scholarly journals VARIETY OF CLINICAL MANIFESTATIONS IN MUTATIONS IN THE DYNC1H1 GENE

2019 ◽  
pp. 31-36
Author(s):  
I. V. Sharkova ◽  
P. A. Shatalov ◽  
E. L. Dadali
Keyword(s):  
Protein Function ◽  
Muscular Atrophy ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Hereditary Diseases ◽  
Clinical Markers ◽  
Tail Domain ◽  
Genetic Characteristics ◽  
Main Method ◽  
Brain Malformations

Introduction. To date, DYNC1H1 gene mutations are known for large number of hereditary diseases. It is believed that different mutations have variable effects to protein function and, accordingly, to various clinical manifestations. Results. There are a clinical and genetic characteristics of two Russian patients with two types of diseases: spinal muscular atrophy with predominant lesion of the lower extremities (SMALED) and non-syndromic mental retardation type 13 (MR13) in combination with a brain malformations and epilepsy due to newly identified mutations in the DYNC1H1 gene. Conclusion There is some evidence in support of the hypothesis that the amino acid sequence changing in the tail domain of dynein lead to the appearance of SMALED, and in the motor domain lead to MR13. Exome or genome sequencing are required as the main method for their diagnosis due to the high genetic heterogeneity of non-syndromic MR and SMALED, the lack of specific clinical markers and hotspot mutations in the DYNC1H1 gene.

scholarly journals Clinical and genetic characteristics of new allele variants of the Mowat–Wilson syndrome caused by ZEB2 gene mutations

2018 ◽  
Vol 8 (3) ◽  
pp. 28-33
Author(s):  
I. A. Akimova ◽  
T. V. Markova ◽  
F. A. Konovalov ◽  
A. V. Antonets ◽  
E. L. Dadali
Keyword(s):  
Intellectual Development ◽  
Survey Methods ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Speech Development ◽  
Hereditary Diseases ◽  
Genetic Characteristics ◽  
Monogenic Diseases ◽  
Long Time ◽  
Nextgeneration Sequencing

To date, a large number of monogenic diseases and syndromes, in the clinical picture of which there are convulsions, a psycho-speech development delay and dysmorphic features have been described. One of the hereditary syndromes with a specific phenotype is the Movat–Wilson syndrome. To diagnose the syndrome, a set of survey methods was used: genealogical analysis, neurological examination, evaluation of intellectual development with the help of psychological tests, and sequencing of the new generation exome. As a result of sequencing exome on the panel of genes responsible for the emergence of hereditary epilepsy, two patients of different sex at the age of 10 and 5 years were identified with previously not described mutations in the ZEB2 gene in the heterozygous state. Clinical manifestations of the disease in these patients were of varying degrees of severity, which can be explained in terms of the functional significance of the changes detected. The variety of clinical manifestations of the same disease leads to considerable difficulties in diagnosing, however, due to the introduction of the nextgeneration sequencing in medical practice, the effectiveness of diagnosing hereditary diseases and syndromes, the verification of which has been difficult for a long time, has increased significantly.

scholarly journals Spinal muscular atrophy with lower limbs phenotype: clinical and genetic description of novel mutation in the DYNC1H1 gene

2018 ◽  
Vol 8 (2) ◽  
pp. 59-67
Author(s):  
E. L. Dadali ◽  
S. S. Nikitin ◽  
F. A. Konovalov ◽  
I. A. Akimova ◽  
S. A. Korostelev
Keyword(s):  
Exome Sequencing ◽  
Muscular Atrophy ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Lower Extremities ◽  
Sensory Neuropathy ◽  
Lower Limbs ◽  
Study Objective ◽  
Genetic Characteristics ◽  
Wide Range

Background. Spinal muscle atrophies (SMA) are a group of diverse heterogenous diseases caused by mutations in several dozens of genes. A rare form of autosomal dominant SMA predominantly affects muscles of the lower extremities.The study objective is to describe clinical and genetic characteristics of Russia-living patients with SMA predominantly affecting muscles of the lower extremities caused by the DYNC1H1 gene mutation discovered by next-generation exome sequencing.Materials and methods. To diagnose the syndrome a complex of examination techniques was used: genealogical analysis, neurological examination, electromyography, and DNA diagnostics. Changes in the nucleotide sequence in the probands and their parents identified with massive parallel sequencing were studied using direct automatic sequencing with oligonucleotide primers.Results. Five (5) patients from 4 families with heterozygous mutations in the DYNC1H1 gene were identified. In the patients, one type of SMA predominantly affecting the lower extremities was assumed. Prior to exome sequencing, all patients were monitored for myelodysplasia diagnosis, and magnetic resonance imaging of the spine has showed protrusions and/or spondylolisthesis of the lumbar spine in 4 of the patients. The obtained results can demonstrate both hyperdiagnosis and that spinal pathology is one of the characteristic symptoms of SMA predominantly affecting the lower extremities.Conclusion. The obtained results allow to make an assumption about a wide range of clinical polymorphisms in patients with mutations of the DYNC1H1 gene. Apart from typical clinical manifestations of SMA predominantly affecting the lower extremities, patients can be diagnosed with hereditary motor and sensory neuropathy 2, myelodysplasia, and congenital arthrogryposis which has to be taken into account during diagnostic search.

