Pathogenic heterozygous variants in the PIEZO2 gene cause distal arthrogryposis type 5 – a rare autosomal dominant disease, which is characterized by the development of congenital contractures, ophthalmoparesis, ptosis and restrictive respiratory disorders. We have presented clinical and genetic characteristics of seven Russian patients with distal arthrogryposis type 5 caused by previously described and newly identified nucleotide variants in the PIEZO2 gene. It was shown that the most severe clinical manifestations were found in patients with newly identified nucleotide variants c.8238G>A (p.Trp274Ter) and c.7095G>T (p.Trp2365Cys), while in patients with other previously described variants c.8181_8183delAGA (p.Glu2727del) and c.2134A>G (p.Met712Val) the clinical phenotype is more moderately expressed. The dynamics of phenotype formation were also noted. It has been shown that the disease progression may occur as the child grows and requires monitoring of this group of patients.

Geroderma osteodysplasticum (OMIM #231070) is a rare autosomal recessive disorder characterized by congenital wrinkled skin on the dorsal surface of the limbs and abdomen; marked osteoporosis in childhood. Pathogenic variants of the nucleotide sequence in the GORAB gene, which encodes the GORAB protein located in the Golgi apparatus and plays a crucial role in vesicle transport in the Golgi complex, lead to the disease. This is the first report of 2 patients with this disease in Russia. A detailed description of the clinical-radiological and genetic characteristics of these patients with new nucleotide variants in the GORAB gene in a compound heterozygous state is presented: c.170C>G (p.Ser57Ter) and c.790G>C (p.Ala264Pro); c.295C>T (p.Gln99Ter) and heterozygous deletion on chromosome 1 (chr1:g.170531967–170539494del), affecting exons 1 and 2 of the gene. The main clinical manifestations of the syndrome were congenital wrinkled skin, sagging cheeks, hypoplasia of the cheekbones, prognathism, muscle hypotonia and joint hypermobility. Radiological signs included congenital bilateral dislocation of the hip, compression fractures of the vertebral bodies, and disruption of the continuity of the growth plate of the distal femur and proximal tibia, referred to as “insertion.” The rarity of the syndrome, as well as the similarity of clinical manifestations with a heterogeneous group of hereditary diseases accompanied by decreased skin elasticity, leads to a late correct diagnosis. This necessitates the description of the clinical-genetic characteristics of the disease, the study of the dynamics of the formation of its phenotypic manifestations, and the methods of molecular-genetic diagnostics.

A description of the clinical and genetic characteristics of four Russian patients with Schaaf–Yang syndrome, caused by previously described and newly identified nucleotide variants in MAGEL2 gene, is presented. It was shown that the most severe clinical manifestations were found in a patient with the new identified variant c.1828C>T (p.Gln610Ter), while in a patient with a new nucleotide variant c.1609C>T (p.Gln537Ter) the manifestations of the disease were moderate. Considering the significant similarity of the clinical manifestations of Schaaf–Yang syndrome with Prader–Willi syndrome, the criteria for their differential diagnosis are outlined, the use of which will help optimize the process of molecular genetic analysis aimed at finding the etiologic factor.

TRPV4‑associated neuromuscular diseases represent a clinical spectrum of neuropathies and motor neuron disorders. To date, 3 phenotypic forms are distinguished. There are Charcot–Marie–Tooth disease type 2C, distal hereditary motor neuropathy type 8 (DHMN8), scapulo‑peroneal spinal muscular atrophy (SPSMA). Here we report 3 families with DNMN8 and one family with SPSMA. In all cases, DNA‑analysis revealed single nucleotide variants in the TRPV4 gene previously reported as pathogenic. In 3 probands, a combination of signs of both motor and motor‑sensory neuropathies led to difficulties in the establishment of the clinical diagnosis. Patients had mild sensory disturbances in the feet, but in all of these cases nerve conduction study revealed normal sensory nerve action potentials. Considering the prevailing signs of motor neuropathy, these patients were diagnosed with DNMN8. Clinical signs of sensory disturbances are regarded as not contradicting the diagnosis, since they can be observed in various forms of distal motor neuropathies. The clinical features of SPSMA in one patient corresponded to those previously described in the literature. The involvement of the shoulder girdle muscles and the peroneal muscles and neurogenic changes in needle electromyography allow suspecting SPSMA clinically. A distinctive features of TRPV4‑associated neuromuscular diseases are the vocal cords paresis, sensorineural hearing loss and respiratory failure, however they are not obligatory according to our clinical reports.

