scholarly journals Molecular genetic features of the development of restrictive cardiomyopathy in Russian children

2021 ◽  
Vol 26 (10) ◽  
pp. 4590
Author(s):  
K. V. Savostyanov ◽  
E. N. Basargina ◽  
E. E. Ryabova ◽  
A. A. Pushkov ◽  
I. S. Zhanin ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Clinical Symptoms ◽  
Massively Parallel Sequencing ◽  
Molecular Genetic ◽  
Restrictive Cardiomyopathy ◽  
Common Mutation ◽  
Genetic Characteristics ◽  
Pathogenic Variants ◽  
Significant Difference ◽  
Restrictive Type

Aim. To identify the proportion of restrictive cardiomyopathy (RCM), as well as cardiomyopathy (CMP) with a restrictive type of hemodynamics among all cases of genetic CMP and to determine the relative frequencies and spectrum of nucleotide variants in Russian children with RCM, as well as to search for phenogenotypic correlations.Material and methods. The study included 689 children with CMPs. All children underwent a molecular genetic testing of the target regions of 419 genes responsible for various cardiomyopathies and channelopathies using the method of massively parallel sequencing (MPS).Results. In 668 (97,0%) children, pathogenic, likely pathogenic nucleotide variants, as well as nucleotide variants with unknown clinical significance, were identified. Of these, 45 (6,7%) patients were selected to determine the molecular genetic characteristics of RCM, 20 of whom had clinical symptoms and morphofunctional structure of RCMP (3,0%), while the remaining 25 (3,7%) children were diagnosed with another CMP type with a restrictive type of hemodynamics. In total, these patients had 41 nucleotide variants in 15 different genes, while 19 (46,3%) variants were pathogenic, 12 (29,3%) — likely pathogenic, 10 (24,4%) — uncertain clinical significance. Pathogenic and likely pathogenic variants were identified in a total of 38 (84,4%) patients, while in 19 (42,2%) patients, the pathogenic variants described earlier were found. The most common genetic marker of RCM in Russian children was TNNI3 gene mutations. In total, they were identified in 12 (25%) children: with RCP — 8 (40%) patients; with CMP with a restrictive type of hemodynamics — 4 (16%) patients. At the same time, the most common mutation of the TNNI3 gene was the nucleotide variant c.575G>A, leading to the amino acid variant p.R192H, described earlier in patients with RCM and identified by us in three (15%) unrelated children with RCM. In addition, a significant difference was found between the averaged values of N-terminal pro-brain natriuretic peptide in patients with mutations in the MYH7 and TNNI3 genes (0,0039, p<0,05), as well as between the peak flow gradient values in children with mutations in TNNI3 and FLNC genes (0,0016, p<0,05), TNNI3 and MYH7 genes (0,039, p<0,05).Conclusion. The results of this study indicate a significant genetic heterogeneity of RCM in Russian children and the need for further research aimed at finding genotype-phenotype associations in order to predict the course of the disease and select the proper therapy.

Clinical and genetic characteristics of rare pathogenic variants of the CFTR gene in Russian patients with cystic fibrosis

2021 ◽  
Vol 31 (2) ◽  
pp. 148-158
Author(s):  
A. Yu. Voronkova ◽  
Yu. L. Melyanovskaya ◽  
N. V. Petrova ◽  
T. A. Adyan ◽  
E. K. Zhekaite ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Variants ◽  
Pancreatic Insufficiency ◽  
Protein Energy Malnutrition ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Cftr Gene ◽  
Genetic Characteristics ◽  
Missense Variants ◽  
Pathogenic Variants