scholarly journals Analysis on the pathogenic genes of 60 Chinese children with congenital hyperinsulinemia

2018 ◽  
Vol 7 (12) ◽  
pp. 1251-1261
Author(s):  
Zi-Di Xu ◽  
Wei Zhang ◽  
Min Liu ◽  
Huan-Min Wang ◽  
Pei-Pei Hui ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Gene Mutations ◽  
Chinese Children ◽  
Treatment Modalities ◽  
Partial Pancreatectomy ◽  
Genetic Characteristics ◽  
Pathogenic Genes ◽  
Second Generation Sequencing ◽  
Long Term Prognosis

This study aims to summarize and analyze the clinical manifestations, genetic characteristics, treatment modalities and long-term prognosis of congenital hyperinsulinemia (CHI) in Chinese children. Sixty children with CHI, who were treated at Beijing Children’s Hospital from January 2014 to August 2017, and their families, were selected as subjects. The CHI-related causative genes in children were sequenced and analyzed using second-generation sequencing technology. Furthermore, the genetic pathogenesis and clinical characteristics of Chinese children with CHI were explored. Among the 60 CHI children, 27 children (27/60, 45%) carried known CHI-related gene mutations: 16 children (26.7%) carried ABCC8 gene mutations, seven children (11.7%) carried GLUD1 gene mutations, one child carried GCK gene mutations, two children carried HNF4α gene mutations and one child carried HADH gene mutations. In these 60 patients, eight patients underwent 18F-L-DOPA PET scan for the pancreas, and five children were found to be focal type. The treatment of diazoxide was ineffective in these five patients, and hypoglycemia could be controlled after receiving partial pancreatectomy. In conclusion, ABCC8 gene mutation is the most common cause of CHI in Chinese children. The early genetic analysis of children’s families has an important guiding significance for treatment planning and prognosis assessment.

scholarly journals Clinical and genetic characteristics and orthopedic manifestations of the Saul–Wilson syndrome in two Russian patients

2021 ◽  
Vol 8 (4) ◽  
pp. 451-460
Author(s):  
Tatyana V. Markova ◽  
Vladimir M. Kenis ◽  
Evgenii V. Melchenko ◽  
Nina A. Demina ◽  
Polina Gundorova ◽  
...  
Keyword(s):  
Age Groups ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Protein Molecule ◽  
Published Data ◽  
Genetic Characteristics ◽  
Major Mutation ◽  
The Face ◽  
Modern Classification ◽  
Thin Bone

Background. SaulWilson syndrome (SWS, microcephalic osteodysplastic dysplasia) is a rare genetic variant of skeletal dysplasia and is determined based on the modern classification for thin bone dysplasias. To date, 16 patients with SWS from different countries have been identified. Clinical cases. We presented the first description of the clinical and genetic characteristics of two Russian patients with SWS and compared them with published data. The main clinical manifestations of SWS are characterized by a combination of nanism and pathology of long tubular bones, spine, and eyes. Changes in the phenotype of patients in different age groups were analyzed. Discussion. In the analysis of the clinical manifestations of the observed patients and patients described in the literature, typical dysmorphic features of the face and radiographic data help in the diagnosis of SWS upon clinical examination. In the majority of the described patients, the nucleotide substitution c.1546GA is the major mutation in the gene responsible for SWS, which leads to the replacement of the amino acid Gly516Arg in the protein molecule. Conclusion. Based on the identified specific features of the phenotype of patients with SWS and the presence of a major mutation in the COG4 gene, a priority analysis of gene mutations is necessary. Orthopedic manifestations of SWS can lead to life-threatening conditions (cervical spine instability) and motor limitations (progressive osteoarthritis) and thus should be monitored dynamically.

scholarly journals Six New Mutations of the Thyroglobulin Gene Discovered in Taiwanese Children Presenting with Thyroid Dyshormonogenesis