Duchenne muscular dystrophy is a genetic orphan neuromuscular disease caused by a mutation in the DMD gene encoding the protein dystrophin. As a result of developing and progressive muscle damage and atrophy, children lose the ability to walk, develop respiratory and cardiac disorders. The core elements of good care standards are early diagnosis, prevention and treatment of osteoporosis, daily physical therapy, regular rehabilitation, glucocorticosteroids, and control of heart and lung function. The clinical effect of new targeted pathogenetic therapies for Duchenne muscular dystrophy, restoring synthesis of full or truncated dystrophin, depend on their appropriate combination with existing standards of care.

Distal arthrogryposis is a group of genetically heterogeneous congenital diseases characterized by non-progressive contractures predominantly distal joints of the upper and lower extremities. 11 genes have been identified as pathogenic variants causing the occurrence of autosomal dominant and autosomal recessive types of distal arthrogryposis. Almost all products of these genes are expressed in the structures of the neuromuscular system, which makes it possible to classify distal arthrogryposis as a neuromuscular disease. Type 7 distal arthrogryposis is a rare autosomal dominant disease characterized by two main symptoms: mandibular trismus and pseudocamptodactyly, a specific symptom of limited mobility of the interphalangeal joints during hand dorsiflexion with no restriction during palmar flexion. In all patients described in the literature from different populations with type 7 distal arthrogryposis, the same pathogenic variant c.2021G>A(p.Arg674Gln) was found in the MYH8 gene, the protein product of which is one of the myosin isoforms functioning in the embryonic period and providing the formation of muscle fiber structures.The aim of the work is to describe the clinical and genetic characteristics of the first family case of type 7 distal arthrogryposis in Russian patients. The patients underwent clinical examination and electromyography. Exome sequencing after DNA isolation from the proband’s blood according to the standard method was carried out on the NextSeq 500 platform (Illumina, USA) using the pairedend reading method (2 × 75 bp). Confirmation of the pathogenicity of the identified variants was carried out using automatic Sanger sequencing.As a result of molecular genetic analysis in a father and son with clinical manifestations of type 7 distal arthrogryposis, a heterozygous c.2021G>A variant in exon 18 of the MYH8 gene, which was previously described in all patients published in the literature, was detected, leading to the replacement of p.Arg674Gln(NM_002472.2) in a protein molecule. The examined patients did not reveal focal neurological symptoms, as well as minor developmental abnomalities, pathology of internal organs, ulnar deviations, equinovarus feet deformities, vertical orientation of the talus, contractures of the hip joints, which were found with varying frequency in previously described patients with variants in the MYH8 gene. Specific clinical signs of type 7 distal arthrogryposis, combined with the presence of a major nucleotide variant, make it possible to optimize the process of molecular genetic diagnosis of this type of hereditary arthrogryposis.

