Medical Genetic Counseling Research Articles

ТЕЧЕНИЕ НОВОЙ КОРОНАВИРУСНОЙ ИНФЕКЦИИ COVID-19 У РЕБЕНКА С РЕДКИМ СИНДРОМОМ СМИТА–ЛЕМЛИ–ОПИЦА: КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

Severe forms of COVID-19 are more likely to develop in children of the first year of life with genetic disorders and congenital malformations. Only a few lethal outcomes of the disease in children have been registered ongoing Worldwide over the entire period of the COVID-19 pandemic. This Article represents a clinical case of COVID-19 in a child with a rare Smith-Lemli-Opitz syndrome. On the 2nd day after the reported contact with a family member with COVID-19 the patient aged 3 years and 2 months old was hospitalized in the infectious diseases department with the diagnoses of “Severe coronavirus infection (PCR-confirmed); cardiopulmonary insufficiency; and congenital heart disease.” Since the age of 1.5 months old the patient repeatedly underwent inpatient examination and treatment with the Psycho-Neurological Department of the Belgorod Oblast Regional Children's Clinical Hospital (located in Belgorod, Russia). Furthermore, at the age of 1.5 y/o, according to the results of the medical genetic counseling, the diagnosis of Smith-Lemli-Opitz syndrome was established. Due to the COVID-19, the patient's condition deteriorated rapidly, and on the 5th day after the hospitalization the patient has died due to acute heart failure, cardiogenic pulmonary edema and pulmonary hemorrhage.

Возможности персонализированной медицины в кардиологической практике

Significant changes have taken place in cardiology over the past 15 years within the framework of a personalized approach to the management of patients with cardiovascular diseases. This review provides up-to-date information on the genetic aspects of the development of various cardiovascular diseases, including heart and vascular malformations, cardiomyopathy, cardiac arrhythmias, dyslipidemia, arterial hypertension, thrombosis, and some others. In the current paper cardiovascular pathologies are divided according to the etiological principle into the chromosomal, monogenic and polygenic diseases. The problems of introducing intensively developing genetic technologies and medical genetic counseling into the practice of cardiologists, as well as the appropriate and rational usage and interpretation of genetic tests, remain actual issue. The necessity of a multidisciplinary approach in the management of cardiological patients with close cooperation of a cardiologist and a clinical geneticist is shown. Key words: cardiogenetics, hereditary diseases, cardiology, cardiovascular diseases, chromosomal diseases, gene diseases, congenital heart defects, cardiomyopathy, cardiac arrhythmia, cardiomyopathy, arterial hypertension, thrombosis, personalized medicine, mutations, polymorphisms

Clusters of oculocutaneous albinism in isolated populations in Brazil: A community genetics challenge.

Oculocutaneous albinism (OCA) is a heterogeneous group of genetic disorders involving deficiencies in melanin biosynthesis, with consequent skin, hair, and eye hypopigmentation. The world prevalence is estimated at 1/17,000, but there is high variability among populations. The affected individuals, besides clinical complications, can suffer from discrimination. The Brazilian population is highly admixed, with isolated and inbred communities. Previous reports indicated the presence of diverse isolated communities with a high prevalence of OCA in Brazil. The present work sought to review and characterize clusters of albinism in this country based on scientific literature search, newspapers, and websites. We identified and characterized 18 clusters, 13 confirmed by scientific studies. Seven clusters are in the Northeast region, with predominant African ancestry, and seven others in indigenous communities, particularly among the Kaingaing in South Brazil. Isolation and inbreeding associated with founder effects seem to be the most plausible explanation. Molecular studies and clinical classification are still limited. Their localization in deprived regions with poor infrastructure makes them particularly vulnerable to the social and clinical consequences of lacking melanin. We reinforce the need for a tailored approach to these communities, including appropriate medical care, social support, and genetic counselling.

