Higher levels of plasma Adrenocorticotropic hormone (ACTH) are associated with lower suicidal ideation in depressed patients compared to controls and suicide attempters, independently from depression severity.

Introduction: Suicidal ideation, an important risk factor for suicide attempts, has an unclear neurobiological basis and is potentially linked to the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and immune-inflammatory systems. While inflammatory markers have been associated with suicide attempts and, to a lower extent suicidal ideation, the data on the role of a stress-response system is less robust, with most studies carried out with cortisol showing inconsistent results. The present study extends on the previous studies implicating stress-response and immune-inflammatory systems in suicidal thoughts and behaviours, focusing on the associations of several stress-response (adrenocorticotropic hormone (ACTH), cortisol, and dehydroepiandrosterone (DHEA)) and immune-inflammatory (C-reactive protein (CRP),interle ukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha)) with suicidal ideation severity in recent suicide attempters, patients with major depressive disorder, and non-psychiatric controls. Methods: This observational study included 156 adults from three Vilnius hospitals, recruited into one of the three groups in equal parts: recent suicide attempters, patients with major depressive disorder in current depressive episode, and non-psychiatric controls. Measures included the Hamilton Depression Rating Scale (HDRS-17) and the Beck Scale for Suicide Ideation/Suicide Severity Index (BSS/SSI), alongside sociodemographic data, alcohol, tobacco use, and morning blood samples, measuring plasma ACTH, cortisol, DHEA, CRP, and IL-6. Data were analysed with non-parametric tests, Kendall's tau correlation, and multivariate linear regression adjusted for confounders. Results: We found a negative correlation between the plasma ACTH levels and suicidal ideation severity (tau = -0.130, p = 0.033), which was driven by the patients with major depressive disorder (tau = -0.237, p = 0.031). Suicidal ideation severity was also negatively correlated with TNF-alpha (tau = -0.231; p < 0.001), positively correlated with IL-6 (tau = 0.154, p = 0.015), and CRP levels (tau = 0.153, p = 0.015), but no differences were observed in group-stratified analyses. The association between plasma ACTH levels and suicidal ideation severity in patients with major depressive disorder remained robust to adjustment for major confounders (adjusted for age, sex, education years, body mass index, smoking status, plasma CRP and PEth concentration (measuring chronic alcohol exposure), and antidepressant use) in the linear regression model (t = -2.71, p = 0.011), as well as additionally adjusting for depression severity (t = -2.99, p = 0.006). Discussion: The present study shows an association between plasma ACTH levels and suicidal ideation severity in patients with major depressive disorder, robust to adjustment for antidepressant use and depression severity. This finding highlights the potential role of ACTH, in elucidating the effects of stress and mental health disorders. Our findings underscore the importance of the HPA axis in the diagnosis and treatment of suicidal ideation in major depressive disorder and invite further research on interventions targeting this pathway.

Putative protective genomic variation in the Lithuanian population.

Genomic effect variants associated with survival and protection against complex diseases vary between populations due to microevolutionary processes. The aim of this study was to analyse diversity and distribution of effect variants in a context of potential positive selection. In total, 475 individuals of Lithuanian origin were genotyped using high-throughput scanning and/or sequencing technologies. Allele frequency analysis for the pre-selected effect variants was performed using the catalogue of single nucleotide polymorphisms. Comparison of the pre-selected effect variants with variants in primate species was carried out to ascertain which allele was derived and potentially of protective nature. Recent positive selection analysis was performed to verify this protective effect. Four variants having significantly different frequencies compared to European populations were identified while two other variants reached borderline significance. Effect variant in SLC30A8 gene may potentially protect against type 2 diabetes. The existing paradox of high rates of type 2 diabetes in the Lithuanian population and the relatively high frequencies of potentially protective genome variants against it indicate a lack of knowledge about the interactions between environmental factors, regulatory regions, and other genome variation. Identification of effect variants is a step towards better understanding of the microevolutionary processes, etiopathogenetic mechanisms, and personalised medicine.

Wide diagnostic and genotypic spectrum in patients with suspected mitochondrial disease.

