular genetic analysis of whole-exome sequencing (WES) was carried out for a 49-year-old male patient presenting with rapid cognitive decline, behavioural symptoms and impaired sphincteric control.DiscussionWES identified the heterozygous deletion–insertion variant c.2356_2357delinsAC p.(Leu786Thr) (chr5:149435867-49435868; hg19) in the CSF1R gene. To the best of our knowledge the variant has not been described in the literature so far (HGMD 2019.3). No allele frequencies in the general population have been documented.ConclusionWe believe that we have identified a novel mutation in the CSF1R gene. This mutation is likely to be linked to this patient presenting with young-onset dementia.

scholarly journals An unregistered TARDBP mutation in a case presenting with young-onset dementia

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S116-S116
Author(s):  
Mahmoud Gad ◽  
Walid Nasr ◽  
Tareq Qassem
Keyword(s):  
Novel Mutation ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Heterozygous Mutation ◽  
Neurocognitive Deficits ◽  
Young Onset ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
Young Onset Dementia

ObjectiveThis poster aims to report an unregistered mutation in Transactive Response DNA Binding Protein (TARDBP) gene in a patient presenting young-onset dementia.Hypothesis: Novel heterozygous mutation in the TARDBP gene is linked to a case of with young-onset dementia.BackgroundPathogenic variants in TARDBP cause autosomal dominant fronto-temporal degeneration, characterized by TDP43-positive inclusions, dystonia, dyslexia, receptive dysphasia, and paraphrasic errors. In addition to the neurocognitive deficits, patients might suffer from cardiomyopathy and amyotrophic lateral sclerosis.Case reportMolecular genetic analysis of whole-exome sequencing (WES) was carried out for a 45-year-old male patient presenting with cognitive decline and behavioural symptoms.DiscussionWES Identified the heterozygous variant c.527A > T p.(Lys 176lle) in TARDBP gene. To the best of our knowledge the variant has not been described in the literature so far (HGMD 2019.3). No allele frequencies in the general population have been documented.ConclusionWe believe that we have identified a novel mutation in the TARDBP gene. This mutation is likely to be linked to this patient presenting with young-onset dementia.

scholarly journals A Novel Mutation of ATP7B Gene in a Case of Wilson Disease

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 123
Author(s):  
Cigdem Yuce Kahraman ◽  
Ali Islek ◽  
Abdulgani Tatar ◽  
Özlem Özdemir ◽  
Adil Mardinglu ◽  
...  
Keyword(s):  
Wilson Disease ◽  
Novel Mutation ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Compound Heterozygous ◽  
Atp7b Gene ◽  
Loss Of Function ◽  
Clinical Presentations ◽  
The Family ◽  
The Brain

Wilson disease (WD) (OMIM# 277900) is an autosomal recessive inherited disorder characterized by excess copper (Cu) storage in different human tissues, such as the brain, liver, and the corneas of the eyes. It is a rare disorder that occurs in approximately 1 in 30,000 individuals. The clinical presentations of WD are highly varied, primarily consisting of hepatic and neurological conditions. WD is caused by homozygous or compound heterozygous mutations in the ATP7B gene. The diagnosis of the disease is complicated because of its heterogeneous phenotypes. The molecular genetic analysis encourages early diagnosis, treatment, and the opportunity to screen individuals at risk in the family. In this paper, we reported a case with a novel, hotspot-located mutation in WD. We have suggested that this mutation in the ATP7B gene might contribute to liver findings, progressing to liver failure with a loss of function effect. Besides this, if patients have liver symptoms in childhood and/or are children of consanguineous parents, WD should be considered during the evaluation of the patients.

Population-Based Screening in Children For Early Diagnosis and Treatment of Familial Hypercholesterolemia: Design of The VRONI Study

2021 ◽  
Author(s):  
Veronika Sanin ◽  
Raphael Schmieder ◽  
Sara Ates ◽  
Lea Dewi Schlieben ◽  
Jens Wiehler ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Screening Program ◽  
Molecular Genetic ◽  
Population Based ◽  
Molecular Genetic Analysis ◽  
Cascade Screening ◽  
Screening Programs ◽  
Pathogenic Variants ◽  
Risk Indices ◽  
Training Courses