Генетически детерминированный синдром детского церебрального паралича, обусловленный интрагенной делецией гена EBF3

Cerebral palsy (CP) is a group of non-progressive disorders of a heterogeneous nature that develop from an early period of neuroontogeny; its clinical manifestation is mainly disturbances in motor development, posture control, and activity limitation. The estimated prevalence of cerebral palsy in developed countries is between 1.0 and 2.3 per 1000 live births. The most common causes of cerebral palsy are hypoxic-ischemic encephalopathy, periventricular leukomalacia, brain malformations, intrauterine infections, and neonatal strokes; however, in up to 20% of patients with cerebral palsy, the etiology remains unspecified. The technological development and the possibility of conducting genomic studies make it possible to identify many genetic factors that are of great importance not only in the cerebral palsy etiology, but also in differentiating genetic syndromes that manifest neuromotor dysfunctions similar to those in cerebral palsy. Mutations at many genetic loci can cause a cerebral palsy-like phenotype. The establishment of an etiological diagnosis is of great clinical importance for optimal treatment. The purpose — to update the need for a genetic examination of patients with severe cerebral palsy and comorbid disorders through the example of our own clinical observation of a family with a genetically determined cerebral palsy syndrome caused by an intragenous deletion of the EBF3 gene. We present our own observation of a family with a genetically determined syndrome of cerebral palsy, three people in which are carriers of an intragenous deletion of the EBF3 gene. A literature review, data from clinical and anamnestic, laboratory, instrumental and genetic research methods are presented. Results. The presented results demonstrate the clinical polymorphism of gene mutations that disrupt transcriptional regulation. Intragenic deletion of the EBF3 gene leads to severe motor disorders that mimic cerebral palsy, manifested by a delay in psychomotor and speech development and in higher brain functions from birth. Conclusion. Timely detection of genetically determined disorders under the guise of cerebral palsy will help to timely establish a diagnosis and refer the family for medical genetic counseling.

Phelan-McDermid syndrome associated with a novel heterozygous mutation in the SHANK3 gene

Phelan-McDermid syndrome (PMS) is a hereditary disorder associated with microdeletions of chromosome 22q13 or point mutations in SHANK3, characterized by mental and speech delays, intellectual disability, epilepsy and autism spectrum disorder. We describe a case PMS associated with a heterozygous mutation c.2486delC (p.Pro829fs) in SHANK3. The diagnostic pathway of a female patient with PMS took more than 7 years; the reason for treatment was the onset of epileptic seizures and impaired speech development. The existence of different types of rearrangements and genomic variations can explain the high clinical variability observed in individuals with PMS. Only molecular diagnosis can accurately diagnose individuals with PMS for follow-up and medical genetic counselling of families.

Spectrum of Mutations and Clinical Manifestations of Rett Syndrome in Girls from Western Ukraine

Rett syndrome is one of the most common causes of mental retardation in girls. The aim of our work was to study a spectrum of genetic heterogeneity and various clinical manifestations of Rett syndrome in girls Western Ukraine. Materials and methods: there were used clinical, molecular and genetic methods. We observed seven girls with Rett syndrome aged from 6 months to 15 years who were diagnosed and followed-up at the Institute of Hereditary Pathology, National Academy of Medical Sciences of Ukraine, Lviv for three years (2019–2021) and underwent molecular genetic analyses confirmed by next-generation sequencing. Results: In this study, patients with Rett syndrome had individual clinical heterogeneity and age variability due to different mutations. Mental retardation was not observed among siblings in families with Rett syndrome. We identified seven different pathogenic mutations among seven girls, including two deletions and one duplication of the MECP2 gene. Microcephaly was observed in two girls with MECP2 c.880C>T (p.Arg294*) and MECP2 Gain (Entire coding sequence) at birth. The following developmental disabilities were found in five girls: lack of independent sitting, lack of independent gait (regression of development). Among musculoskeletal disorders, there were diagnosed scoliosis, X-shaped deformation of the lower extremities and muscular hypotonia. A two-year-old girl with Rett syndrome, along with other clinical symptoms, had breathing problems - hyperventilation (rapid shallow breathing). Conclusions: in cases with unknown cause of delayed developmental disability and mental retardation the patients should be referred for medical genetic counselling.