BACKGROUND: Mitochondrial Diseases (MDs) are a diverse group of neurometabolic disorders characterized by impaired mitochondrial oxidative phosphorylation and caused by pathogenic variants in more than 400 genes. The implementation of next-generation sequencing (NGS) technologies helps to increase the understanding of molecular basis and diagnostic yield of these conditions. The purpose of the study was to investigate diagnostic and genotypic spectrum in patients with suspected MD. The comprehensive analysis of mtDNA variants using Sanger sequencing was performed in the group of 83 unrelated individuals with clinically suspected mitochondrial disease. Additionally, targeted next generation sequencing or whole exome sequencing (WES) was performed for 30 patients of the study group. RESULTS: The overall diagnostic rate was 21.7% for the patients with suspected MD, increasing to 36.7% in the group of patients where NGS methods were applied. Mitochondrial disease was confirmed in 11 patients (13.3%), including few classical mitochondrial syndromes (MELAS, MERRF, Leigh and Kearns-Sayre syndrome) caused by pathogenic mtDNA variants (8.4%) and MDs caused by pathogenic variants in five nDNA genes. Other neuromuscular diseases caused by pathogenic variants in seven nDNA genes, were confirmed in seven patients (23.3%). CONCLUSION: The wide spectrum of identified rare mitochondrial or neurodevelopmental diseases proves that MD suspected patients would mostly benefit from an extensive genetic profiling allowing rapid diagnostics and improving the care of these patients.

Implementing Core Genes and an Omnigenic Model for Behaviour Traits Prediction in Genomics.

A high number of genome variants are associated with complex traits, mainly due to genome-wide association studies (GWAS). Using polygenic risk scores (PRSs) is a widely accepted method for calculating an individual's complex trait prognosis using such data. Unlike monogenic traits, the practical implementation of complex traits by applying this method still falls behind. Calculating PRSs from all GWAS data has limited practical usability in behaviour traits due to statistical noise and the small effect size from a high number of genome variants involved. From a behaviour traits perspective, complex traits are explored using the concept of core genes from an omnigenic model, aiming to employ a simplified calculation version. Simplification may reduce the accuracy compared to a complete PRS encompassing all trait-associated variants. Integrating genome data with datasets from various disciplines, such as IT and psychology, could lead to better complex trait prediction. This review elucidates the significance of clear biological pathways in understanding behaviour traits. Specifically, it highlights the essential role of genes related to hormones, enzymes, and neurotransmitters as robust core genes in shaping these traits. Significant variations in core genes are prominently observed in behaviour traits such as stress response, impulsivity, and substance use.

Molecular and Functional Characterisation of a Novel Intragenic 12q24.21 Deletion Resulting in MED13L Haploinsufficiency Syndrome.

Background and Objectives: Heterozygous pathogenic variants in the MED13L gene cause impaired intellectual development and distinctive facial features with or without cardiac defects (MIM #616789). This complex neurodevelopmental disorder is characterised by various phenotypic features, including plagiocephaly, strabismus, clubfoot, poor speech, and developmental delay. The aim of this study was to evaluate the clinical significance and consequences of a novel heterozygous intragenic MED13L deletion in a proband with clinical features of a MED13L-related disorder through extensive clinical, molecular, and functional characterisation. Materials and Methods: Combined comparative genomic hybridisation and single-nucleotide polymorphism array (SNP-CGH) was used to identify the changes in the proband's gDNA sequence (DECIPHER #430183). Intragenic MED13L deletion was specified via quantitative polymerase chain reaction (qPCR) and Sanger sequencing of the proband's cDNA sample. Western blot and bioinformatics analyses were used to investigate the consequences of this copy number variant (CNV) at the protein level. CRISPR-Cas9 technology was used for a MED13L-gene-silencing experiment in a culture of the control individual's skin fibroblasts. After the MED13L-gene-editing experiment, subsequent functional fibroblast culture analyses were performed. Results: The analysis of the proband's cDNA sample allowed for specifying the regions of the breakpoints and identifying the heterozygous deletion that spanned exons 3 to 10 of MED13L, which has not been reported previously. In silico, the deletion was predicted to result in a truncated protein NP_056150.1:p.(Val104Glyfs*5), partly altering the Med13_N domain and losing the MedPIWI and Med13_C domains. After MED13L gene editing was performed, reduced cell viability; an accelerated aging process; and inhibition of the RB1, E2F1, and CCNC gene expression were found to exist. Conclusions: Based on these findings, heterozygous intragenic 12q24.21 deletion in the affected individual resulted in MED13L haploinsufficiency due to the premature termination of protein translation, therefore leading to MED13L haploinsufficiency syndrome.

Psychological distress 35 years after the Chornobyl accident in the Lithuanian clean-up workers.