The variety of clinical manifestations of cystic fibrosis is driven by the diversity of the CFTR gene nucleotide sequence. Descriptions of the clinical manifestations in patients with the newly identified genetic variants are of particular interest.The aim of this study was to describe clinical manifestations of the disease with the newly identified genetic variants.Methods. Data from Registry of patients with cystic fibrosis in the Russian Federation (2018) were used. The data review included three steps — the search for frequent mutations, Sanger sequencing, and the search for extensive rearrangements by MLPA. 38 pathogenic variants were identified that were not previously described in the international CFTR2 database. We selected and analyzed full case histories of 15 patients with 10 of those 38 pathogenic variants: p.Tyr84*, G1047S, 3321delG, c.583delC, CFTRdele13,14del18, CFTRdele19-22, c.2619+1G>A, c.743+2T>A, p.Glu1433Gly, and CFTRdel4-8del10-11.Results. A nonsense variant p.Tyr84* was found in 5 patients (0.08 %). Two missense variants c.3139G>A were found in 2 siblings (0.03 %). The c.4298A>G was found in 1 patient. Other variants were detected in a single patient (0.02 %) each. They included two variants of a deletion with a shift of the reading frame 3321delG and c.583delC, two splicing disorders c.2619+1G>A and c.743+2T>A, three extended rearrangements CFTRdele19-22, CFTRdele13,14del18, and CFTRdel4-8del10-11. The last two variants include 2 rearrangements on one allele, which cause the severe course in two young children. 8 of the 10 variants are accompanied by pancreatic insufficiency (PI). Among patients with p.Tyr84*, one had ABPA, one had liver transplantation, and all had Pseudomonas aeruginosa infection. Nasal polyps were diagnosed in 2 patients with p.Tyr84*, 1 with G1047S, 1 with CFTRdel4-8del10-11, and 1 patient with 3321delG, who also had osteoporosis and cystic fibrosis-related diabetes (CFRD). 2 patients with PI with 3321delG and CFTRdel4-8del10-11 genetic variants, and 1 with PI with p.Glu1433Gly genetic variant had severe protein-energy malnutrition (PEM).Conclusion. Clinical manifestations of previously undescribed CFTR genetic variants were described. 5/10 genetic variants should be attributed to class I, 3/10 – to class 7 of the function classification of pathogenic CFTR gene variants associated with transcription and translation disruptions. Class of the identified missense variants c.3139G>A and c.4298A>G has not been established and requires further functional, cultural, and molecular genetic studies.

scholarly journals Clinical and genetic characteristics of congenital muscular dystrophies (Part 1)

2020 ◽  
Vol 10 (1) ◽  
pp. 10-21 ◽  
Author(s):  
P. A. Chausova ◽  
O. P. Ryzhkova ◽  
A. V. Polyakov
Keyword(s):  
Muscular Dystrophy ◽  
Clinical Symptoms ◽  
Muscle Protein ◽  
Molecular Genetic ◽  
Laboratory Data ◽  
Congenital Muscular Dystrophy ◽  
Neuromuscular Diseases ◽  
Muscular Hypotonia ◽  
Genetic Characteristics ◽  
Progressive Muscle Weakness

Congenital muscular dystrophy is an extremely heterogeneous group of hereditary neuromuscular diseases that are clinically characterized by muscular hypotonia, progressive muscle weakness, and dystrophic changes in the muscles. Overlapping clinical symptoms and many genes that have to be analyzed to determine the specific form of the disease in the patient make diagnosis difficult. The molecular genetic stage of diagnosis includes many different methods depending on the clinical hypothesis and their application has not lost its relevance even in the era of massive parallel sequencing. In addition to DNA sequence analysis, the analysis of muscle protein expression can also play a significant role in the diagnosis of congenital muscular dystrophy. In the review, we will consider the most important etiological, pathophysiological, clinical and laboratory data of the main forms of congenital muscular dystrophy known today.

scholarly journals Analysis of the characteristics of terminal ileal ulcers: prognosis and clinical significance

2019 ◽  
Author(s):  
Liping Yang ◽  
Zhongchen Zhang ◽  
Xinxin Zhou ◽  
Chunxiao Chen
Keyword(s):  
Regression Analysis ◽  
Clinical Significance ◽  
Treatment Guidelines ◽  
Clinical Symptoms ◽  
Good Prognosis ◽  
The Other ◽  
Treatment Programs ◽  
Significant Difference ◽  
And Gender

Abstract Background Although terminal ileal ulcers can be observed occasionally in colonoscopy examination, the prognosis, clinical significance and treatment guidelines are unclear. Methods All patients diagnosed with terminal ileal ulcers from March 2014 to March 2018 were enrolled. We extracted data of gender, age, clinical symptoms, number of terminal ileal ulcers, pathological outcome, treatment programs. Results Of 42 individuals, one patient diagnosed with tuberculosis and received anti-tuberculosis treatment. The other 41 individuals chose to follow up or 5-ASA plus probiotics treatment. Logistic regression analysis showed no significant difference in treatment selection and gender (P=0.848), age (P=0.481), ulcers (p=0.116), symptoms (P=0.326). All individuals had good prognosis. Conclusion Individuals with terminal ileal ulcers have a good prognosis regardless of follow-up or treatment.