РЕДКИЕ ТИПЫ СИНДРОМА ЭЛЕРСА–ДАНЛО В ПРАКТИКЕ ПЕДИАТРА

Clinical observations of patients with arthrochalasia and classical-like types of Ehlers-Danlos syndrome (EDS) caused by mutations in the COL1A2 and TNXB genes, respectively, are presented in the article. These genes are involved in the organization of the correct structure and function of collagen. The presence of common links of pathogenesis, apparently, determines the formation of common clinical signs identified in patients (hypermobility syndrome, increased skin extensibility, impaired posture, deformity of the lower extremities, flat feet, mitral valve prolapse) and similar complaints (increased fatigue during exercise, pain in the legs). The peculiarity of the clinical picture in a female patient with arthrochalasia type of EDS were repeated dislocations/subluxations of large and small joints; and in a female patient with a classical-like type of EDS were repeated nosebleeds and the occurrence of paraorbital hematoma. In both observed cases it was possible to determine the type of disease only after a molecular genetic study and a joint analysis of phenotypic and genetic data. Establishing the type of EDS is important for determining the tactics of further medical observation of the patient and medical genetic counseling.

Whole-exome sequencing of patients with juvenile myoclonic epilepsy

Background. Juvenile myoclonic epilepsy (JME) is the most common type of idiopathic generalized epilepsy with onset in adolescence and adulthood. During medical genetic counseling in probands with JME, aggravated epilepsy-related heredity is often detected. However, specific genetic variants of JME predisposition remain inconclusive. The use of contemporary methods of genetic analysis, particularly whole-exome and whole-genome sequencing, allows to detect, confirm and strengthen an association of any certain pathological phenotype with one or another pathogenic variant in a number of genes.Objective: to analyze the results of whole exome sequencing in patients with JME and seek for JME associations.Material and methods. The study included 7 patients with established JME diagnosis and 1 proband child without clinical signs of epilepsy. Whole exome sequencing was carried out by using MiSeq (Illumina, USA), bioinformatics analysis was performed on the Genomenal platform (Novel Software Systems, Russia).Results. Heterozygous carriage of pathogenic variants in the genes of recessive diseases was revealed: SACS, AHI1, CEP164, ANO10, RMND1, POMGNT1, FLG, ACTB. The analysis of the identified genetic variants in the patients examined showed no association with the clinical picture of the disease. Heterozygous missense mutations in CLCN2, EFHC1, JRK, ME2 genes and frameshift mutation in the CACNB4 gene were detected. Conclusion. In recent years, significant efforts were made to identify genes which predispose to JME. During our study, monogenic and/or polygenic pathogenic variants in patients with JME and a child of proband with JME were not identified. The high genetic heterogeneity of JME can explain numerous unsuccessful attempts to find genes predisposing to JME. Further research is necessary to confirm variants associated with potential JME. Advances in genomic technology can expand our understanding of the genetics of this pathology.

A role of genetic studies in aggravated obstetric history: a clinical observation

Primary health care specialists play one of the defining roles in shaping treatment and diagnostic strategy by attracting colleagues from related specialties, including those dealing with medical genetic counseling. At the current stage, additional examinations allow to implement a patient-oriented integrated approach. Genetic studies can substantially improve quality of diagnostics and should be more actively used in primary care. This confirms the clinical observation using extended diagnostic tactics in the patient with non-specific complaints and a burdened obstetric history.

Hereditary leiomyomatosis and renal cell cancer: a case report

This article presents a case report of hereditary leiomyomatosis and renal cell cancer (HLRCC) with new mutation in a 25-year-old female patient admitted to the clinic for diagnosis and treatment due to multiple skin and uterus leiomyomas. The patient has a history of surgery to remove adrenal pheochromocytoma and papillary kidney cancer. Clinical and laboratory examination as well as medical genetic counseling of the patient were performed. We have detected the heterozygous c.395_399del (p.L132*) germline nonsense mutation in exon 4 of the FH gene using polymerase chain reaction/Sanger sequencing of exons 1–10 of this gene and confirmed the diagnosis of HLRCC. The mutation c.395_399del in a patient with HLRCC was described for the first time. The identical mutation was also found in the mother and sister of the patient. Based on the obtained results, medical genetic counseling was carried out in this family, recommendations were given for further oncological monitoring. The case report could be useful for geneticists, oncologists and other specialists to interpretate the clinical heterogeneity of HLRCC and improve the genetic diagnosis of this rare hereditary oncological syndrome.

