Age-dependent ferritin elevations and HFE C282Y mutation as risk factors for symptomatic knee osteoarthritis in males: a longitudinal cohort study

Background

The Close Kinetic Chain Upper Extremity Stability Test (CKCUES test) is a low cost shoulder functional test that could be considered as a complementary and objective clinical outcome for shoulder performance evaluation. However, its reliability was tested only in recreational athletes’ males and there are no studies comparing scores between sedentary and active samples. The purpose was to examine inter and intrasession reliability of CKCUES Test for samples of sedentary male and female with (SIS), for samples of sedentary healthy male and female, and for male and female samples of healthy upper extremity sport specific recreational athletes. Other purpose was to compare scores within sedentary and within recreational athletes samples of same gender.

Methods

A sample of 108 subjects with and without SIS was recruited. Subjects were tested twice, seven days apart. Each subject performed four test repetitions, with 45 seconds of rest between them. The last three repetitions were averaged and used to statistical analysis. Intraclass Correlation Coefficient ICC_2,1 was used to assess intrasession reliability of number of touches score and ICC_2,3 was used to assess intersession reliability of number of touches, normalized score, and power score. Test scores within groups of same gender also were compared. Measurement error was determined by calculating the Standard Error of the Measurement (SEM) and Minimum detectable change (MDC) for all scores.

Results

The CKCUES Test showed excellent intersession reliability for scores in all samples. Results also showed excellent intrasession reliability of number of touches for all samples. Scores were greater in active compared to sedentary, with exception of power score. All scores were greater in active compared to sedentary and SIS males and females. SEM ranged from 1.45 to 2.76 touches (based on a 95% CI) and MDC ranged from 2.05 to 3.91(based on a 95% CI) in subjects with and without SIS. At least three touches are needed to be considered a real improvement on CKCUES Test scores.

Conclusion

Results suggest CKCUES Test is a reliable tool to evaluate upper extremity functional performance for sedentary, for upper extremity sport specific recreational, and for sedentary males and females with SIS.     

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

Improving the accuracy of variant interpretation during diagnostic sequencing is a major goal for genomic medicine. To explore an often‐overlooked splicing effect of missense variants, we developed the functional assay (“minigene”) for the majority of exons of CAPN3, the gene responsible for limb girdle muscular dystrophy. By systematically screening 21 missense variants distributed along the gene, we found that eight clinically relevant missense variants located at a certain distance from the exon–intron borders (deep exonic missense variants) disrupted normal splicing of CAPN3 exons. Several recent machine learning‐based computational tools failed to predict splicing impact for the majority of these deep exonic missense variants, highlighting the importance of including variants of this type in the training sets during the future algorithm development. Overall, 24 variants in CAPN3 gene were explored, leading to the change in the American College of Medical Genetics and Genomics classification of seven of them when results of the “minigene” functional assay were considered. Our findings reveal previously unknown splicing impact of several clinically important variants in CAPN3 and draw attention to the existence of deep exonic variants with a disruptive effect on gene splicing that could be overlooked by the current approaches in clinical genetics.     

Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity

Primary immune deficiencies are usually attributed to genetic defects and, therefore, frequently referred to as inborn errors of immunity (IEI). We subjected the genomic DNA of 333 patients with clinical signs of IEI to next generation sequencing (NGS) analysis of 344 immunity-related genes and, in some instances, additional genetic techniques. Genetic causes of the disease were identified in 69/333 (21%) of subjects, including 11/18 (61%) of children with syndrome-associated IEIs, 45/202 (22%) of nonsyndromic patients with Jeffrey Modell Foundation (JMF) warning signs, 9/56 (16%) of subjects with periodic fever, 3/30 (10%) of cases of autoimmune cytopenia, 1/21 (5%) of patients with unusually severe infections and 0/6 (0%) of individuals with isolated elevation of IgE level. There were unusual clinical observations: twins with severe immunodeficiency carried a de novo CHARGE syndrome-associated SEMA3E c.2108C>T (p.S703L) allele; however, they lacked clinical features of CHARGE syndrome. Additionally, there were genetically proven instances of Netherton syndrome, Х-linked agammaglobulinemia, severe combined immune deficiency (SCID), IPEX and APECED syndromes, among others. Some patients carried recurrent pathogenic alleles, such as AIRE c.769C>T (p.R257*), NBN c.657del5, DCLRE1C c.103C>G (p.H35D), NLRP12 c.1054C>T (p.R352C) and c.910C>T (p.H304Y). NGS is a powerful tool for high-throughput examination of patients with malfunction of immunity.     

Copy number alterations involving 59 ACMG-recommended secondary findings genes

In clinical exome/genome sequencing, the American College of Medical Genetics and Genomics (ACMG) recommends reporting of secondary findings unrelated to a patient's phenotype when pathogenic single-nucleotide variants (SNVs) are observed in one of 59 genes associated with a life-threatening, medically actionable condition. Little is known about the incidence and sensitivity of chromosomal microarray analysis (CMA) for detection of pathogenic copy number variants (CNVs) comprising medically-actionable genes. Clinical CMA has been performed on 8865 individuals referred for molecular cytogenetic testing. We retrospectively reviewed the CMA results to identify patients with CNVs comprising genes included in the 59-ACMG list of secondary findings. We evaluated the clinical significance of these CNVs in respect to pathogenicity, phenotypic manifestations, and heritability. We identified 23 patients (0.26%) with relevant CNV either deletions comprising the entire gene or intragenic alterations involving one or more secondary findings genes. A number of patients and/or their family members with pathogenic CNVs manifest or expected to develop an anticipated clinical phenotype and would benefit from preventive management similar to the patients with pathogenic SNVs. To improve patients' care standardization should apply to reporting of both sequencing and CNVs obtained via clinical genome-wide analysis, including chromosomal microarray and exome/genome sequencing.     

