Leigh syndrome (LS), also known as infantile subacute necrotizing encephalopathy, is the most frequent mitochondrial disorder in children. Recently, more than 80 genes have been associated with LS, which greatly complicates the diagnosis. In this article, we present clinical and molecular findings of 219 patients with LS and give the detailed description of three cases with rare findings in nuclear genes MORC2, NARS2 and VPS13D, demonstrating wide genetic heterogeneity of this mitochondrial disease. The most common cause of LS in Russian patients are pathogenic variants in the SURF1 gene (44.3% of patients). The most frequent pathogenic variant is c.845_846delCT (66.0% of mutant alleles; 128/192), which is also widespread in Eastern Europe. Five main LS genes, SURF1, SCO2, MT-ATP6, MT-ND5 and PDHA1, account for 70% of all LS cases in the Russian Federation. Using next generation sequencing (NGS) technique, we were able to detect pathogenic variants in other nuclear genes: NDUFV1, NDUFS2, NDUFS8, NDUFAF5, NDUFAF6, NDUFA10, SUCLG1, GFM2, COX10, PMPCB, NARS2, PDHB and SLC19A3, including two genes previously associated with Leigh-like phenotypes—MORC2 and VPS13D. We found 49 previously undescribed nucleotide variants, including two deep intronic variants which affect splicing.

Calvarial doughnut lesions (CDL) with bone fragility with or without spondylometaphyseal dysplasia (MIM: #126550) is a rare autosomal dominant skeletal disorder characterized by low bone mineral density, spinal and peripheral fractures, and specific sclerotic lesions of the cranial bones. In the current classification of skeletal disorders, the disease is included in the group of bone fragility disorders along with osteogenesis imperfecta. The disease is caused by pathogenic variants in the SGMS2 gene, the protein product of which is sphingomyelin synthase 2, which primarily contributes to sphingomyelin (SM) synthesis—the main lipid component of the plasma membrane essential for bone mineralization. To date, 15 patients from eight families with CDL with bone fragility have been described in the literature, and a recurrent variant c.148C>T (p.Arg50Ter) in the SGMS2 gene has been identified, which was found in patients from six families. We diagnosed the disease in 11 more patients from three unrelated families, caused by the same heterozygous nonsense variant c.148C>T (p.Arg50Ter) in the SGMS2 gene. Our results show wide interfamilial and intrafamilial phenotypic variability in patients with a detected recurrent variant in the SGMS2 gene, the presence of which must be taken into consideration in the diagnosis of the disease. The primary analysis of this variant will contribute to optimal molecular genetic diagnostics, which can reduce diagnostic costs and time.

Here we present a patient with a cranioectodermal phenotype associated with pathogenic variants in the IFT140 gene. Most frequently, pathogenic variants in IFT140 correspond to the phenotype of Mainzer–Saldino syndrome. Only four patients have previously been described with this cranioectodermal phenotype and variants in IFT140. In comparison to other IFT140-cranioectodermal patients, our proband had similar skeletal features among with early onset end-stage renal failure that required kidney transplantation but did not have common ophthalmological features such as retinopathy, optic nerve atrophy, or nystagmus. Following exome sequencing, a splicing variant and exons 27–30 tandem duplication were suspected and further validated. The two other patients with Mainzer–Saldino syndrome that we described displayed a typical clinical picture but a special diagnostic journey. In both cases, at first only one pathogenic variant was detected following panel or exome NGS sequencing. Further WGS was performed for one of them where tandem duplication was found. Screening the third patient for the same tandem duplication was successful and revealed the presence of this duplication. Thus, we suggest that the description of the clinical feature polymorphism in a rare IFT140-cranioectodermal phenotype is extremely important for providing genetic counseling for families, as well as the formation of the correct diagnostic path for patients with a variant in IFT140.

This study is aimed at investigating the clinical and genetic characteristics of 244 unrelated probands diagnosed with multiple osteochondromas (MO). The diagnosis of MO typically involves identifying multiple benign bone tumors known as osteochondromas (OCs) through imaging studies and physical examinations. However, cases with both OCs and enchondromas (ECs) may indicate the more rare condition metachondromatosis (MC), which is assumed to be distinct disease. Previous cohort studies of MO found heterozygous loss-of-function (LoF) variants only in the EXT1 or EXT2 genes, with DNA diagnostic yield ranging from 78 to 95. The PTPN11 gene, which is causative for MC, was not previously investigated as a gene candidate for MO. In this study, we detected a total of 177 unique single nucleotide and copy number variants in three genes across 220 probands, consisting of 80 previously reported and 97 novel variants. Specifically, we identified five cases with OCs and no ECs as well as four cases with MC carrying LoF variants in the PTPN11 gene and two additional cases with ECs harboring variants in the EXT1/2 genes. These findings suggest a potential overlap between the MO and MC both phenotypically and genetically. These findings highlight the importance of expanding genetic testing beyond the EXT1 and EXT2 genes in MO cases, as other genes such as PTPN11 may also be causative. This can improve the accuracy of diagnosis and treatment for individuals with MO and MC. It is essential to determine whether MO and MC represent distinct diseases or if they encompass a broader clinical spectrum.