Genotype-phenotypic correlation of Peutz-Jeghers syndrome on the example of a series of clinical cases

Introduction: Peutz-Jeghers syndrome (PEUTZ-JEGHERS SYNDROME; PJS; OMIM#175200) is hereditary tumor syndrome and is characterized by the occurrence of hamartomatous polyps of gastrointestinal tract, melanocytic pigmentation of the skin and mucous membranes, as well as a high predisposition to malignant tumors of various locations. Despite the fact that the clinical features of PJS are currently well understood, the nature of the variability in the phenotypic manifestations of the disease has not been fully described. Aims: to determine the phenotypic and clinical features in patients with PJS depending on the type of mutation in the STK11 gene. Patients and methods: the clinical and genetic data of 3 patients aged 21, 28 and 39 years with clinical signs of PJS are presented. All patients underwent medical genetic counseling and molecular genetic diagnostics of the STK11 gene using NGS and MLPA methods. Results: large deletions of ex2-8 and ex1 in the STK11 gene were revealed in two patients, and one patient showed a splice site variant c.921-1G > A. The identified variant ex2-8 has not previously been described in international databases. When evaluating the clinical and genetic features, the most severe picture of the disease was in a patient with an extended deletion of exons 2-8, large number of polyps and surgical procedures in history. However, in this case, melanocytic pigmentation became less with age, in contrast to patients with a splice site mutation and a single exon deletion. No cancers were detected in the patients. Conclusion: the molecular genetic test made it possible to confirm the clinical diagnosis of PJS, based on various phenotypic features, and to work out the personalized plan for follow-up. Evaluation of the genotype-phenotype correlations will be possible with the development of a unified register of mutation carriers.

The importance of plasma amino acid profiling in the diagnosis of inborn errors of metabolism: analytical – prospective study

Introduction. Inborn errors of metabolism (IEM) make up a large group of disorders caused by an inherited defect of proteins that have enzymatic, carrier, receptor or structural roles. The cumulative prevalence of IEM in different populations is around 1:500 – 800 newborns, despite the fact that some of these disorders are extremely rare when taken individually. Early recognition and intervention are essential to avoiding disastrous consequences associated with IEM. The phenotype of IEM patients is very heterogeneous and only in combination with specialized metabolic test it can lead to a correct diagnosis. The aim of the study was defined as evaluation of importance of plasma amino acid profile in the diagnosis of IEM. Material and methods. Plasma amino acids quantification have been performed by high performance liquid chromatography on Shimadzu LC-20 with post column derivatization with OPA in 15 patients aged from 0 to 13 years old, selected through medical genetic counseling, based on inclusion and exclusion criteria. Inform consent has been signed by parents after receiving all necessary information regarding the study. Additionally, liquid chromatography-tandem mass spectrometry (LC-MS/MS) on dried blood spots and Nuclear Magnetic Resonance Spectroscopy (H1-NMR) on urine has been done as complementary tests. Results. The first line investigations showed acid-base imbalance (33,3%), hypoglycemia (46,6%), high lactate level (46,6%) and high ammonia level (20%). Plasma amino acid concentrations were abnormal in 4 patients (27%). Increased glycine (544 μmol/L, reference values 70,72 – 256,36 μmol/L), along with elevated glycine in cerebrospinal fluid (CSF) / plasma ratio (0,147, normal < 0.02) was detected in a patient with seizures, coma, and respiratory arrest indicating non-ketotic hyperglycinemia. High level of phenylalanine (Phe 1568µmol/L, reference values 26.52 – 221 µmol/L) has been identified in a patient suspected for Phenylketonuria after neonatal screening results (Phe > 3mg/dL). Also the ratio Phe / Tyr around 17 was specifically appreciated as for classical form of PKU. High alanine concentration (> 450 µmol/L) has been observed in two patients presenting severe metabolic acidosis and high lactate level, suggesting for a metabolic error with mitochondrial involvement. The results from extended newborn screening and NMR spectroscopy narrowed the spectrum of suspected diseases, facilitating the diagnosis. Molecular genetic tests are required for the confirmation of disease in all cases. Conclusions. Quantitative amino acids analysis is an important tool for the diagnosis of “intoxication type” of IEMs and nutritional monitoring of individuals with already established diagnosis.