Abstract Background: Heterozygous Familial Hypercholesterolemia (FH) represents the most frequent monogenic disorder with an estimated prevalence of 1:250 in the general population. Diagnosis during childhood enables early initiation of preventive measures, reducing the risk of severe consecutive atherosclerotic manifestations. Nevertheless, population-based screening programs for FH are scarce.Methods: In the VRONI study children aged 5 to 14 years in Bavaria are invited to participate in a FH screening program during regular pediatric visits. The screening is based on LDL-C measurements from capillary blood. If exceeding 130 mg/dl (3.34 mmol/l), i.e. the expected 95th percentile in this age group, subsequent molecular genetic analysis for FH is performed. Children with FH pathogenic variants enter a registry and are treated by specialized pediatricians. Furthermore, qualified training centers offer FH-focused training courses to affected families. For first degree relatives, reverse cascade screening is recommended to identify and treat affected family members.Results: Implementation of VRONI required intensive prearrangements for addressing ethical, educational, data-safety, legal and organisational aspects, which will be outlined in this paper. Recruitment started in January of 2021, within two months more than 280 pediatricians screened over 1,150 children. Approximately 60,000 children are expected to be enrolled in the VRONI study until 2024. Conclusion: VRONI aims to test the feasibility of a population-based screening for FH in children in Bavaria, intending to set the stage for a nation-wide FH screening infrastructure. Further we aim to validate genetic variants of unclear significance, detect novel causative mutations, and contribute to polygenic risk indices. (German Clinical Trials Register: DRKS00022140; registered August 21st2020.)

Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB

2017 ◽  
Vol 30 (4) ◽  
Author(s):  
Qingwen Zeng ◽  
Yanjie Fan ◽  
Lili Wang ◽  
Zhuo Huang ◽  
Xuefan Gu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Unknown Etiology ◽  
Mendelian Disease ◽  
Atypical Form ◽  
Pathogenic Variants ◽  
Diagnostic Potential ◽  
Whole Exome ◽  
Related Enzyme

AbstractBackground:Mucopolysaccharidosis IIIB (MPS IIIB) is a genetic disease characterized by mutations in theCase presentation:Whole exome sequencing (WES) was conducted and the putative pathogenic variants were validated by Sanger sequencing. The activity of MPS IIIB related enzyme in the patient’s blood serum was assayed. A heterozygous, non-synonymous mutation (c.1562C>T, p.P521L) as well as a novel mutation (c.1705C>A, p.Q569K) were found in theConclusions:Our results describe an atypical form of MPS IIIB and illustrate the diagnostic potential of targeted WES in Mendelian disease with unknown etiology. WES could become a powerful tool for molecular diagnosis of MPS IIIB in clinical setting.

scholarly journals Analysis of the mutational spectrum of the SLC26A4 gene and its contribution to the etiology of inherited hearing loss in the indigenous population of Southern Siberia

2020 ◽  
pp. 43-45
Author(s):  
В.Ю. Данильченко ◽  
М.В. Зыцарь ◽  
Е.А. Маслова ◽  
М.С. Бады-Хоо ◽  
И.В. Морозов ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Unknown Etiology ◽  
Southern Siberia ◽  
Pathogenic Variants ◽  
Slc26a4 Gene ◽  
Wide Range ◽  
Polymorphic Variants ◽  
Tyva Republic

Мутации в гене SLC26A4 являются частой причиной потери слуха во многих регионах мира. В работе приводятся результаты молекулярно-генетического анализа (с использованием секвенирования по Сэнгеру) последовательности гена SLC26A4, впервые проведенного в выборке пациентов с потерей слуха неустановленной этиологии (n=232) из Республик Тыва и Алтай. Установлены контрастные различия патогенетического вклада мутаций в гене SLC26A4 в этиологию нарушения слуха у коренных жителей этих географически близких регионов: 28,2% - для тувинцев и 4,3% - для алтайцев. Выявлены как уже известные, так и новые патогенные варианты, а также широкий спектр полиморфных вариантов гена SLC26A4. Mutations in the SLC26A4 gene are a common cause of hearing loss in many regions of the world. This paper presents the results of molecular genetic analysis (by Sanger sequencing) of the SLC26A4 sequence, first performed in the sample of patients with hearing loss of unknown etiology (n=232) from the Tyva Republic and the Altai Republic. Contrast differences of the pathogenic contribution of SLC26A4 mutations to the etiology of hearing impairment were revealed in the indigenous peoples of these geographically close regions: 28.2% for Tuvinians and 4.3% for Altaians. Both known and novel pathogenic variants as well as a wide range of polymorphic variants were found in the SLC26A4 gene sequence.

scholarly journals Pathogenic variants identified by whole-exome sequencing in 43 patients with epilepsy

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Linlin Zhang ◽  
Jinshuang Gao ◽  
Hailiang Liu ◽  
Yuan Tian ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Treatment Options ◽  
Molecular Genetic ◽  
Epileptic Encephalopathy ◽  
Molecular Genetic Analysis ◽  
Specific Diagnosis ◽  
Whole Exome ◽  
Early Establishment