Inflammatory Pseudotumor-Like Follicular/Fibroblastic Dendritic Cell Sarcomas of the Spleen Are EBV-Associated and Lack Other Commonly Identifiable Molecular Alterations

2020 ◽  
pp. 106689692094967
Author(s):  
Frido K. Bruehl ◽  
Elizabeth Azzato ◽  
Lisa Durkin ◽  
Daniel H. Farkas ◽  
Eric D. Hsi ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Clinical Significance ◽  
Inflammatory Pseudotumor ◽  
Molecular Genetic ◽  
Sequencing Analysis ◽  
Genetic Characteristics ◽  
Molecular Alterations ◽  
Barr Virus ◽  
Molecular Features ◽  
Dendritic Cell Sarcoma

Inflammatory pseudotumor-like follicular/fibroblastic dendritic cell sarcoma (IPT-like FFDCS) is a rare, indolent neoplasm that occurs in the spleen or liver and harbors Epstein-Barr virus (EBV) integrated into the host genome. The molecular genetic characteristics of IPT-like FFDCS have not been well studied and there are no established and actionable molecular features to guide treatment decisions or diagnosis beyond the recognition of viral genome integration. We subjected two cases of IPT-like FFDCS to a comprehensive next-generation sequencing analysis. Several variants of uncertain clinical significance were detected in both tumors. No variants of potential or strong clinical significance were detected within the targeted regions of the evaluated genes. Additionally, no fusion events were detected involving the genes in either tumor. The performed molecular analysis identified no genetic aberrations in IPT-like FFDCS and its genomic landscape remains, with the exception of a monoclonal EBV gene, largely undefined.

3-Methylcrotonyl-CoA carboxylase deficiency newborn screening in a population of 536,008: is routine screening necessary?

2019 ◽  
Vol 32 (12) ◽  
pp. 1321-1326
Author(s):  
Huaiyan Wang ◽  
Shuang Liu ◽  
Benjing Wang ◽  
Yuqi Yang ◽  
Bin Yu ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Metabolic Diseases ◽  
Clinical Symptoms ◽  
Massively Parallel Sequencing ◽  
Dried Blood Spots ◽  
Jiangsu Province ◽  
Common Mutation ◽  
Illumina Hiseq ◽  
Feeding Difficulties

Abstract Objective To evaluate whether 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) should be routinely screened in newborns. Methods Dried blood spots (DBS) were collected and analyzed by tandem mass spectrometry (TMS). Blood samples were collected from infants with positive 3-MCCD results. Targeted sequencing was performed using the extended panel for inherited metabolic diseases to detect 306 genes. The sequencing libraries were quantified and used for massively parallel sequencing on the Illumina HiSeq 2500 platform. Results A total of 536,008 infants underwent newborn screening (NBS) and 14 cases of 3-MCCD were diagnosed. The incidence of 3-MCCD in Jiangsu province was 1:38,286. During the last 3 years of follow-up, none of the subjects with 3-MCCD exhibited obvious clinical symptoms. Only two children had mild feeding difficulties and vomiting. Eleven patients had complex variants of the MCCC1 gene, and three patients had mutations in MCCC2. In total, 17 types of MCCC1 or MCCC2 variants were found, and c.639 + 2t > a was the most common mutation. Conclusions As far as the current results are concerned, 3-MCCD may be benign in Jiangsu province. However, additional investigations and a longer follow-up period are necessary to decide whether NBS of 3-MCCD is necessary or not.

scholarly journals Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Anna Skorczyk-Werner ◽  
Zuzanna Niedziela ◽  
Marcin Stopa ◽  
Maciej Robert Krawczyński
Keyword(s):  
Gene Therapy ◽  
Molecular Genetic ◽  
Retinal Disease ◽  
Severe Form ◽  
Gene Variants ◽  
Genetic Characteristics ◽  
Leber Congenital Amaurosis ◽  
Pathogenic Variants ◽  
Intronic Mutation ◽  
Novel Variants