The adverse effects on the health of the Chornobyl nuclear power plant accident clean-up workers have been reported previously. However, there is a lack of studies on the mental health of Chornobyl clean-up workers. The current study explored psychological distress in a sample of Lithuanian clean-up workers 35 years after the accident. In total, 107 Lithuanian Chornobyl clean-up workers (Mage = 62.5) and 107 controls were included in the study. The Hospital Anxiety and Depression Scale (HAD) was used for the assessment of anxiety and depression. The depression symptoms were significantly higher in the clean-up workers compared to the control group. The prevalence of severe depression symptoms was 23.4% and 4.7% in the Chornobyl clean-up workers and control groups, respectively. The risk for severe depression was associated with Chornobyl clean-up work (adjusted OR = 5.9). No differences in the anxiety symptoms were found between clean-up workers and controls. The study revealed the deteriorated mental health of the Lithuanian Chornobyl clean-up workers 35 years after the disaster - in particular, high levels of depression. Psychosocial support programmes for clean-up workers should be provided to mitigate the adverse effects of the disaster.

Identifying Genomic Signatures of Positive Selection to Predict Protective Genomic Loci in the Cohort of Lithuanian Clean-Up Workers of the Chornobyl Nuclear Disaster.

Some people resist or recover from health challenges better than others. We studied Lithuanian clean-up workers of the Chornobyl nuclear disaster (LCWC) who worked in the harshest conditions and, despite high ionising radiation doses as well as other factors, continue ageing relatively healthily. Thus, we hypothesised that there might be individual features encoded by the genome which act protectively for better adaptiveness and health that depend on unique positive selection signatures. Whole-genome sequencing was performed for 40 LCWC and a control group composed of 25 men from the general Lithuanian population (LTU). Selective sweep analysis was performed to identify genomic regions which may be under recent positive selection and determine better adaptiveness. Twenty-two autosomal loci with the highest positive selection signature values were identified. Most important, unique loci under positive selection have been identified in the genomes of the LCWC, which may influence the survival and adaptive qualities to extreme conditions, and the disaster itself. Characterising these loci provide a better understanding of the interaction between ongoing microevolutionary processes, multifactorial traits, and diseases. Studying unique groups of disease-resistant individuals could help create new insights for better, more individualised, disease diagnostics and prevention strategies.

Significantly elevated phosphatidylethanol levels in recent suicide attempters, but not in depressed controls and healthy volunteers.

INTRODUCTION: Suicide is a complex transdiagnostic phenomenon. It is strongly associated with, but not exclusive to major depressive disorder (MDD). Hazardous alcohol drinking has also been linked to an increased risk of suicidal behaviours, however, it is often underreported. The study aimed to evaluate whether an objective measure of chronic alcohol use, phosphatidylethanol (PEth) could be useful as a biomarker in clinical practice. METHOD: ology. The present case-control multi-centric study recruited 156 participants into three study groups: 52 patients treated for major depressive disorder (MDD), 51 individuals immediately following a suicide attempt (SA), and 53 volunteers. Sociodemographic data, medical history, and laboratory data, including PEth concentrations and C-reactive protein levels, were collected from study participants. RESULTS: PEth concentrations were the highest in suicide attempters (232,54 ± 394,01 ng/ml), followed by patients with MDD (58,39 ± 135,82 ng/ml), and the control group (24,45 ± 70,83 ng/ml) (Kruskall Wallis χ2 = 12.23, df = 2, p = .002). In a multinomial logistic regression model with adjustments, PEth concentration was able to predict belonging to suicide attempters' group, but not to depression group (p = .01). Suicide attempters were also more likely to underreport their recent alcohol consumption. LIMITATIONS: We did not analyze SA methods, psychiatric comorbidity and several other factors that might be associated with PEth levels, such as body mass index, race, and haemoglobin levels. Sample recruited in hospital settings may not be representative of the whole population. The results of this adult-only study cannot be generalized to adolescents. CONCLUSIONS: PEth levels in recent suicide attempters significantly exceeded those of patients with MDD and controls. Suicide attempters also were more likely to underreport their alcohol consumption when questioned about their consuption. PEth might be an interesting biomarker to evaluate individuals at risk of SA.

Kearns-Sayre syndrome case. Novel 5,9 kb mtDNA deletion.