Introduction. Juvenile idiopathic arthritis (JIA) is a common multifactorial disease characterized by the presence of chronic inflammation in the joints, entheses and other structures of the musculoskeletal system in combination with a certain range of extraskeletal disorders. Vast variety of JIA clinical variants and the variability of the disease course make primary and differential diagnosis difficult, which often leads to a delayed start of treatment and an inadequate choice of medical therapy or, conversely, an excess of medication. In the range of differential diagnostic conditions that have similar symptoms and are manifested by severe arthralgia, gait disturbance, joint stiffness, as well as the presence of effusion and gradual progression of bone destruction mainly in the epiphyseal plate, one should remember about hereditary skeletal dysplasias, primarily from a genetically heterogeneous group of multiple epiphyseal dysplasias (MED). The aim of the study – description of the clinical and genetic characteristics of three patients with various genetic variants of MED and defining approaches for their differential diagnosis with JIA. Materials and methods. There were three patients from three unrelated families aged from 7 to 13 years old under our supervision. To clarify the diagnosis, a genealogical analysis, a clinical examination of patients and first-degree relatives, as well as an assessment of X-ray images of long tubular bones were carried out. Molecular genetic confirmation of the MED diagnosis types 1 and 2 was based on the results of custom panel sequencing consisting of 166 genes responsible for the development of hereditary skeletal pathology. To clarify the molecular genetic diagnosis of MED type 4, an analysis of the SLC26A2 gene was performed using automated Sanger sequencing. Results. Anamnestic, clinical, radiological, and molecular genetic characteristics of three unrelated patients with different genetic types of MED caused by variants in the COMP, SLC26A2, and COL9A2 genes were analyzed. The first symptoms of the disease in observed patients with three different genetic variants of MED occurred at the age of 2–3 years old and were characterized by gait disturbance and climbing stairs difficulties. Gradually, these symptoms were accompanied by pain in large joints. According to the ultrasound examination of the joints, signs of synovitis were noted, as a result they were diagnosed with JIA (polyarticular variant, seronegative for rheumatoid and antinuclear factor) and immunosuppressive therapy were prescribed without significant effect. The atypical course of the JIA was the reason for additional examination of patients by an orthopedist and geneticist. Careful analysis of the large joints radiographs made it possible to suspect one of the variants of MED in our patients based on the detection of distinctive signs, which were characterized by abnormal ossification (diminished size and flattening) of the epiphyses and abnormal shape and structure of the femoral head epiphysis. Molecular genetic analysis was performed to confirm the diagnosis. As a result, a pathogenic variant of the nucleotide sequence in the COMP gene was detected in one of the patients, two pathogenic variants in the SLC26A2 gene in another patient, and one pathogenic variant in the COL9A2 gene in the third patient, which made it possible to confirm the final diagnosis of MED type 1 with an autosomal dominant type of inheritance, MED type 4 with an autosomal recessive type of inheritance and MED type 2 with an autosomal dominant type of inheritance, respectively. Based on the results of our own research and analysis of the literature data, key directions for the differential diagnosis of MED and JIA were formulated. It is shown that the analysis of the X-ray images of patients is essential in differential diagnosis. Conclusion. Despite the significant overlap of the clinical symptoms between JIA and MED, the key to the early diagnosis of MED is a comprehensive examination, which included genealogical analysis, features of clinical manifestations and disease course in combination with distinctive radiological signs including delayed ossification of the epiphyses of tubular bones typical for MED. However, the question remains about the probability of a combined nature of osteoarticular disorders, i. e., the possible development of JIA in patients with hereditary skeletal dysplasias which requires in-depth study in the future.

Supplement to the 2023 Issue 6 (Volume 102) of the Journal PEDIATRIA named after G.N. Speransky. Guidelines for Practitioners: Duchenne Muscular Dystrophy (DMD). Becker Muscular Dystrophy (BMD). Early diagnosis. Therapy with the use of drugs that are currently not registered properly in Russia/by the Ministry of Healthcare of Russia. DOI: 10.24110/0031-403X-2023-102-6-217-256. https://doi.org/10.24110/0031-403X-2023-102-6-217-256

Craniofacial dysmorphia-deafness-anomalies of the upper limbs is a rare autosomal dominant syndrome caused by variants in the PAX3 gene. In contrast to the two main nosological forms – Waardenburg syndrome types 1 and 3, caused by variants in this gene, the syndrome of craniofacial dysmorphias-deafness-anomalies of the upper limbs is not characterized by the presence of hair hypopigmentation and heterochromia of the iris, while congenital contractures of the wrist and interphalangeal joints of the hands. There is a description in the literature of three patients from the same family with a syndrome caused by the c.141C>G(p.Asn47Lys) variant in the PAX3 gene. Aim of the work is to present the clinical and genetic characteristics of the first Russian patient with the syndrome of craniofacial dysmorphia-deafness-anomalies of the upper extremities.Molecular genetic analysis of a 1-year and 10-month-old proband with phenotypic signs of the syndrome of craniofacial dysmorphia-deafness-anomalies of the upper limbs was carried out by direct automatic Sanger sequencing of the entire coding sequence of the PAX3 gene. Genotyping of parents was carried out by direct automatic sequencing according to Sanger. Sequencing was carried out on an ABIPrism3500хI instrument (Applied Biosystems) in accordance with the manufacturer’s protocol; primer sequences were selected according to the reference sequence of the target regions of the PAX3 gene (NM_181459.4).In Russian proband 1 year 10 months-old, the phenotypic characteristics of the syndrome of craniofacial dysmorphia-deafness-anomalies of the upper limbs did not differ from the description of sick family members presented in the literature. A molecular genetic study revealed a heterozygous variant c.141C>G(p.Asn47Lys) in the PAX3 gene in the presented patient.

