Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.
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.
The Classic Ehlers–Danlos syndrome (cEDS) is an autosomal dominant hereditary disease caused by type V collagen defect. The incidence of pathology is estimated at 1:20,000 of the population. The results of a long-term (15 years) follow-up of a group of patients (n=18) with cEDS, including 5 boys and 13 girls aged from 3 to 18 years, are presented. The diagnosis was made based on the presence of 2 large and 5 small international diagnostic criteria in all patients. The progreduated character of the disease is shown, which is most obvious in the dynamics of the state of the musculoskeletal system. Genetic verification of the diagnosis was performed in 6 patients; 5 probands had mutations in the COL5A1 gene, and one in the COL5A2 gene. Mutations already registered in the database were detected only in 2 children. Previously unknown substitutions were found in 4 patients. The article presents the issues of differential diagnosis of this severe pathology and touches upon the issue of continuity between medical pediatric specialists and doctors of various specialties working with the adult population.
A description of a patient with a rare form of Camurati-Engelmann Disease (CED), also known as progressive diaphyseal dysplasia, manifested by gait disturbance, pain in the limbs and muscle weakness is presented. It is only ca. 300+ patients with this disease have been described worldwide to date. It was discovered in various ethnic groups regardless of gender. A clinical case observation of this disease with molecular genetic confirmation of the diagnosis is presented for the first time in a Russian language scientific periodical. Establishing an accurate diagnosis in the described observation became possible only thanks to the use of a modern molecular genetic method, Next-generation sequencing (NGS). The clinical case observed in the article showed non-specificity of symptoms in this disease. It would be impossible to establish an accurate diagnosis without the use of top notch, modern genetic technologies in this case. The absence of specific symptoms coupled with the late manifestation of the disease suggest that not all of the cases of this disease are detected and diagnosed.
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