BACKGROUND: Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder characterized by onset before 20 years of age and a typical clinical triad: progressive external ophthalmoplegia, pigmentary retinopathy and cardiac conduction anomalies. In most cases KSS is caused by spontaneous heteroplasmic single large-scale mitochondrial DNA (mtDNA) deletions. Long-range polymerase chain reaction (LR-PCR), next generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) are the most widely applied methods for the identification of mtDNA deletions. Here, we report the case of 20-year-old male who presented with classic Kearns-Sayre syndrome, confirmed by novel 5,9 kb mtDNA deletion. METHODS AND RESULTS: LR-PCR and MLPA methods were applied to identify the mitochondrial DNA deletion for the patient, but the results were conflicting. Molecular analysis using primer walking and Sanger sequencing identified a novel 5888 base pairs mtDNA deletion (NC_012920.1:m.6069_11956del) with CAAC nucleotides repeat sequence at the breakpoints. CONCLUSION: Our study enriched the mtDNA variation spectrum associated with KSS and demonstrated the importance of choosing relevant molecular genetic methods.

HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling.

BACKGROUND: Recessive loss-of-function variations in HINT1 cause a peculiar subtype of Charcot-Marie-Tooth disease: neuromyotonia and axonal neuropathy (NMAN; OMIM[#137200]). With 25 causal variants identified worldwide, HINT1 mutations are among the most common causes of recessive neuropathy. The majority of patients are compound heterozygous or homozygous for a Slavic founder variant (c.110G>C, p.Arg37Pro) that has spread throughout Eurasia and America. RESULTS: In a cohort of 46 genetically unresolved Lithuanian patients with suspected inherited neuropathy, we identified eight families with HINT1 biallelic variations. Most patients displayed sensorimotor or motor-predominant axonal polyneuropathy and were homozygous for the p.Arg37Pro variant. However, in three families we identified a novel variant (c.299A>G, p.Glu100Gly). The same variant was also found in an American patient with distal hereditary motor neuropathy in compound heterozygous state (p.Arg37Pro/p.Glu100Gly). Haplotype analysis demonstrated a shared chromosomal region of 1.9 Mb between all p.Glu100Gly carriers, suggesting a founder effect. Functional characterization showed that the p.Glu100Gly variant renders a catalytically active enzyme, yet highly unstable in patient cells, thus supporting a loss-of-function mechanism. CONCLUSION: Our findings broaden NMAN's genetic epidemiology and have implications for the molecular diagnostics of inherited neuropathies in the Baltic region and beyond. Moreover, we provide mechanistic insights allowing patient stratification for future treatment strategies.

Diagnostic Significance of FNAB miRNA Expression in Papillary Thyroid Carcinoma.

The aim of the study was to evaluate the diagnostic utility of specific miRNAs in the preoperative assessment of thyroid nodules. One hundred and sixty thyroid fine needle aspiration biopsy (FNAB) samples with suspected thyroid carcinoma were collected. To detect the levels of miRNA expression in FNAB, next generation small RNA sequencing was performed in 60 samples. Based on the results obtained, three miRNAs (miR125A, miR200B, miR4324) were selected for further analysis. Based on the most frequently reported miRNAs in the literature associated with thyroid papillary carcinoma (PTC), two more miRNA (miR146B, miR221) were selected for further validation, using real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 36 benign and 64 PTC samples. Expression of miR125A, miR146B, miR221, and miR4324 was significantly higher in patients with PTC compared with benign thyroid nodules (p ˂ 0.05). miR125A and miR4324 were also significantly more highly expressed in patients with extrathyroidal tumor extension compared to those without extrathyroidal PTC extension (p < 0.001). We also found a significantly higher expression of miR221 (p = 0.043) in patients with multifocal carcinomas compared to patients with single foci carcinomas. This prospective study showed that the expression analysis of four miRNAs (miR125A, miR146B, miR221, and miR4324) improve accuracy of FNAB, which could allow a better pre-operative diagnostic and prognostic assessment of thyroid malignancies.

Donor Splice Site Variant in SLC9A6 Causes Christianson Syndrome in a Lithuanian Family: A Case Report.

Background and Objectives: The pathogenic variants of SLC9A6 are a known cause of a rare, X-linked neurological disorder called Christianson syndrome (CS). The main characteristics of CS are developmental delay, intellectual disability, and neurological findings. This study investigated the genetic basis and explored the molecular changes that led to CS in two male siblings presenting with intellectual disability, epilepsy, behavioural problems, gastrointestinal dysfunction, poor height, and weight gain. Materials and Methods: Next-generation sequencing of a tetrad was applied to identify the DNA changes and Sanger sequencing of proband's cDNA was used to evaluate the impact of a splice site variant on mRNA structure. Bioinformatical tools were used to investigate SLC9A6 protein structure changes. Results: Sequencing and bioinformatical analysis revealed a novel donor splice site variant (NC_000023.11(NM_001042537.1):c.899 + 1G > A) that leads to a frameshift and a premature stop codon. Protein structure modelling showed that the truncated protein is unlikely to form any functionally relevant SLC9A6 dimers. Conclusions: Molecular and bioinformatical analysis revealed the impact of a novel donor splice site variant in the SLC9A6 gene that leads to truncated and functionally disrupted protein causing the phenotype of CS in the affected individuals.