Background . Primary hypertrophic osteoarthropathy is a rare genetically heterogeneous disease with three clinical variants. The classic one is a combination of hyperostosis, arthropathy and pachyderma and two variants with damage to only bone structures or pachyderma. Two genes responsible for the occurrence of primary hypertrophic osteoarthropathy have been identified: HPGD (debut age up to one year) and SLCO2A1 (debut in puberty and adolescence), whose products are involved in prostaglandin E2 metabolism. Two recurrent variants were identified in the HPGD gene: c.175_176delCT(p.Leu59fs) in patients from Europe and c.310_311delCT in patients from China. There were no clinical and genetic correlations in patients with different variants in the identified genes, which may be due to a small number of observations. The analysis of clinical manifestations in patients with newly identified variants or previously unidentified combinations of variants in a compound‑heterozygous state helps to understand the pathogenesis and prognosis of the course of the disease. Aim. To present the clinical and genetic characteristics of two Russian patients with primary hypertrophic osteoarthropathy caused by a newly identified combination of nucleotide variants in a compound‑heterozygous state in the HPGD and SLCO2A1 genes. Materials and methods. Clinical examination, radiography of the skeleton and chest, electrocardiography, echocardiography. Confirmation of the pathogenicity of the identified variants and clarification of the type of disease was carried out using automatic Sanger sequencing. Results. The clinical and genetic characteristics of two unrelated patients with primary hypertrophic osteoarthropathy caused by an undescribed combination of variants in the compound heterozygous state in the HPGD and SLCO2A1 genes were analyzed. In a patient with variants in the SLCO2A1 gene, the disease debuts at the age of 14 with deformities of the fingers, nails on the hands and feet, followed by the addition of burning pain in the distal parts of the arms and legs. At the age of 33, the examination revealed deformity of the fingers of the hands and feet by the type of drumsticks and nails by the type of watch glasses, enlargement of the knee joints, pronounced arthralgia. There were no signs of pachyderma. The new generation sequencing revealed two variants in the SLCO2A1 gene c.764G>A(p.Gly255Glu) in exon 6 and c.1333C>T(p.Arg445Cys) in exon 10. These variants were identified earlier in a compound‑heterozygous combination with other variants in patients with the classical phenotype of the disease, which were not present in the patient we observed. A feature of the case was pronounced hyperhidrosis and burning pain in the extremities, which may be due to stimulation of nociceptors in the musculoskeletal structures. Deformities of the fingers, nails of the hands and feet occurred in a patient with variants in the HPGD gene at 6 months. At the age of 9 years, a change in shape, stiffness and arthralgia of the knee and elbow joints without pachyderma were revealed. The identified variant with c.175_176delCT(p.Leu59fs) in this gene is often found in patients from European countries, and the other is c.1A>G(p.Met1?) discovered for the first time. Conclusion . The results allow us to conclude that when we found combinations of two variants in the HPGD and SLCO2A1 genes, there will be no pachyderma in the spectrum of clinical manifestations of primary hypertrophic osteoarthropathy. Sequencing of the new generation exome is the optimal diagnostic method.

