VI тип несовершенного остеогенеза. Наблюдение редкого случая

Osteogenesis imperfect is genetically heterogeneous group of diseases which are characterized by bone brittleness and fractures. It was thought for a long time that this is happening due to mutations in collagen genes. However, within past decade the understanding of osteogenesis imperfecta etiology has changed as a result of genetics development. The majority of all cases is related to mutations in collagen genes whereas rare mostly recessive forms are related to mutations in genes encoding collagen post-translational modification. Mutations in SERPINF1 gene were chosen as molecular cause of osteogenesis imperfecta type VI in 2011. Thus the new pathophysiology of this disease was revealed. Children with osteogenesis imperfecta type VI have high-frequency of fractures despite the management with bisphosphonates because mineralized bone osteoid is considerably reduced.Несовершенный остеогенез — генетически гетерогенная группа заболеваний, отличительной чертой которых являются хрупкость костей и переломы, возникающие, как считалось долгое время, вследствие мутаций в генах коллагена. Однако, в течение последнего десятилетия скачок в области генетических открытий обусловил появление новой парадигмы понимания этиологии несовершенного остеогенеза, где большинство случаев связано с наличием дефекта в коллагеновых генах, в то время как редкие, в основном рецессивные формы связаны с дефектами генов, влияющих на посттрансляционную модификацию коллагена. В 2011 г. мутации в гене SERPINF1 были идентифицированы в качестве молекулярной причины развития VI типа несовершенного остеогенеза, и тем самым, была выявлена новая патофизиология заболевания. Дети с несовершенным остеогенезом VI типа имеют высокую частоту переломов, несмотря на проведение стандартной терапии бисфосфонатами, т.к. площадь минерализованного остеоида кости при данном типе заболевания значительно уменьшена

Targeted NGS in Diagnostics of Genodermatosis Characterized by the Epidermolysis Bullosa Symptom Complex in 268 Russian Children

The pathogenic variants of genes encoding proteins, participating in the formation and functioning of epidermis and dermo-epidermal junctions, create a large variety of clinical phenotypes from: small localized to severe generalized dermatitis, as well as early, or even, prenatal death due to extensive epidermis loss. The diagnostic panel in this study was developed for the purposes of identifying these pathogenic genetic variants in 268 Russian children, who possessed the epidermolysis bullosa symptom complex in a selection of 247 families. This panel included the targeted areas of 33 genes, which are genetic variants that can lead to the development of the phenotype mentioned above. The usage of next generation sequencing allowed the revelation of 192 various altered alleles (of which 109 alleles were novel, i.e., had not been described previously). In addition, it allowed the definition of the genetic variants that are both typical for most of the examined children and for the separate ethnic groups inhabiting modern Russia. We found that the most characteristic mutations for the Dargin and Chechen ethnic groups are the c.3577del deletion in the COL7A1 gene and the c.2488G>A missense mutation in the COL17A1 gene, respectively. In addition, the study of haplotypes of microsatellite markers, which we managed to conduct in the Dargin population, confirmed the presence of the founder effect

Brief Guidelines on Preparation of Manuscripts Containing Information on the Results of Molecular Genetic Research

Guidelines are given on terminology, nomenclature and determination of the clinical significance of various variants of the genome nucleotide sequence. Information on the use of specialised databases and literary sources when describing and interpreting molecular genetic research data is provided

Clinic Case of Rare Type VI Osteogenesis Imperfecta

Osteogenesis imperfect is genetically heterogeneous group of diseases which are characterized by bone brittleness and fractures. It was thought for a long time that this is happening due to mutations in collagen genes. However, within past decade the understanding of osteogenesis imperfecta etiology has changed as a result of genetics development. The majority of all cases is related to mutations in collagen genes whereas rare mostly recessive forms are related to mutations in genes encoding collagen post-translational modification. Mutations in SERPINF1 gene were chosen as molecular cause of osteogenesis imperfecta type VI in 2011. Thus the new pathophysiology of this disease was revealed. Children with osteogenesis imperfecta type VI have high-frequency of fractures despite the management with bisphosphonates because mineralized bone osteoid is considerably reduced

AUTOSOMAL RECESSIVE PERIPHERAL NEUROPATHY WITH NEUROMYOTONIA (ARAN-NM): DESCRIPTION OF A CLINICAL CASE CONFIRMED BY A MUTATION IN THE HINT1 GENE

Autosomal recessive  peripheral neuropathy with neuromyotonia  (ARAN-NM)  is a relatively newly described  disease associated  with mutations  in the HINT1 gene.  It accounts  for a significant  part of the poorly  differentiated  forms  of axonal polyneuropathies.  We present the first in Russia description of the genetically confirmed case of ARAN-NM in a boy aged 14 years and 11 months without the hereditary-tainted anamnesis. On presentation,  the patient experienced  progressive  distal muscular weakness, asymmetric foot deformity,  gait disorders  and minimal manifestations  of neuromyotonia  (stiffness  in the fingers).  During examination,  we detected an increase in the level of creatine phosphokinase up to 635 U/l, a disturbance of conduction of motor and, to a lesser extent, sensory fibers  of  the  peripheral  nerves  (according  to  the  stimulation  electromyography,  EMG),  denervation-reinnervation  changes,  single positive acute waves, fibrillation potentials, complex repeated discharge (according to the data of needle EMG). In the study of exome, a homozygous mutation c.110G>C, p.R37P was determined in exon 01 of the HINT1 gene, which confirmed the presence of ARAN-NM. A molecular-genetic  examination of the patient's immediate relatives was carried out. The described case is compared with literature data. An overview of currently available information on ARAN-NM is provided. Diagnostic criteria of the disease are presented