Abstract Background Leber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of congenital blindness in children and the most severe form of inherited retinal dystrophies. To date, 25 genes have been implicated in the pathogenesis of LCA. As gene therapy is becoming available, the identification of potential treatment candidates is crucial. The aim of the study was to report the molecular basis of Leber congenital amaurosis in 22 Polish families. Methods Single Nucleotide Polymorphism-microarray for LCA genes or Next Generation Sequencing diagnostic panel for LCA genes (or both tests) were performed to identify potentially pathogenic variants. Bidirectional Sanger sequencing was carried out for validation and segregation analysis of the variants identified within the families. Results The molecular background was established in 22 families. From a total of 24 identified variants, 23 were predicted to affect protein-coding or splicing, including 10 novel variants. The variants were identified in 7 genes: CEP290, GUCY2D, RPE65, NMNAT1, CRB1, RPGRIP1, and CRX. More than one-third of the patients, with clinical LCA diagnosis confirmed by the results of molecular analysis, appeared to be affected with a severe form of the disease: LCA10 caused by the CEP290 gene variants. Intronic mutation c.2991+1655A>G in the CEP290 gene was the most frequent variant identified in the studied group. Conclusions This study provides the first molecular genetic characteristics of patients with Leber congenital amaurosis from the previously unexplored Polish population. Our study expands the mutational spectrum as we report 10 novel variants identified in LCA genes. The fact that the most frequent causes of the disease in the studied group of Polish patients are mutations in one out of three genes that are currently the targets for gene therapy (CEP290, GUCY2D, and RPE65) strongly emphasizes the importance of the molecular background analyses of LCA in Polish patients.

scholarly journals Some clinical morphological and molecular genetic aspects in patients with clinical signs of hereditary breast cancer

2018 ◽  
Vol 99 (2) ◽  
pp. 224-229
Author(s):  
Yu S Shatova ◽  
E A Chebotareva ◽  
E Yu Zlatnik ◽  
I A Novikova ◽  
D I Vodolazhskiy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hereditary Breast Cancer ◽  
Sporadic Breast Cancer ◽  
Molecular Genetic ◽  
Clinical Signs ◽  
Receptor Expression ◽  
Proliferation Index ◽  
Common Mutation ◽  
Aneuploid Cell ◽  
Genetic Characteristics

Aim. To study the clinical morphological and molecular genetic characteristics of clinically hereditary breast cancer with and without verified mutation of BRCA1, BRCA2 compared to sporadic breast cancer. Methods. The study included 191 female patients with verified breast cancer stage I-IIA and clinical signs of hereditary breast cancer. In order to identify mutations in genes ВRCA1/2 molecular genetic analysis of deoxyribonucleic acid from peripheral blood leukocytes was performed. Results. The total frequency of mutations in the genes BRCA1 and ВRCA2 amounted 14.1% of the total number of examined patients. The most common mutation in clinically hereditary breast cancer among residents of the Rostov Region was 5382insC in BRCA1 gene, which corresponds to the nationwide data. Also common features of hereditary breast cancer compared to sporadic breast cancer were identified: young age at the time of disease manifestation, high prevalence of triple-negative cancer, history of infertility, increased level of p53 and androgen receptor expression, decreased level of aneuploid cell and proliferation index in the tumor. Conclusion. In a number of clinical morphological and molecular genetic parameters, clinically hereditary breast cancer differs from sporadic breast cancer. These indicators in the future can be used as criteria for selection of patients with clinically hereditary breast cancer without confirmed BRCA1/2 mutation by standard panels for in-depth genetic testing.

scholarly journals Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8

2018 ◽  
Vol 103 (3) ◽  
pp. 390-397 ◽  
Author(s):  
Kaoru Fujinami ◽  
Rupert W Strauss ◽  
John (Pei-Wen) Chiang ◽  
Isabelle S Audo ◽  
Paul S Bernstein ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Stargardt Disease ◽  
Genetic Characteristics ◽  
Mild Phenotype ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Significant Difference ◽  
Novel Variants ◽  
The Usa ◽  
Subsequent Comparison

Background/aimsTo describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency.Methods345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.Results211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.ConclusionsThere is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

MO1010CLINICAL VARIABILITY OF ALPORT SYNDROME IN CHILDREN WITH MISSENSE COL4A5  VARIANTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Marina Aksenova ◽  
Tatjana Lepaeva ◽  
Tatjana Nikishina ◽  
Oxana Piruzeeva ◽  
Varvara Obuhova ◽  
...  
Keyword(s):  
Alport Syndrome ◽  
Clinical Symptoms ◽  
Age At Onset ◽  
Sensorineural Deafness ◽  
Missense Mutations ◽  
Mild Phenotype ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Significant Difference ◽  
The Mean

