scholarly journals Molecular Genetic Study of Congenital Ichthyosiform Erythroderma (CIE) Reveals a Novel Likely Pathogenic Variant in an Iranian Pedigree

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Aazam Ahmadi Shadmehri ◽  
Javad Tavakkoly Bazzaz ◽  
Mojtaba Darbouye ◽  
Mohmmad Amin Tabatabaeifar
Keyword(s):  
Novel Mutation ◽  
Molecular Genetic ◽  
Missense Variant ◽  
Missense Mutations ◽  
Molecular Genetic Study ◽  
Iranian Patient ◽  
Congenital Ichthyosis ◽  
Pathogenic Variants ◽  
And Function ◽  
Congenital Ichthyosiform Erythroderma

Introduction: Congenital ichthyosiform erythroderma (CIE) is a subtype of autosomal recessive congenital ichthyosis (ARCI), a group of ineffective keratinization disorders, which mainly results from missense mutations in the transglutaminase 1 (TGM1) gene. Case Presentation: Herein, a 9-year-old male case of CIE is presented, for whom we conducted genetic testing to uncover the underlying molecular cause of his condition. We performed whole-exome sequencing (WES) on the DNA extracted from blood, and the data was analyzed for checking pathogenic variants. Analysis of the WES data identified a novel missense variant, c.1165C >T (p. Arg389Cys), in the TGM1 gene. Evaluation of this variant via in silico tools showed its detrimental consequences on the stability and function of the encoded protein. The variant was characterized as likely pathogenic based on the American College of Medical Genetics and Genomics guidelines for variant interpretation. Analysis of all available family members confirmed the co-segregation of this novel variant with the CIE disease within the family. Conclusions: This study reported the successful application of WES and bioinformatics analysis to identify a novel mutation in a well-established ARCI-causing residue in an Iranian patient.

scholarly journals Novel compound heterozygous EYS variants may be associated with arRP in a large Chinese pedigree

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Chunli Wei ◽  
Ting Xiao ◽  
Jingliang Cheng ◽  
Jiewen Fu ◽  
Qi Zhou ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Gene Mutations ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
The Novel ◽  
Pathogenic Variants ◽  
Pathogenic Genes ◽  
Compound Heterozygous Variants ◽  
Normal Controls

Abstract As a genetically heterogeneous ocular dystrophy, gene mutations with autosomal recessive retinitis pigmentosa (arRP) in patients have not been well described. We aimed to detect the disease-causing genes and variants in a Chinese arRP family. In the present study, a large Chinese pedigree consisting of 31 members including a proband and another two patients was recruited; clinical examinations were conducted; next-generation sequencing using a gene panel was used for identifying pathogenic genes, and Sanger sequencing was performed for verification of mutations. Novel compound heterozygous variants c.G2504A (p.C835Y) and c.G6557A (p.G2186E) for the EYS gene were identified, which co-segregated with the clinical RP phenotypes. Sequencing of 100 ethnically matched normal controls didn’t found these mutations in EYS. Therefore, our study identified pathogenic variants in EYS that may cause arRP in this Chinese family. This is the first study to reveal the novel mutation in the EYS gene (c.G2504A, p.C835Y), extending its mutation spectrum. Thus, the EYS c.G2504A (p.C835Y) and c.G6557A (p.G2186E) variants may be the disease-causing missense mutations for RP in this large arRP family. These findings should be helpful for molecular diagnosis, genetic counseling and clinical management of arRP disease.

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 PHENOTYPIC CHARACTERISTICS IN OSTEOGENESIS IMPERFECTA PATIENTS

2019 ◽  
Vol 21 (5) ◽  
pp. 266-271
Author(s):  
Olga N. Ignatovich
Keyword(s):  
Osteogenesis Imperfecta ◽  
Molecular Genetic ◽  
Genetic Research ◽  
Clinical Manifestations ◽  
Hereditary Disease ◽  
Type I ◽  
Missense Mutations ◽  
Phenotypic Characteristics ◽  
Molecular Genetic Study ◽  
Collagen Genes