Background. Progressive muscular dystrophies (PMD) are a group of genetically heterogeneous diseases that manifest in the age range from early childhood to adulthood. Depending on the predominant topography of the muscular lesion, there are: limb-girdle, distal, oculopharyngeal, facial-shoulder-scapular-peroneal variants of PMD.Aim. Creation of algorithms for the differential diagnosis of PMD with multiple topography of muscle lesions.Materials and methods. We observed 192 patients aged 1.5 to 66 years with PMD with a debut after a period of normal motor development. The diagnosis was established on the basis of genealogical analysis, neurological examination, assessment of non-muscular manifestations, results of instrumental, biochemical molecular genetic studies.Results. Four groups of patients were identified, differing in the topography of muscle damage and 19 genetic variants of PMD were diagnosed. An algorithm for diagnosing PMD that manifest after a period of normal motor development is proposed, which is based on the frequency of occurrence of individual genetic variants and their proportion in the analyzed sample, the presence of major mutations in causal genes, the features of phenotypic characteristics, the gender of the patient and the possibility of conducting etiopathogenetic therapy developed by for some genetic variants.Conclusion. The use of the proposed algorithm in clinical practice can significantly reduce the economic and time costs for confirmatory molecular genetic diagnosis, and promptly recommend etiopathogenetic therapy for some genetic variants of this group of diseases.

Background. Multiple epiphysal dysplasia (MED) type 1 (OMIM: 132400) is one of 7 genetic variants of this group of skeletal dysplasias described to date. The disease is caused by mutations in the COMP gene located on chromosome 19p13.1. The presence of muscle hypotonia and ligamentous laxity, as well as a moderate increase in the level of creatinephosphokinase activity, can lead to misdiagnosis of myopathy.Objective: to analyze the clinical and genetic characteristics of type 1 MED caused by mutations in the COMP gene in a series of Russian patients. Differential diagnosis was focused on the distinctive features of the disorder and hereditary myopathies.Materials and methods. We observed 8 patients from 7 families aged 7 to 15 years with MED type 1 caused by heterozygous mutations in the COMP gene. To confirm the diagnosis, the following methods were used: genealogical analysis, clinical examination, neurological examination with psycho-emotional testing, radiography and targeted sequencing of a panel consisting of 166 genes responsible for the development of inherited skeletal pathology.Results. Case history, clinical, radiological and genetic characteristics of 8 patients with MED type 1 caused by mutations in the COMP gene were analyzed. The first clinical manifestations of the disease were recorded from the age of 2–3 years and were characterized by gait disturbances, muscle weakness, difficulties with climbing stairs, frequent falls when walking, the inability to get up from the floor and from a squatting position and hypermobility of the joints. Electroneuromyographic study did not reveal the signs of miopathy. In two patients, a moderate increase in the creatinekinase level of up to 250–360 u / l was found. All patients were surveyed by neurologists for several years with a clinical diagnosis of congenital myopathy. At the age of 5–6 years patients COMPlained knee and ankle pain, which was assumed as rheumatic arthropathy. X-ray examination revealed typical signs of deficient ossification of the epiphyses. The next-generation sequencing analysis revealed seven single nucleotide variants in the COMP gene that lead to MED type 1. Three of the found variants here identified for the first time. As previously described, the majority of nucleotide variants (six out of seven) were localized in the 8–14 exons of the COMP gene and led to amino acid substitutions in calmodulin-like protein domain repeats, and only one substitution was localized in the C-terminal region of the protein molecule.Conclusion. In most patients with MED caused by mutations in the COMP gene, the first symptoms of the disease are gait disturbance, muscle weakness, and Gowers» maneuvers. The presence of these symptoms, along with a moderate increase in the level of creatinephosphokinase activity, often precedes the onset of clinical manifestations of skeletal dysplasia, leading to a misdiagnosis with myopathies. Accession of expressive arthralgias to these symptoms was mistakenly identified as reactive arthritis. X-ray examination of patients’ long bones helps to suspect the presence of MED. This X-ray imaging shows specific signs of epiphyses damage. A molecular-genetic analysis needs to be done to diagnose the genetic variant, caused by mutations in gene COMP.