Duchenne muscular dystrophy (DMD) is typically described in boys with a pathogenic variant in the DMD. However, in certain cases, females may also exhibit symptoms of this X-linked disorder. In the present study, the cause of Duchenne muscular dystrophy in three girls was reciprocal translocations t(X;2), t(X;12), and t(X;16), with breakpoints located within the DMD gene sequence. All patients had global development delay, predominantly proximal muscle weakness, calf muscle hypertrophy, and elevated creatine kinase levels up to 100 times the normal range (16,000–26,694 U/L). All underwent cardiac ultrasound and electromyography, and two of the girls also had muscle MRI data. After receiving negative results of MLPA aimed at the detection of DMD deletions and duplications, as well as the limb-girdle muscular dystrophy gene panel sequencing, the patients were referred to whole genome sequencing, which allowed to detect a translocation involving the short arm of the X chromosome and with breakpoints in the DMD. Karyotyping confirmed reciprocal translocations in all patients, with de novo status established in all three cases. The results of this study contribute to the understanding of clinical polymorphism and genetic heterogeneity of the disease, highlighting the importance of a comprehensive approach to genetic diagnostics in atypical cases.

Введение. Синдром Криглера–Найяра характеризуется генетически детерминированным нарушением трансформации фракций билирубина в гепатоцитах вследствие недостаточного (II тип) либо полного (I тип) отсутствия фермента уридиндифосфатглюкуронидазы-1. Синдром имеет вариабельную экспрессивность, а степень снижения активности фермента и клинические проявления варьируют у пациентов, при нарастании неконъюгированной гипербилирубинемии в крови отмечается желтуха с формированием билирубиновой энцефалопатии. Диагноз подтверждается при обнаружении мутаций на обеих копиях гена UGT1A1. Привлекательным терапевтическим подходом становится генная терапия синдрома Криглера–Найяра II типа, которая позволит заменить трансплантацию печени на альтернативную технологию лечения. Данная тактика поможет больным улучшить позитивный прогноз на качество и продолжительность их жизни. Цель исследования — представить наблюдение редкого в практике врача-педиатра синдрома Криглера–Найяра II типа, особенности диагностики и перспективы внедрения новой технологии лечения. Основные положения. В статье описан клинический случай дебюта синдрома Криглера–Найяра II типа в периоде новорожденности у девочки из двойни. Представлены этапы диагностического поиска, проведен анализ результатов молекулярно-генетического обследования. Изложены сложности ведения ребенка на участке из-за недостаточной эффективности существующего симптоматического протокола лечения, перспективы применения современных генно-инженерных лечебных технологий. Заклю­чение. Диагноз «синдром Криглера–Найяра II типа» установлен после проведения молекулярно-генетического исследования. Тактика курации пациента участковым педиатром и врачами узких специальностей требует разработки единых протоколов наблюдения и патогенетического лечения, улучшающих качество жизни. Introduction. Crigler–Najjar syndrome is characterized by a genetically determined disorder of transformation of bilirubin fractions in hepatocytes due to insufficient (type II) or complete (type I) absence of the enzyme uridine diphosphate glucuronidase-1. The syndrome has variable expressivity, and the degree of decrease in enzyme activity and clinical manifestations vary among patients; with an increase in unconjugated hyperbilirubinemia in the blood, jaundice is observed with the formation of bilirubin encephalopathy. The diagnosis is confirmed by detecting mutations in both copies of the UGT1A1 gene. Gene therapy for Crigler–Najjar syndrome type II is emerging as an attractive therapeutic approach, allowing patients to replace liver transplantation with an alternative treatment option. This tactic will help patients improve their prognosis for the quality and length of their lives. The aim of the study is to present a case report of type II Crigler–Najjar syndrome, rarely encountered in pediatric practice, diagnostic features and potential for implementing new therapeutic technologies. Basic provisions. The article describes a clinical case of type II Crigler–Najjar syndrome manifesting in the neonatal period in one of a pair of twins. The stages of the diagnostic work-up are outlined, and the results of molecular genetic testing are analyzed. The challenges of managing the child in outpatient settings due to the limited effectiveness of the current symptomatic treatment protocol are discussed, along with the prospects for applying modern genetically engineered therapeutic technologies. Conclusion. The diagnosis of Crigler–Najjar syndrome type II was established after conducting a molecular genetic study. The tactics of patient supervision by a district pediatrician and doctors of narrow specialties require the development of unified protocols for monitoring and pathogenetic treatment that improve the quality of life of children.