Abstract Background and Aims The phenotype-genotype relation is well established in patients (especially male) with X-linked Alport syndrome (XLAS). The aim of study was to define the spectrum of COL4A5 pathogenic variants and impact of missense mutation on disease progression. Method The NGS-based genetic testing of COL4A3, COL4A4, COL4A5 was performed in 186 children with suspected Alport syndrome. The comparison of clinical symptoms (frequency, age of presentation of macrohematuria, proteinuria, eGFR decrease, sensorineural deafness (SND), level of proteinuria (mg/m2/day) and eGFR (ml/min/1.73m2) at the last presentation) was carried out in male with XLAS due to different COL4A5 variants. Results The XLAS was diagnosed in 93 children (Ме 7,5[4;11], 51М) from 79 families. The following COL4A5 variants were revealed: missense (n=70, q=0.75), splice site (n=10 from 9 families, q=0.11), frame shift (n=6, q=0.06), nonsense (n=7, q=0.08). Missense variants were presented by COL4A5 c.1871G&gt;A, p.(Gly624Asp) in 26% of cases (n=18). The mean age of ESRD was lower in male family member (35[24;35] years vs 48[40;55], p=0.023) with non COL4A5 p.(Gly624Asp). There was no difference in age on last presentation (13[9;14] vs 12[8;15], p=0.091) between pts with COL4A5 p.(Gly624Asp) and other missense variants. There was significant difference between the male with p.Gly624Asp and other missense variants in frequency of proteinuria (0.61 vs 0.25, p=0.043), SND (0.5 vs 0.08, p=0.03), age at onset (5[3;7] vs 14[8;16], p=0.02) and degree of proteinuria (441[78;1158] vs 66[22;160], p=0.023) and eGFR level (83[66;109] vs 96[91;104], p=0.048) at the last examination. Conclusion The XLAS is caused by missense variants in ¾ of cases in our cohort. We confirmed the other European studies results: the COL4A5 p.(Gly624Asp) is the most common variant of missense mutations characterized by mild phenotype of XLAS.

scholarly journals The significance of genetic verification of the diagnosis for children with a dilated phenotype of cardiomyopathy with non-compact myocardium and increased trabecularity

2021 ◽  
Vol 24 (3) ◽  
pp. 173-180
Author(s):  
Natalia A. Sdvigova ◽  
Elena N. Basargina ◽  
Kirill V. Savostyanov ◽  
Aleksandr A. Pushkov ◽  
Olga P. Zharova
Keyword(s):  
De Novo ◽  
Massively Parallel Sequencing ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Bioinformatic Analysis ◽  
Left Ventricular ◽  
De Novo Mutation ◽  
National Medical ◽  
Pathogenic Variants ◽  
Sick Children

Purpose: to compare the course of the disease in the dilated phenotype of cardiomyopathy with a non-compact myocardium and increased trabecularity, verify the molecular genetic diagnosis using the new generation sequencing method, and study the segregation of nucleotide variants in families. Materials and methods. The study included 50 patients, divided into two groups: 27 patients with a dilated phenotype of cardiomyopathy and non-compact myocardium and 23 patients with a dilated phenotype and increased trabecularity. Changes in the laboratory and instrumental parameters, events and outcomes were analyzed. The massively parallel sequencing of a panel of genes developed at the National Medical Research Center of Children’s Health of the Ministry of Health of the Russian Federation (81 genes) was applied. For data processing, the IBM SPSS Statistics 24.0 application package was used for bioinformatic analysis and assessment of the pathogenicity of the identified nucleotide variants, the Russian guidelines for interpreting human DNA nucleotide data, Alamut software and the HGMD Professional database were used. Results. Following a year of therapy for chronic heart failure in DF CMP patients, the content of terminal natriuretic peptide in the blood of patients with increased trabecularity was found to decline significantly. In patients in both groups, myocardial contractility improved and left ventricular end-diastolic size decreased. Significant nucleotide variants when using the cardiopanel were verified in 85% of cases in patients with non-compact myocardium and 91% in patients with increased trabecularity. At the same time, predictors of poor prognosis and severe course of cardiomyopathy were identified - pathogenic variants c.2647G>A in the MYH7 gene, c.688G>A in the TPM1 gene, c.2350C> T in the CACNA1C gene. In one clinical case, when laminopathy was detected, a cardioverter-defibrillator was installed as prophylaxis for sudden death. In addition, 18 families were examined, 3 cases of de novo mutation were identified, confirming the high frequency of asymptomatic and low-symptom carriers of nucleotide variants. Conclusion. The determination of the molecular and genetic cause of the dilated cardiomyopathy phenotype allows optimizing the management tactics of sick children. Furthermore, the identification of family segregation of mutations with the identification of carriers ensures timely monitoring by specialists.

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