Osteogenesis imperfecta (OI) is a heterogeneous hereditary disease characterized by low bone density and frequent fractures. There are presented data of molecular genetic study and examination of 45 children with a clinically established diagnosis of types I, III and IV. The aim of investigation. To study the variety of clinical manifestations in OI children with and to compare with the identified genetic mutations in the genes COL1A1 and COL1A2. Materials and methods. The data of molecular genetic research and evaluation of clinical manifestations of 45 children with diagnosis OI of types I, III and IV is presented. Results. In the study, mutations in the genes COL1A1 and COL1A2 were detected in 43 (95.6%). The most of the mutations (74,4%) were found to be localized in the gene COL1A1 (n=32), smaller (25.6%) - in the gene COL1A2 (n=11). Glycine-to-serine substitutions in the Gly-X-Y triplet are the most frequent type of mutation among missense mutations. In children with type I qualitative mutations were found to be less common than in types III and IV (representing clinically severe and moderate, respectively). Conclusion. Majority of OI patients had mutations in the collagen genes. The most frequent mutation was the missense mutation, the most often detected in children with OI type III having a severe course, leading to a qualitative violation of collagen.

Truncation of Glycoprotein (GP) IIIa (▵ 616-762) Prevents Complex Formation With GPIIb: Novel Mutation in Exon 11 of GPIIIa Associated With Thrombasthenia

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4712-4720 ◽  
Author(s):  
Milagros Ferrer ◽  
Jianming Tao ◽  
Gema Iruı́n ◽  
Matilde Sánchez-Ayuso ◽  
José González-Rodrı́guez ◽  
...  
Keyword(s):  
Complex Formation ◽  
Novel Mutation ◽  
Molecular Genetic ◽  
Coding Region ◽  
Chain Reaction ◽  
Molecular Genetic Study ◽  
Nonsense Mutations ◽  
Glanzmann Thrombasthenia ◽  
Polymerase Chain ◽  
Exon 11

This work reports the molecular genetic study of a patient who suffered from Glanzmann thrombasthenia (GT). Structural analysis of the glycoprotein (GP) IIb and GPIIIa genes showed the presence of a homozygous G1846→T transversion in exon 11 of GPIIIa that changes Glu616→Stop. Cytometric and immunochemical analysis indicated that platelet GPIIb-IIIa was absent in the proband but present at normal levels in the heterozygous relatives. The following observations indicate that this mutation is responsible for the thrombasthenic phenotype of the proband. (1) We failed to detect mutations other than [T1846]GPIIIa in the coding region of both GPIIb and GPIIIa genes. (2) The G1846→T mutation was observed in either parent and a brother of the proband, but none of 100 unrelated individuals carried this defect. (3) Pulse-chase and immunoprecipitation analysis of GPIIb-IIIa complexes in cells transiently cotransfected with cDNAs encoding normal GPIIb and [T1846]GPIIIa showed neither maturation of GPIIb nor complex formation and surface exposure of GPIIb-▵GPIIIa. These observations indicate that the sequence from Glu616 to Thr762 in GPIIIa is essential for heterodimerization with GPIIb. Polymerase chain reaction-based analysis demonstrated the presence of normal levels of full-length GPIIIa-mRNA in the proband and in heterozygous relatives. In addition, a shortened transcript, with a 324-nucleotide deletion, resulting from in-frame skipping of exons 10 and 11, was detectable upon reamplification of the DNA. Thus, unlike other nonsense mutations, [T1846]GPIIIa does not lead to abnormal processing or reduction in the number of transcripts with the termination codon.

Truncation of Glycoprotein (GP) IIIa (▵ 616-762) Prevents Complex Formation With GPIIb: Novel Mutation in Exon 11 of GPIIIa Associated With Thrombasthenia

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4712-4720 ◽  
Author(s):  
Milagros Ferrer ◽  
Jianming Tao ◽  
Gema Iruı́n ◽  
Matilde Sánchez-Ayuso ◽  
José González-Rodrı́guez ◽  
...  
Keyword(s):  
Complex Formation ◽  
Novel Mutation ◽  
Molecular Genetic ◽  
Coding Region ◽  
Chain Reaction ◽  
Molecular Genetic Study ◽  
Nonsense Mutations ◽  
Glanzmann Thrombasthenia ◽  
Polymerase Chain ◽  
Exon 11