PECULIARITIES OF PREGNANCY AND DELIVERY IN WOMEN WITH HISTORY OF INFERTILITY

Institute of Hereditary Pathology of the National Academy of Medical Sciences of Ukraine, Lviv. Ukraine. Objective: to analyze data on somatic, reproductive, gynaecological history, pregnancy course and outcomes in women with a history of infertility residing in the Lviv region. Material and methods. The data and results of medical genetic counselling of 170 women aged 18-42 with a history of infertility (main group) were analyzed. The comparison was carried out with similar parameters of 80 healthy women aged 18-42 years in the control group. The data of somatic, reproductive, gynecological anamnesis, the pregnancy course and outcomes were studied. Statistical processing of the findings obtained was carried out by the Statistica 7.0 software package using the standard Excel 2013 statistical analysis package. Differences were considered statistically significant at p <0.05. Results. The analysis of the data of the results of medical genetic counselling of 170 women with a history of infertility for 2019-2021 was carried out. The patients with a history of infertility were significantly more likely to be over 36 years of age compared to the same indicators in the control group. They had a complicated somatic anamnesis, 80.0% versus 20.0% in the control group, with a significant predominance of cardiovascular pathology (21.8% and 11.2%), and they also more often had reproductive history complications, 51 (30.0%) versus 11 (13.7%), mainly due to spontaneous miscarriages and missed pregnancies: 46 (27.0%) and 11 (13.7%), respectively. The gynaecological history in all these patients was complicated by infertility, and only infertility was in 113 (66.5%); infertility in combination with ovarian apoplexy was found in 17 (10.0%) and with ectopic pregnancy in 15 (8.8%) that was significantly higher in relation to respective data in the control group of women: 2 (2.6%) and 1 (1.3%), respectively. In women with a history of infertility, a high incidence of pregnancy complications was noted: 146 (85.9%) versus 39 (48.75%) in the control group: they more often gave birth for the first time: 110 (64.7%), and 35 (43.7%) in the control group. Analysis of the data obtained showed the presence of a large number of maternal risk factors for obstetric complications in this group of women. Conclusion. The study has demonstrated the risk factors for the occurrence of obstetric pathology in women with a history of infertility include presumably older age (over 36 years) (13.5%), a complicated reproductive history (30.0%) mainly due to spontaneous miscarriages and missed pregnancies (27.0%); complicated somatic history (80.0%) with a significant predominance of the pathology of the cardiovascular system (21.8%). A gynaecological history aggravated by infertility was found in all 170 (100.0%) women of the main group, and a significant increase in the combination of infertility with ovarian apoplexy was detected in 17 (10.0%) and with ectopic pregnancy in 15 (8.8%) women compared with the control group: 2 (2.6%) and 1 (1.3%), respectively. The complicated course of pregnancy was found in 85.9% of women with a history of infertility and in 48.75% of women in the control group; they more often gave birth for the first time: 110 (64.7%) versus 35 (43.7%) patients in the control group (p<0.05). Women with a history of infertility are at risk for obstetric complications.