2009 ◽  
Vol 94 (12) ◽  
pp. 5045-5052 ◽  
Author(s):  
Dau-Ming Niu ◽  
Ju-Hui Hsu ◽  
Kah-Wai Chong ◽  
Cheng-Hung Huang ◽  
Yung-Hsiu Lu ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Amino Acid Residues ◽  
De Novo Mutations ◽  
Study Objective ◽  
Genetic Characteristics ◽  
Thyroid Dyshormonogenesis ◽  
Taiwan Chinese ◽  
Thyroglobulin Gene

Background: Thyroglobulin (TG) defect is a rare cause of congenital hypothyroidism. Although only 44 mutations of the human TG gene have been identified, we have suspected a TG defect in 38% of Taiwan Chinese children/adolescents presenting with moderate or severe thyroidal dyshormonogenesis. Study Objective: The aim of the study is to report the discovery of new TG gene mutations and associated clinical manifestations of the defective TG protein. Patients and Results: In seven patients from six families, we detected six new TG gene mutations, including c.1348delT, p.R432X (c.1351C>T), g.IVS3 + 2T>G, c.1712delT, p.Q1765X (c.5350C>T), and c.6047delA. The c.1348delT and p.R432X mutations were the most common, detected in 33 and 25%, respectively, of alleles studied. Haplotype analysis suggested that the c.1348delT and g.IVS3 + 2T>G mutations are due to founder effects, whereas p.R432X is probably due to independently recurrent de novo mutations. mRNA transcript of the g.IVS3 + 2T>G mutant, detected in whole blood by reverse transcription-nested PCR, showed skipping of exon 3 (98-bp deletion) and a frameshift, with a terminal signal after 17 altered amino acid residues. Conclusions: TG defects have an important role in severe thyroidal dyshormonogenesis (pretreatment, or after a 3-wk T4 withdrawal, plasma T4 ≦ 30 nmol/liter) in Taiwanese. Its genetic characteristics are markedly different from those described in other populations presenting with mutations of the TG gene.

scholarly journals Clinical and genetic characteristics of patients with type 2 early infantile epileptic encephalopathy caused by CDKL5 gene mutations

2020 ◽  
Vol 14 (3) ◽  
pp. 28-36
Author(s):  
E. L. Dadali ◽  
I. A. Akimova ◽  
F. A. Konovalov ◽  
P. A. Shatalov ◽  
A. Yu. Krasnenko ◽  
...  
Keyword(s):  
Genetic Variant ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Epileptic Seizures ◽  
Epileptic Encephalopathy ◽  
Psychomotor Retardation ◽  
Dominant Inheritance ◽  
Common Genetic Variant ◽  
Genetic Characteristics

Early infantile epileptic encephalopathies (EIEE) are a group of disorders characterized by pharmacoresistant epileptic seizures manifesting in infancy and leading to psychomotor retardation. The most common genetic variant with X-linked dominant inheritance is type 2 EIEE associated with CDKL5 gene mutations. We evaluated the prevalence of this type of EIEE among Russian patients (n = 148) with epileptic seizures manifesting in infancy and analyzed their clinical and genetic characteristics. We performed exome sequencing for all patients; 15 (10 %) of them (aged between 2 months and 5 years) were found to have CDKL5 gene mutations and were, therefore, diagnosed with type 2 EIEE. The results of correlation analysis suggest that the severity of clinical manifestations of type 2 EIEE is largely determined by the location of mutations affecting the function of the protein encoded by this gene. This is important to ensure better understanding of type 2 EIEE etiology and predict it severity in patients with different allelic variants.

Neoplastic potential for malformations of the development of ecto- and mesodermal structures

2020 ◽  
Vol 1 (4) ◽  
pp. 208-216
Author(s):  
Zhuzhuna M. Tsotsonava ◽  
Vladimir V. Belopasov ◽  
Natal’ya V. Tkacheva
Keyword(s):  
Nervous System ◽  
Abdominal Cavity ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Epileptic Seizures ◽  
Neurofibromatosis Type ◽  
Hereditary Diseases ◽  
Organ Specificity ◽  
Type Iv ◽  
Skin Blood Vessels