'Lethal' combination of Mycobacterium tuberculosis Beijing genotype and human CD209 -336G allele in Russian male population

An interaction of different human alleles and endemic bacterial strains may be clinically manifested as different outcome of the disease in different hosts infected with the same genotype. The primary objective of this study was to investigate this issue in the model of Mycobacterium tuberculosis and human DC-SIGN encoding CD209 promoter SNP (rs4804803) in Russian Siberian population. We sought to find a possible combination of M. tuberculosis lineage and human host allele/genotype correlating with unfavorable outcome of the disease. The 101 paired DNA samples from patients with pulmonary TB (human and M. tuberculosis DNA) were studied by 12-loci MIRU-VNTR typing (M. tuberculosis strains) and CD209 -336 A/G typing (human DNA). Ninety autopsy DNA samples as a source of human and mycobacterial nucleic acids from persons who died from TB were also subjected to the same genotyping procedures. A human control group consisted of 177 healthy individuals. The Beijing genotype was more frequently identified in autopsy versus patient samples, in 70.0% and 51.5%, respectively (χ(2)=6.06, P=0.01). Regarding other M. tuberculosis genetic families, no significant difference in LAM family distribution among patient strains and autopsy samples has been found. In contrast, Ural genotype was significantly less frequently detected in the autopsy samples (χ(2)=6.12, P=0.01). Allelic and genotypic frequencies of the CD209 -336A/G did not differ significantly under global comparison when contrasting controls versus patients versus autopsy samples. However intriguing and contrasting significant associations were found in the male subgroup under M. tuberculosis genotype-stratified comparisons. Firstly, male carriers of -336AA genotype were more frequently infected with Beijing genotype (χ(2)=5.2, P=0.02). Secondly and remarkably, this association was inverted in the autopsy sample: male carriers of -336AA genotype died less frequently due to TB caused by a Beijing rather than a non-Beijing strain (χ(2)=5.37, P=0.02). In conclusion, we hypothesize that although carriers of CD209 -336A allele are more sensitive to infection with a Beijing strain, a combination of human CD209 -336G allele and M. tuberculosis Beijing genotype leads more frequently to the lethal outcome in pulmonary TB male patients in Russian (Caucasian) population.     

Defining genetic risk factors for scleroderma-associated interstitial lung disease

Clinical Rheumatology - Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease...     

Food addiction and symptoms of depression among inhabitants of the European North of Russia: Associations with sleep characteristics and photoperiod

The purpose of this investigation was to study the sleep‐wake rhythm characteristics of young persons with food addiction (FA) and symptoms of depression. A total of 2,360 young persons living in northern European Russia were included in the study. The average age of the respondents (± standard deviation [SD]) was 17.9 [4.6] years (66.6% female). Each participant provided personal data and filled in three questionnaires: the Munich Chronotype Questionnaire, the Zung Self‐Rating Depression Scale, and the Yale Food Addiction Scale. FA was detected in 8.9% of respondents, and moderate‐to‐severe symptoms of depression were detected in 16.7% of respondents. FA and depressive symptoms were more often detected in females. Age and body mass index were shown to be significantly associated with FA. There were positive associations between the time of sunrise and FA and depressive symptoms. Persons who had symptoms of depression also tended to have a later chronotype, lower sleep efficiency, later sleep onset, higher sleep inertia, and greater sleep latency on school days. A positive relationship between FA and the time of sleep onset on school days was also revealed. Thus, the results indicate that prolonged wakefulness in the evening after sunset was associated with FA.     

How intramolecular coordination bonding (ICB) controls the homolysis of the C–ON bond in alkoxyamines

Because the C–ON bond homolysis rate constant k_d is an essential parameter of alkoxyamine reactivity, it is especially important to tune k_d without a major alteration of the structure of the molecule. Recently, several approaches have become known, e.g., protonation of functional groups and formation of metal complexes. In this paper, coordination reactions of [Zn(hfac)₂(H₂O)₂] with a series of new SG1-based alkoxyamines affording complexes with different structures are presented. The k_d values of the complexed forms of the alkoxyamines were compared to those of free and protonated ones to reveal the contribution of the electron-withdrawing property and structure stabilization. Together with previously published data, this work provides clues to the design of alkoxyamines that can be effectively activated upon coordination with metal ions. Furthermore, our results provide insight into the mechanism underlying the influence of complexation on the reactivity of alkoxyamines. This led us to describe different types of coordination: intramolecular in nitroxyl fragment, intramolecular in alkyl fragment, intramolecular between alkyl and nitroxyl fragment, and intermolecular one. All of them exhibit different trends which are dramatically altered by changes in conformation.

Because the C–ON bond homolysis rate constant k_d is an essential parameter of alkoxyamine reactivity, it is especially important to tune k_d without a major alteration of the structure of the molecule.