Введение. TRPV4-ассоциированные скелетные дисплазии - группа генетически гетерогенных заболеваний с аутосомно-доминантным типом наследования, обусловленных мутациями в гене TRPV4. Он содержит 16 экзонов и кодирует белок семейства трансмембранных кальциевых каналов. К настоящему времени описано семь нозологических форм этой группы скелетных дисплазий, общая распространенность которых не превышает 1:1 000 000. Основными являются спондилометафизарная дисплазия Козловского (OMIM:184252) и метатропная дисплазия (OMIM:156530). Цель: описание клинико-генетических характеристик российских больных со скелетными дисплазиями, вызванными ранее описанными и впервые выявленными мутациями в гене TRPV4. Методы. Проведено комплексное обследование 15 детей из неродственных семей в возрасте от 10 суток жизни до 15 лет, с клинико-рентгенологическими признаками TRPV4-ассоциированных скелетных дисплазий. Для уточнения диагноза использовались генеалогический анализ, клиническое обследование, неврологический осмотр по стандартной методике с оценкой психоэмоциональной сферы, рентгенография и таргетное секвенирование панели, состоящей из 166 генов, ответственных за развитие наследственной скелетной патологии. Результаты. У 7 пациентов диагностирована спондилометафизарная дисплазия Козловского, у 8 пациентов - метатропная дисплазия. В результате молекулярно-генетического исследования у наблюдаемых нами пациентов идентифицировано 7 патогенных вариантов в гене TRPV4, два из которых обнаружены впервые. Как и у ранее обследованных пациентов, у российских пациентов обнаружены две мажорные мутации в гене TRPV4: p.Arg594His у пациентов со спондилометафизарной дисплазией Козловского и p.Pro799Leu у пациентов с метатропной дисплазией. Заключение. Полученные результаты в совокупности с данными литературы позволяют высказать предположение о целесообразности создания системы для скрининга мажорных мутаций у пациентов со спондилометафизарной дисплазией Козловского и метатропной дисплазией, имеющих сходные клинико-рентгенологические проявления. Первоочередное использование такой системы позволит оптимизировать процесс молекулярно-генетической диагностики этих заболеваний. Introduction. TRPV4 -associated skeletal dysplasias are a genetically heterogeneous group of autosomal dominant disorders caused by mutations in the TRPV4 gene. TRPV4 contains 16 exons and encodes a Ca2+-permeable transmembrane channel protein. To date, seven nosological forms within this group of skeletal dysplasias have been described. The overall prevalence of these disorders does not exceed 1:1,000,000. The most frequent forms among this group are spondylometaphyseal dysplasia, Kozlowski type (OMIM:184252) and metatropic dysplasia (OMIM:156530). Objective: to describe the clinical and genetic characteristics of Russian patients with skeletal dysplasia caused by previously reported and newly identified mutations in the TRPV4 gene. Methods. A comprehensive examination of 15 children from unrelated families aged 10 days-15 years with clinical and radiological signs of TRPV4-associated skeletal dysplasia was carried out. To specify diagnosis we used genealogical analysis, clinical examination, neurological examination according to a standard method with an assessment of the psycho-emotional sphere, radiography and sequencing a targeted gene panel including 166 genes responsible for the development of hereditary skeletal disorders. Results. Spondylometaphyseal dysplasia, Kozlowski type was diagnosed in 7 and metatropic dysplasia in 8 patients. 7 pathogenic variants in the TRPV4 gene were identified, of which two were novel. As in previously reported cases, two major mutations in the TRPV4 gene were found in Russian patients: p.Arg594His in patients with spondylometaphyseal dysplasia, Kozlowski type and p.Pro799Leu in patients with metatropic dysplasia. Conclusion. Our findings combined with previously reported results suggest the rationale for creating a genetic screening test to detect major mutations in patients with spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia, which have similar clinical and radiological manifestations. Foremost use of this test will improve the molecular diagnostics of these diseases.