GENOTYPE-PHENOTYPE CORRELATIONS OF THE COURSE OF CYSTIC FIBROSIS IN RUSSIAN CHILDREN. THE FIRST DESCRIPTION OF ELEVEN NEW MUTATIONS

Background. Cystic fibrosis is a hereditary disease that occurs as a result of mutations in the regulator gene of chloride ion transmembrane transport (CFTR). Finding mutations in the CFTR gene is necessary for identification of the clinical features of cystic fibrosis.Objective. Our aim was to identify genotype-phenotype correlations between mutations of the first class of pathogenicity and clinical manifestations of cystic fibrosis based on studying the prevalence and structure of CFTR gene mutations.Methods. The study included children under 18 years with cystic fibrosis admitted to hospital between 2013 and 2017. Biallelic mutations in the CFTR gene were the noninclusion criterion. The CFTR gene variants were analyzed by next-generation sequencing method.Results. In 125 patients with cystic fibrosis, 59 different variants of the CFTR gene were detected, 11 of them not previously described. The most common was the deletion c.1521_1523del found in 98 (39.2%) of the 250 analyzed CFTR gene alleles and the deletion c.1545_1546del found in 22/250 (8.8%) alleles. It has been shown that the mutation c.1545_1546del, p.Y515* was more often found in children of the Chechen nation — odds ratio (OR) 139 (95% confidence interval 15–1,257). It has been established that meconium ileus, pancreatic deficiency and cirrhosis are more common in patients with mutations of the first category of pathogenicity: OR 3.9 (95% CI 1.0–15.0), 4.4 (95% CI 1.8–11.1), and 351 (95% CI 17.5–7,046), respectively. The association of CFTR gene mutations with the development of bronchiectases and polypous pancinusitis has not been found.Conclusion. Correlations between the genotype and clinical manifestations of cystic fibrosis in Russian children with CFTR gene mutations of the first class of pathogenicity have been established

22q11.2 DELETION SYNDROME: ALGORITHM FOR THE EARLY DIAGNOSIS AND TREATMENT

Chromosomal diseases, in particular microdeletions, determine the child's condition as well as the prognosis for a disease even at birth. With timely identified chromosomal abnormalities, we can diagnose not only obvious but also hidden disorders in the organs and their systems and timely correct the child's treatment at an early age. The algorithm for diagnosis of chromosomal abnormalities in children is an important component of a modern pediatric practice. It allows to increase the effectiveness of chromosomal pathology treatment

Comorbid Cardiovascular Malformation and Type II Mucolipidosis: Clinical Case

Background. Type II mucolipidosis (I-cell disease, ICD) is one of the lysosomal storage diseases. It is very rare disease; the literature describes only few cases with confirmed diagnosis of mucolipidosis. Cardiovascular changes in children with such pathology are even less often. Clinical case description. The article describes the clinical case of type II mucolipidosis alongside with cardiovascular pathology — valvular heart apparatus defect with abdominal aortic hypoplasia and reversible myocardial dysfunction on the therapy of chronic heart failure (CHF). The patient has coarse face, gingival hyperplasia, macroglossia, dysostosis multiplex, diffuse muscular hypotonia, and mass of subcutaneous tissue. Arterial hypertension, heart cavities dilatation, left ventricular (LV) walls hypertrophy, and data of CT aortography let us to diagnosis abdominal aortic hypoplasia. Conclusion. Cardiovascular malformation in patients with mucolipidosis leads to severe, life-threatening conditions development. Untimely diagnosis can worsen the course of disease. Multidisciplinary approach is needed for the patient management

THE URGENCY OF GENETIC VERIFICATION OF NON-COMPACTION CARDIOMYOPATHY IN CHILDREN: CLINICAL CASES

Background. Non-compaction cardiomyopathy is a group of genetically heterogeneous, poorly studied myocardial diseases with a variety of clinical manifestations (from asymptomatic course to progressive systolic dysfunction with symptoms of chronic heart failure, arrhythmias, and thromboembolic complications). Considering the variety of genetic disorders associated with the development of noncompaction cardiomyopathy, genetic verification of the diagnosis is important for determining the prognosis and conducting genetic counselling of families with cases of the disease.Description of the Clinical Case. The article presents two clinical observations of a severe course of non-compaction cardiomyopathy with remodeling of the heart cavities according to the dilated phenotype. In order to clarify the disease etiology, a molecular genetic study was conducted using the method of direct automatic sequencing with the analysis of targeted regions of 404 genes which mutations are described in hereditary diseases of the heart and blood vessels. After verifying the mutation (in the ACTC1 and MYBPC3 genes), we performed a search for the detected nucleotide substitution in the venous blood samples of parents and in one case — in the fetal DNA sample. The mode of inheritance has been determined; the probability of recurrence of the disease in siblings in subsequent pregnancies has been estimated.Conclusion. The description of clinical cases shows the importance of genetic verification of the diagnosis in patients with non-compaction cardiomyopathy for determining the disease prognosis and developing an algorithm for monitoring relatives of a proband