Abstract Background Epilepsy is a group of neurological disorders characterized by recurrent epileptic seizures. Epilepsy is affected by many factors, approximately 20–30% of cases are caused by acquired conditions, but in the remaining cases, genetic factors play an important role. Early establishment of a specific diagnosis is important to treat and manage this disease. Methods In this study, we have recruited 43 epileptic encephalopathy patients and the molecular genetic analysis of those children was performed by whole-exome sequencing (WES). Results Fourteen patients (32.6%, 14/43) had positive genetic diagnoses, including fifteen mutations in fourteen genes. The overall diagnostic yield was 32.6%. A total of 9 patients were diagnosed as pathogenic mutations, including 4 variants had been reported as pathogenic previously and 6 novel variants that had not been reported previously. Therefore, WES heralds promise as a tool for clinical diagnosis of patients with genetic disease. Conclusion Early establishment of a specific diagnosis, on the one hand, is necessary for providing an accurate prognosis and recurrence risk as well as optimizing management and treatment options. On the other hand, to unveil the genetic architecture of epilepsy, it is of vital importance to investigate the phenotypic and genetic complexity of epilepsy.

scholarly journals Molecular Genetic Analysis of FOXL2 Gene in Two Iranian Families with Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome

2017 ◽  
Vol 1 (1) ◽  
Author(s):  
Nooshin Asgari ◽  
Mohammad Taghi Akbari ◽  
Faravareh Khordadpoor Deilamani ◽  
Gholamreza Babamohammadi
Keyword(s):  
Novel Mutation ◽  
Direct Sequencing ◽  
Genetic Disorder ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Premature Menopause ◽  
Type I ◽  
Forkhead Transcription Factor ◽  
Salting Out ◽  
Foxl2 Gene

Background: Blepharophimosis-ptosis-epicanthus syndrome (BPES) is a rare genetic disorder with autosomal dominant inheritance. There are two distinct phenotypes: BPES type I, which is associated with eyelid abnormalities as well as female infertility or premature menopause due to ovarian resistance to gonadotropins, whereas in type II only eyelid abnormalities are present. Mutations in the forkhead transcription factor 2 (FOXL2) gene are responsible for both types of BPES. Objectives: The purpose of this study was to identify mutations in FOXL2 in two Iranian families (from Tehran) with BPES who were referred to Tehran Medical Genetics laboratory. Methods: The peripheral blood was collected from the affected members of two BPES families and genomic DNA was extracted using salting out method. Then, direct sequencing of whole exon of FOXL2 genewas performed. Results: Two frameshift mutations were identified in FOXL2 gene in two familial cases including NM_023067:c.102_103insA (p.G35Rfs*61)as a novel mutation and NM_023067:c.855_871dup (p.H291Rfs*71) (17-bp insertion). Both mutations cause the protein to be truncated and are responsible for a severe phenotype (BPES type I) which was in harmony with our finding. Conclusions: Our results increased the spectrum of FOXL2 mutations and confirm the mutations associated with BPES type I.

scholarly journals Hypoglycemia and Dandy-Walker variant in a Kabuki syndrome patient: a case report

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Guo ◽  
Yanguo Zhao ◽  
Shuwei Li ◽  
Jingqun Wang ◽  
Xiang Liu
Keyword(s):  
De Novo ◽  
Early Stage ◽  
Novel Mutation ◽  
Molecular Testing ◽  
Kabuki Syndrome ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Chinese Girl ◽  
Neonatal Stage ◽  
Congenital Condition

Abstract Background Kabuki syndrome (KS) is a rare congenital condition with cardinal manifestations of typical facial features, developmental delays, skeletal anomalies, abnormal dermatoglyphic presentations, and mild to moderate intellectual disability. Pathogenic variants in two epigenetic modifier genes, KMT2D and KDM6A, are responsible for KS1 and KS2, respectively. Case presentation A Chinese girl had persistent neonatal hypoglycemia and Dandy-Walker variant. Whole-exome sequencing identified a novel single nucleotide deletion in KMT2D (NM_003482.3 c.12165del p.(Glu4056Serfs*10)) that caused frameshift and premature termination. The mutation was de novo. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this variant is considered pathogenic. The patient was diagnosed with KS by molecular testing. Conclusion A single novel mutation in KMT2D was identified in a KS patients with hypoglycemia and Dandy-Walker variant in the neonatal stage. A molecular test was conducted to diagnose KS at an early stage.

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