Beare–Stevenson cutis gyrata syndrome (BSS) is a rare autosomal dominant syndrome from the craniosynostosis group caused by mutations in the FGFR2 gene. To date, 25 patients with BSS have been described, most of whom died in infancy as a result of respiratory disorders due to upper airway abnormalities. All children with BSS from birth have specific skin abnormalities in the form of skin convolutions (cutis gyrata), resembling the convolutions of the brain. The protein product of the FGFR2 gene is the fibroblast growth factor tyrosine kinase receptor, which can be synthesized by alternative splicing in two isoforms expressed in ectodermal and mesenchymal tissues. In the previously described cases of BSS two missense mutations in the FGFR2 gene were identified: c.1124A>G and c.1115C>G, which lead to p.Tyr375Cys and p.Ser372Cys amino acid substitutions and affect the function of both isoforms, which causes variability in clinical manifestations with this syndrome. The etiological factor of most hereditary syndromes of craniosynostosis is a mutation in the FGFR2 gene, so their clinical manifestations largely overlap, which can lead to an erroneous diagnosis, make it difficult to predict the course of the disease and patient treatment tactics. Objective of the study: tto describe the clinical and genetic characteristics of the first Russian patient with BSS caused by a mutation in the FGFR2 gene (NM_00141.5): c.1124A>G (p.Tyr375Cys) in a heterozygous state that occurred de novo in the germ cell of one of the parents. The diagnosis was established by screening for mutations in the FGFR1, FGFR2, FGFR3 genes by Sanger sequencing. The existence of polymorphism of clinical manifestations in BSS has been shown. Major clinical features included multisuture craniosynostosis with a trefoil skull configuration, proptosis, cutis gyrata skin changes, acanthosis nigricans, prominent umbilical stump, neonatal teeth, hydrocephalus, choanal atresia, airway obstruction with increased granulation after tracheostomy and tracheal malformations, anterior ectopic anus, conductive hearing loss, developmental delay. Observing the results of studying the features of clinical manifestations in the proband with BSS and analyzing the literature data, helped make a conclusion about the need for differential diagnosis of BSS with various hereditary syndromes and craniosynostosis. Molecular genetic analysis may be used to confirm the diagnosis of BSS. Conclusion: early diagnosis of BSS affects treating tactics of patients and reduces the risk of complications resulting from trachea abnormalities leading to their early mortality.

Синдром Вольфа-Хиршхорна (WHS, OMIM 194190) - это один из наиболее частых микроделеционных синдромов, представленный гетерозиготной делецией короткого плеча хромосомы 4 (4p16.3). К основным клиническим проявлениям относят характерные черепно-лицевые дизморфии («шлем греческого воина»), пренатальный и постнатальный дефицит роста, задержку психо-речевого развития и судороги. На сегодняшний день описано несколько механизмов формирования делеций 4р16.3 и несколько критических областей, ответственных за фенотипические проявления у пациентов. В нашем исследовании мы представляем пять случаев делеции 4p16.3, имеющей различное происхождение и механизмы формирования. Wolf-Hirschhorn syndrome (WHS, OMIM 194190) is one of the most common microdeletion syndromes, represented by a heterozygous deletion of the short arm of chromosome 4 (4p16.3). The main clinical features of patients with WHS include: craniofacial features - “Greek warrior helmet”, prenatal and postnatal growth deficiency, developmental disability of variable degree, and seizures. To date, several mechanisms for the formation of 4p16.3 deletions and several critical regions responsible for phenotypic manifestations in patients have been described. In our study, we present five cases of 4p16.3 deletion with different origins and mechanisms of formation.

Aymé–Gripp syndrome is a rare autosomal dominant syndrome caused by mutations in the MAF gene and is characterized by a pronounced phenotypic polymorphism. The core of clinical signs consists of congenital cataracts, sensorineural hearing loss, specific dysmorphic facial features and intellectual disabilities. With varying frequency, patients have: radioulnar synostosis, Arnold–Chiari malformation, aseptic pericarditis, dental anomaly and osteoarthritis. The article presents the clinical and genetic characteristics of the first Russian patient with Aymé–Gripp syndrome caused by a newly identified mutation s.173C>A (p.Thr58Asn NM_005360.4) in a heterozygous state in the MAF gene. The influence of the lo calization and type of amino acid substitutions in the protein product of the gene on the severity and specificity of the clinical manifestations of the syndrome is discussed.