Introduction.Malformations of ecto- and mesodermal structures represent various forms of abnormality of intrauterine systemic and local morphogenesis, arising at different times of embryonic development due to environmental factors, genomic, chromosomal or gene mutations. Dysregulation of cellular functions due to mutations and accumulation of defective proteins initiates tumor transformation of tissues e.g. hereditary diseases of ectomesodermal origin phakomatosis (hamartomatosis). The aim of the studywas to determine organ specificity, clinical manifestations, morphological features and the degree of progression of tumors of the nervous system and internal organs in hereditary diseases of ectomesodermal origin. Materials and methods.103 patients with hereditary phakomatosis were examined. All of them underwent a comprehensive clinical imaging examination, including magnetic resonance imaging, echocardioscopy, ultrasound examination of the abdominal organs, kidneys, retroperitoneal space, and computed tomography of the abdominal cavity and lungs. Results.The reason for the treatment of patients was the occurrence of focal neurological symptoms, focal and/or generalized epileptic seizures. Clinical manifestations were determined by the form of the disease. The risk of the development and progression of various neoplasms is the highest in neurofibromatosis type III, tuberous sclerosis, neurocutaneous melanosis, multiple endocrine neoplasia, angiomatosis of HippelLindau, Louis-Bar . Favorable benign and stable course, low malignant potential are distinguishing characteristics of pigment-vascular phakomatoses type IV. Conclusion.Knowledge of the clinical manifestations of various malformations of the skin, blood vessels, and the nervous system associated with tumor growth in cells and tissues is practically significant. Early diagnosis and the use of modern technologies of conservative and surgical treatment allow achieving a predictable result, prevent the development of severe complications, and significantly improve the quality of life of patients with this pathology.

scholarly journals Novel missense mutation of SASH1 in a Chinese family with dyschromatosis universalis hereditaria

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lu Cao ◽  
Ruixue Zhang ◽  
Liang Yong ◽  
Shirui Chen ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Sequence Alignment ◽  
Multiple Sequence Alignment ◽  
Molecular Genetic ◽  
Family Members ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Mendelian Inheritance ◽  
Chinese Family ◽  
Multiple Sequence

Abstract Background Dyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH. Methods Sanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations. Results A novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6. Conclusion Although the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene.

scholarly journals Prevalence and clinical phenotype of the triplicated α-globin genes and its ethnic and geographical distribution in Guizhou of China

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xi Luo ◽  
Xiang-mei Zhang ◽  
Liu-song Wu ◽  
Jindong Chen ◽  
Yan Chen
Keyword(s):  
Genetic Counseling ◽  
Peripheral Blood ◽  
Clinical Phenotype ◽  
Globin Gene ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Guizhou Province ◽  
Globin Genes ◽  
Phenotype Correlation ◽  
Chi Square

Abstract Background α-thalassemia is relatively endemic in Guizhou province of southwestern China. To predict the clinical manifestations of α-globin gene aberration for genetic counseling, we examined the prevalence of the α-globin triplication and the genotype–phenotype correlation in this subpopulation Methods A cohort of 7644 subjects was selected from nine ethnicities covering four regions in Guizhou province of China. Peripheral blood was collected from each participant for routine blood testing and hemoglobin electrophoresis. PCR-DNA sequencing and Gap-PCR were used to identify the thalassemia gene mutations. Chi-square tests and one-way analysis of variance (ANOVA) were used to statistically analyze the data. Results We found that the frequency of α-globin triplication in Guizhou province was 0.772% (59/7644). Genotypically, the αααanti4.2/αα accounted for 0.523% (40/7644), the αααanti3.7/αα for 0.235% (18/7644), and the αααanti3.7/–SEA for 0.013% (1/7644). The αααanti4.2/αα is more prevalent than the αααanti3.7/αα in Guizhou. In addition, the frequency of the HKαα/αα (that by GAP-PCR is like αααanti4.2/-α3.7) was 0.235% (18/7644). Ethnically, the Tujia group presented the highest prevalence (2.47%) of α-globin triplication. Geographically, the highest frequency of the α-globin triplication was identified in Qiannan region (2.23%). Of the triplicated α-globin cases, 5 coinherited with heterozygote β-thalassemia and presented various clinical manifestations of anemia. Conclusions These data will be used to update the Chinese triplicated α-globin thalassemia database and provide insights into the pathogenesis of thalassemia. These findings will be helpful for the diagnosis of thalassemia and future genetic counseling in those regions.

4-Jahres-Update der Murano-Studie bestätigt den Stellenwert von Venetoclax in der 2. Therapielinie der CLL

2021 ◽  
pp. 77-79
Author(s):  
Maximilian Schmutz ◽  
Sebastian Sommer
Keyword(s):  
Response Rate ◽  
Residual Disease ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Fixed Duration ◽  
Genetic Characteristics ◽  
Genomic Complexity ◽  
End Of Treatment

<b>Purpose:</b> In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics. <b>Patients and methods:</b> Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed. <b>Results:</b> Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC (<i>P</i> = 0.042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with <i>BIRC3</i> and <i>BRAF</i> mutations at EOCT and with <i>TP53, NOTCH1, XPO1,</i> and <i>BRAF</i> mutations at EOT. <b>Conclusion:</b> Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS. <b>Trial registration:</b> ClinicalTrials.gov NCT02005471.

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