НАСЛЕДСТВЕННАЯ МОТОСЕНСОРНАЯ НЕВРОПАТИЯ I ТИПА (БОЛЕЗНЬ ШАРКО–МАРИ–ТУТА, ТИП I A): КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ РАННЕГО ДЕБЮТА ЗАБОЛЕВАНИЯ

Hereditary motor sensory neuropathies (HMSNs) are the most common degenerative disorders of the peripheral nervous system in children. In this pathology, degenerative lesions of the myelin sheaths and/or axons lead predominantly to distal paralytic amyotrophy, affecting mainly the lower extremities, and are accompanied by areflexia. A clinical case of HMSN type I (Charcot–Marie–Tooth disease, type I A) with an early (up to 1 year) onset of the disease is described. The clinical features of this observation are a very early onset of the disease with a debut before the age of 1 year, the absence of pronounced amyotrophies and characteristic deformities of the feet («hollow foot»). To diagnose this genetic disease, a molecular genetic study was carried out. As a result of DNA sequencing (panel «Neuromuscular diseases»), data were obtained on the presence of a duplication of a segment of chromosome 17 with approximate boundaries of 14005424 – 15162520 bp, covering sections of several genes, including the PMP22 gene. Chromosomal micromatrix targeted analysis revealed a microduplication of the short arm (p) region of chromosome 17 from position 14076430 to position 15441811, covering the 17p12 region. The duplication zone also includes the PMP22 gene, the duplication of which is the cause of Charcot–Marie–Tooth disease, type 1A. At this time, there are no methods of pathogenetic therapy for HMSN, therefore, early diagnosis is of great practical importance, which makes it possible to start rehabilitation measures and prevent the disease in burdened families in a timely manner, based on medical genetic counseling and prenatal DNA diagnostics.

Novel GLIS3 mutation in patient with neonatal diabetes mellitus and congenital hypothyroidism (NDH-syndrome)

Mutations in the GLIS3 gene encoding the GLIS3 transcription factor are cause of a rare syndromic form of neonatal diabetes mellitus (NDM) with congenital hypothyroidism. Additional features include congenital glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay and other anomalies. This disease in foreign literature is called NDH-syndrome (Neonatal diabetes and Hypothyroidism syndrome).We present the description of a patient with this syndrome with novel homozygous GLIS3 mutation.Our patient is a female, who was born with a weight of 1680 gr, length of 44 cm to consanguineous parents. She developed diabetes on 2 day after birth, requiring continuous intravenous insulin. On day 5 of life hypothyroidism was identified. ­Thyroid anatomy was normal on ultrasound scan. NDH syndrome was suspected.Genetic analysis revealed a novel homozygous mutation c.1836delT, p.Ser612ArgfsTer33 in exon 5 in GLIS3 gene.To date, the patient is followed up for 4 years in total. Currently, growth retardation, psychomotor and speech development persist. Carbohydrate metabolism and thyroid profile has been subcompensated against the background of replacement therapy. No other components of the syndrome have been identified.In this report, we have demonstrated the features of the neonatal diabetes mellitus in a patient with a defect in the GLIS3 gene. Early genetic verification of the diagnosis contributes to the timely starting of personalized therapy, can improve the quality of life of such patients, and, given the nature of inheritance, is necessary for medical genetic counseling of the family.

Integrating Medical Genetics Into Precision Oncology Practice in the Veterans Health Administration: The Time Is Now.

Increased access and utilization of tumor profiling of cancers in our veteran population uncovered a modest number of potentially pathogenic germline variants (PPGVs) that require genetics referral for follow-up evaluation and germline sequencing. Challenges identified specific to the veteran population include paucity of genetics providers, either at a veteran's VA facility or nearby non-VA facilities. We sought to investigate the number of veterans who would benefit from having such resources at both local and national levels. Annotated clinical reports of mutations identified by tumor-only profiling and medical records of veterans with solid tumors at the Veterans Administration Ann Arbor Healthcare System (VA AAHS) between 2015 and 2020 were reviewed. PPGVs were identified according to society recommendations (such as ESMO and American Board of Medical Genetics and Genomics), expert review, and/or previously published criteria. After the analysis of our local VA population, these same criteria were then applied to veterans in the National Precision Oncology Program (NPOP). Two hundred eight veterans underwent tumor profiling at the VA AAHS over the defined time period. This included 20 different primary tumor sites with over half (n = 130) being advanced cancer at diagnosis. Of these, 18 veterans (8.5%) had mutations suggestive of a PPGV. Applying these criteria to the larger NPOP database (n = 20,014), a similar percentage (6%) of PPGVs were identified. These results indicate a PPGV frequency (6%-9% of veterans) consistent with the prevalence of inherited cancer predisposition syndromes in the general population, underscoring the need for medical genetics as part of standard oncologic care for veterans. We explore current and future care delivery models to optimize incorporation of medical genetics and genetic counseling to best serve veterans needing such services.

