Here, we report the pediatric cases of sitosterolemia, a rare autosomal-recessive genetic disorder, characterized by high concentrations of plant sterols in blood and heterogeneity manifestations. All three patients (two girls aged 2 and 6 years old, and one boy aged 14 years old) were initially diagnosed with hypercholesterinemia. Next-generation sequencing (NGS) revealed homozygous (p.Leu572Pro/p.Leu572Pro) and compound (p.Leu572Pro/p.Gly512Arg and p.Leu572Pro/p.Trp361*) variants in the ABCG8 gene that allowed for the diagnosis of sitosterolemia. Two patients whose blood phytosterol levels were estimated before the diet demonstrated high levels of sitosterol/campesterol (69.6/29.2 and 28.3/12.4 μmol/L, respectively). Here, we demonstrate that NGS-testing led to the proper diagnosis that is essential for patients’ management. The variant p.Leu572Pro might be prevalent among patients with sitosterolemia in Russia.

We report a case of SYNE1-associated autosomal recessive spinocerebellar ataxia (SCAR8) presenting with a complex multisystemic phenotype, including highly elevated creatine kinase levels and lower-leg muscle atrophy. In addition to identifying two novel pathogenic variants in the SYNE1 gene, whole-exome sequencing revealed three variants of uncertain significance in the DYSF gene. Electromyography and muscle magnetic resonance imaging indicated a neurogenic pattern of muscle involvement. These findings, along with the segregation analysis of the variants, allowed us to exclude DYSF-associated muscular dystrophy; however, we cannot entirely rule out the possibility that the DYSF gene variants may act as modifiers of the patient’s phenotype.

The HOXB1 gene encodes a homeobox transcription factor pivotal in the development of rhombomere 4. Biallelic pathogenic variants in this gene are associated with congenital facial paresis type 3 (HCFP3). Only seven single nucleotide variants have been reported in the literature to date. Here, we report a 27-year-old female with a unique presentation of HCFP3 with two novel compound-heterozygous missense variants: c.763C>G, p.(Arg255Gly), which arose de novo and an inherited c.781C>T, p.(Arg261Cys) variant. The patient exhibited HCFP3 symptoms with mild upward esodeviation and lacked the documented ear malformations common in HCFP. For many years, she was misdiagnosed with facio-scapulo-humeral muscular dystrophy, due to complaints of shoulder girdle and neck muscle weakness. No alternative genetic or acquired causes of neck and shoulder girdle weakness were found, suggesting its potential inclusion in the phenotypic spectrum.

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.1828CT (p.Gln610Ter), while in a patient with a new nucleotide variant c.1609CT (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.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary neuromuscular disorder. The Russian FSHD Patient Registry was established in 2019 following the development of a PCR-based method for genetic confirmation of the diagnosis. Results: The registry included 470 participants (51% male). Genetic confirmation was obtained for 76% (n=356), the remainder were included based on clinical and anamnestic data. Clinical assessment forms and patient-reported questionnaires were analyzed for 310 and 142 patients, respectively. D4Z4 repeat unit (RU) distribution showed patterns consistent with European cohorts, with a predominance of patients with 3 RUs. A moderate inverse correlation was found between RUs number and clinical severity scales. Periscapular weakness was the most common onset manifestation (46.8%), followed by facial weakness (31.6%) which was often unnoticed by patients. The mean age in the Russian cohort was 37.8 years (range 0–97), indicating a younger cohort compared to international data. A delta-adjusted cluster analysis (n=215) identified three distinct trajectories: a classic phenotype with onset before age 14 and early involvement of various muscle groups (n=177), and two clusters characterized by either facial or periscapular onset with slow progression. Conclusion: The Russian FSHD registry provides a comprehensive characterization of a large national cohort, revealing a predominance of patients with 3 D4Z4 repeats and a younger demographic profile compared to international data. Cluster analysis identified three heterogeneous disease trajectories, offering a framework for improved patient stratification.

Описан редкий случай аутосомно-доминантной спастической параплегии у женщины-пробанда 36 лет с выявленными с помощью высокопроизводительного экзомного секвенирования ранее описанными гетерозиготными мутациями двух генов самых частых форм: SPG4 (мутация p.Cys28Leufs*20 в гене SPAST) и SPG3 (мутация p.Val405Met в гене ATL1), унаследованными соответственно от больной матери и клинически здорового отца. Пробанд и 61-летняя мать, а также умерший дед имели картину «неосложненной» параплегии с началом на 4-м десятилетии. У 67-летнего отца не было даже субклинических симптомов болезни, отягощенность в его ветви семьи не прослеживалась, обнаружение отцовской мутации с низкой пенетрантностью стало неожиданным. Методы MPS наиболее информативны для выявления у больного и/или членов семьи комбинированной наследственной неврологической патологии, особенно сочетания сходных форм гетерогенных групп, таких как спастические параплегии.