Abstract This work reports the molecular genetic study of a patient who suffered from Glanzmann thrombasthenia (GT). Structural analysis of the glycoprotein (GP) IIb and GPIIIa genes showed the presence of a homozygous G1846→T transversion in exon 11 of GPIIIa that changes Glu616→Stop. Cytometric and immunochemical analysis indicated that platelet GPIIb-IIIa was absent in the proband but present at normal levels in the heterozygous relatives. The following observations indicate that this mutation is responsible for the thrombasthenic phenotype of the proband. (1) We failed to detect mutations other than [T1846]GPIIIa in the coding region of both GPIIb and GPIIIa genes. (2) The G1846→T mutation was observed in either parent and a brother of the proband, but none of 100 unrelated individuals carried this defect. (3) Pulse-chase and immunoprecipitation analysis of GPIIb-IIIa complexes in cells transiently cotransfected with cDNAs encoding normal GPIIb and [T1846]GPIIIa showed neither maturation of GPIIb nor complex formation and surface exposure of GPIIb-▵GPIIIa. These observations indicate that the sequence from Glu616 to Thr762 in GPIIIa is essential for heterodimerization with GPIIb. Polymerase chain reaction-based analysis demonstrated the presence of normal levels of full-length GPIIIa-mRNA in the proband and in heterozygous relatives. In addition, a shortened transcript, with a 324-nucleotide deletion, resulting from in-frame skipping of exons 10 and 11, was detectable upon reamplification of the DNA. Thus, unlike other nonsense mutations, [T1846]GPIIIa does not lead to abnormal processing or reduction in the number of transcripts with the termination codon.

scholarly journals Persistent Hypoglycemia with Polycystic Kidneys: A Rare Combination – A Case Report

2020 ◽  
Vol 5 (3) ◽  
pp. 1-6
Author(s):  
Priya Prasher ◽  
Katherine Redmond ◽  
Hillarey Stone ◽  
James Bailes ◽  
Edward Nehus ◽  
...  
Keyword(s):  
Case Report ◽  
Promoter Region ◽  
Molecular Genetic ◽  
Missense Variant ◽  
Compound Heterozygous ◽  
Molecular Genetic Testing ◽  
Coding Region ◽  
Polycystic Kidney ◽  
Homozygous State ◽  
Pathogenic Variants

We present the case of an infant referred to our NICU born at 39 weeks’ gestation with persistent hypoglycemia with elevated insulin levels (HI) requiring diazoxide to maintain normoglycemia. Additionally, polycystic kidney disease (PKD) was detected by ultrasound. Molecular genetic testing revealed pathogenic variants in the <i>PMM2</i>gene, i.e., a variant in the promoter region and a missense variant in the coding region. The precoding variant was recently described in 11 European families with similar phenotypes, either in a homozygous state or as compound heterozygous with a pathogenic coding variant. In neonates with HI associated with PKD, this rare recessive disorder should be considered.

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.

Biallelic Loss-of-Function Variants in AIMP1 Cause a Rare Neurodegenerative Disease

2018 ◽  
Vol 34 (2) ◽  
pp. 74-80 ◽  
Author(s):  
Andrea Accogli ◽  
Kether Guerrero ◽  
Maria Daniela D’Agostino ◽  
Luan Tran ◽  
Cécile Cieuta-Walti ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Neurodegenerative Disorder ◽  
Cerebral Atrophy ◽  
Trna Synthetase ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
The Central Nervous System ◽  
And Function

AIMP1/p43, is a noncatalytic component of the mammalian multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their cognate tRNAs. AIMP1 is largely expressed in the central nervous system, where it is part of the regulatory machine of the neurofilament assembly, playing a crucial role in neuronal development and function. To date, nonsense mutations in AIMP1 have been associated with a primary neurodegenerative disorder consisting of cerebral atrophy, hypomyelination, microcephaly and epilepsy, whereas missense mutations have recently been linked to intellectual disability without neurodegeneration. Here, we report the first French-Canadian patient with a novel frameshift AIMP1 homozygous mutation (c.191_192delAA, p.Gln64Argfs*25), resulting in a severe neurodegenerative phenotype. We review and discuss the phenotypic spectrum associated with AIMP1 pathogenic variants.

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