Molecular and Cellular Bases of Lipodystrophy Syndromes.

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

Fundamentals of medical genetic counseling and principles of treatment patients with hereditary disorders of lipid metabolism

Fundamentals of medical genetic counseling and principles of treatment patients with hereditary disorders of lipid metabolism

Spectrum of desmosomal gene variations in patients with arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary myocardial disease with a high risk of sudden cardiac death. The most common genetic forms of the disease are associated with desmosomal gene mutations.Aim. To study the prevalence of desmosomal forms of ARVC and to analyze variations in the PKP2, DSG2, DSP, DSC2 and JUP genes in a sample of Russian patients with ARVC.Material and methods. Included patients with ARVC underwent resting electrocardiography (ECG), 24-hour Holter ECG monitoring, echocardiography, chest x-ray, myocardial biopsy (if indicated), contrast-enhanced cardiac magnetic resonance imaging. All patients underwent medical genetic counseling. Mutations in the PKP2, DSG2, DSP, DSC2, and JUP genes was detected using highthroughput sequencing on the IonTorrent platform, followed by Sanger sequencing of uncovered gene regions. The pathogenicity of identified genetic variations was assessed according to modern guidelines.Results. ARVC was established in 80 Russian unrelated patients. More than half of the probands (57%) in the study sample had definite diagnosis of ARVC, while 30% and 13% — borderline and possible ARVC, respectively. A positive family history of heart disease and/or SCD was noted in 30%. Genetic variants of pathogenicity class IV-V were detected in 15 (18,75%) probands in the PKP2, DSG2, DSP genes. The detection of genetic variants of pathogenicity class IV-V was different in the subgroups of patients with varying degrees of diagnosis reliability: 13 probands (28,3%) in the subgroup with definite ARVC and 2 probands (8,3%) in the subgroup with borderline ARVC. No genotype-positive probands were found in the subgroup with possible ARVC. Variations of unknown clinical significance were found in 13 (16,25%) probands.Conclusion. The diagnostic yield of the desmosomal genes PKP2, DSG2, DSP, DSC2, and JUP was 19% with initial diagnosis of ARVC. The detection of mutations was significantly higher in patients with definite ARVC and severe disease manifestations.

Osteogenesis imperfecta: a literature review and a clinical case of a perinatal-lethal type of disease

The article presents the modern views of clinicians and geneticists on one of the most severe genetic disorders of skeletal and connective tissues - osteogenesis imperfecta. The review provided the literature data that showed the incidence rates, genetic heterogeneity of osteogenesis imperfecta, as well as the role of some proteins involved in the construction of bone tissue, as well as a clinical classification of the main types of the disorder. The authors described a clinical case: a girl with typical clinical and radiological manifestations of the rarest of all types of osteogenesis imperfecta - type II (perinatal-lethal, congenital osteogenesis imperfecta, Vrolik’s syndrome). The child’s diagnosis was verified by a parallel DNA sequence analysis which showed a heterozygous mutation in exon 29 (c.1966G> A) of COL1A1 gene not previously described in the literature. It caused the substitution of glycine for serine at position 656. The role of antenatal diagnostics and the importance of medical genetic counselling of the family before planning the next pregnancy due to the existing risk of re-birth of a sick child is outlined. Due to the fact that majority of the patients with the most prognostically unfavourable type II osteogenesis imperfecta, as a rule, die in utero, the described case of observation of the girl with typical clinical and X-ray signs of the disorder for almost 3 months of postpartum period is extremely rare and highly indicative. The detection of the heterozygous mutation in exon 29 (c.1966G > A) of COL1A1 gene by a parallel DNA sequence analysis which was not previously described in the literature gives an additional significance to the described observation.