Currently, pathogenic variants in more than 25 nuclear genes, involved in mtDNA maintenance, are associated with human disorders. mtDNA maintenance disorders manifest with a wide range of phenotypes, from severe infantile-onset forms of myocerebrohepatopathy to late-onset forms of myopathies, chronic progressive external ophthalmoplegia, and parkinsonism. This study represents the results of molecular genetic analysis and phenotypes of 102 probands with mtDNA maintenance disorders. So far, this is the largest Russian cohort for this group of diseases. Mutations were identified in 10 mtDNA maintenance genes: POLG (n = 59), DGUOK (n = 14), TWNK (n = 14), TK2 (n = 8), MPV17 (n = 2), OPA3 (n = 1), FBXL4 (n = 1), RRM2B (n = 1), SUCLG1 (n = 1) and TYMP (n = 1). We review a mutation spectrum for the DGUOK and TWNK genes, that can be specific for the Russian population. In 34 patients we measured the blood mtDNA copy number and showed its significant reduction. Novel variants were found in 41 cases, which significantly expands the mutational landscape of mtDNA maintenance disorders.

Four cases of autosomal dominant CNS disorders related to CACNA1A mutations and detected by massive parallel sequencing are reported: a non-familial case of episodic ataxia type 2 (EA2) with the previously reported mutation c.269_270insA (p.Tyr90Ter) in a 35-year-old man; familial hemiplegic migraine type 1 (FHM1) in a girl aged 3 years 10 months and her mother aged 38 yrs with a novel mutation 1829C>T (p.Ser610Phe), members of a family with 4 patients and incomplete penetrance; developmental and epileptic encephalopathy 42 (DEE42) in a 9-year-old girl and a 5-year-old boy from different families with the identical de novo mutation c.2137G>A (p.Ala713Thr) reported earlier. Clinical and genetic characteristics are analyzed compared to literature.

Background. Lissencephaly (LIS) is a spectrum of malformations of the cerebral cortex that occur as a result of impaired migration of neuronal precursors to the cortical plate and the formation of furrows and convolutions in the post‑migration period of embryonic development. In recent years, a significant role of hereditary factors in the occurrence of LIS has been shown due to the improvement of methods of molecular genetic diagnostics. Today, 13 genetic variants have been identified in the LIS group, six of which are inherited autosomal recessively, five are autosomal dominant, and two are linked to the X chromosome. It is shown that 80 % of cases of hereditary LIS is caused by mutations in two genes: PAFAH1B1, which is responsible for the occurrence of the LIS 1 type with an au‑ tosomal dominant type of inheritance, and in the DCX gene, localized on the X chromosome. The rest of the genetic variants account for from 1 % to 5 % of cases of defects accompanied by dysgenesis of the cerebral cortex. In recent years, the number of works devoted to the analysis of clinical and genetic characteristics of monogenic variants of LIS has increased. The results of such studies will allow us to improve our understanding not only of the pathogenetic mechanisms of this group of diseases, but also of the molecular basis for the formation of brain structures in the normal embryonic period.Objective: to describe the clinical and genetic characteristics of three Russian patients with autosomal dominant LIS type 3 (OMIM: 611603) caused by mutations in the TUBA1A gene.Materials and methods. All patients were under observation in the consultative and diagnostic department of Research Centre for Medical Genetics. The diagnosis was established on the basis of clinical data, genealogical anamnesis, results of brain MRI, EEG night video monitoring and exome sequencing by NGS. The validation of the identified nucleotide substitutions and analysis of the disease segregation were performed using the Sanger direct automatic sequencing method.Results. The clinical and genetic characteristics of three patients with newly identified and previously described mutation in the TUBA1A gene were analyzed. Possible effects of new missense mutations in the gene on the function of the protein product of the gene are discussed.Conclusions. The results of the analysis of the clinical and genetic characteristics of the patients we observed contribute to the study of the polymorphism of clinical manifestations resulting from mutations in the TUBA1A gene. The previously stated assumption about a wide range of malformations of the brain in patients with mutations in this gene was confirmed, which should be taken into account when making a diagnosis.