CyberGenomics: Application of Behavioral Genetics in Cybersecurity.

Cybersecurity (CS) is a contemporary field for research and applied study of a range of aspects from across multiple disciplines. A cybersecurity expert has an in-depth knowledge of technology but is often also recognized for the ability to view technology in a non-standard way. This paper explores how CS specialists are both a combination of professional computing-based skills and genetically encoded traits. Almost every human behavioral trait is a result of many genome variants in action altogether with environmental factors. The review focuses on contextualizing the behavior genetics aspects in the application of cybersecurity. It reconsiders methods that help to identify aspects of human behavior from the genetic information. And stress is an illustrative factor to start the discussion within the community on what methodology should be used in an ethical way to approach those questions. CS positions are considered stressful due to the complexity of the domain and the social impact it can have in cases of failure. An individual risk profile could be created combining known genome variants linked to a trait of particular behavior using a special biostatistical approach such as a polygenic score. These revised advancements bring challenging possibilities in the applications of human behavior genetics and CS.

Possible Protective Effect of LOXL1 Variant in the Cohort of Chernobyl Catastrophe Clean-Up Workers.

Ionising radiation (IR) is an environmental factor known to alter genomes and therefore challenge organisms to adapt. Lithuanian clean-up workers of the Chernobyl nuclear disaster (LCWC) experienced high doses of IR, leading to different consequences. This study aims to characterise a unique protective genomic variation in a relatively healthy LCWC group. This variation influenced their individual reaction to IR and potentially protects against certain diseases such as exfoliation syndrome and glaucoma. Clinical and IR dosage data were collected using a questionnaire to characterise the cohort of 93 LCWC. Genome-wide genotyping using Illumina beadchip technology was performed. The control group included 466 unrelated, self-reported healthy individuals of Lithuanian descent. Genotypes were filtered out from the microarray dataset using a catalogue of SNPs. The data were used to perform association, linkage disequilibrium, and epistasis analysis. Phenotype data analysis showed the distribution of the most common disease groups among the LCWC. A genomic variant of statistical significance (Fishers' exact test, p = 0.019), rs3825942, was identified in LOXL1 (NM_005576.4:c.458G>A). Linkage disequilibrium and epistasis analysis for this variant identified the genes LHFPL3, GALNT6, PIH1D1, ANKS1B, and METRNL as potentially involved in the etiopathogenesis of exfoliation syndrome and glaucoma, which were not previously associated with the disease. The LOXL1 variant is mostly considered a risk factor in the development of exfoliation syndrome and glaucoma. The influence of recent positive selection, the phenomenon of allele-flipping, and the fact that only individuals with the homozygous reference allele have glaucoma in the cohort of the LCWC suggest otherwise. The identification of rs3825942 and other potentially protective genomic variants may be useful for further analysis of the genetic architecture and etiopathogenetic mechanisms of other multifactorial diseases.

Association study of taste preference: Analysis in the Lithuanian population.

Taste has strong evolutionary basis in the sense of survival by influencing our behavior to obtain food/medicine or avoid poisoning. It is a complex trait and varies among individuals and distinct populations. We aimed to investigate the association between known genetic factors (673 SNPs) and taste preference in the Lithuanian population, as well as to determine a reasonable method for qualitative evaluation of a specific taste phenotype for further genetic analysis. Study group included individuals representing six ethnolinguistic regions of Lithuania. Case and control groups for each taste were determined according to the answers selected to the taste-specific and frequency of specific food consumption questions. Sample sizes (case/control) for each taste are as follows: sweetness (55/179), bitterness (82/208), sourness (32/259), saltiness (42/249), and umami (96/190). Genotypes were extracted from the Illumina HumanOmniExpress-12v1.1 arrays' genotyping data. Analysis was performed using PLINK v1.9. We found associations between the main known genetic factors and four taste preferences in the Lithuanian population: sweetness-genes TAS1R3, TAS1R2, and GNAT3 (three SNPs); bitterness-genes CA6 and TAS2R38 (six SNPs); sourness-genes PKD2L1, ACCN2, PKD1L3, and ACCN1 (48 SNPs); and saltiness-genes SCNN1B and TRPV1 (five SNPs). We found our questionnaire as a beneficial aid for qualitative evaluation of taste preference. This was the first initiative to analyze genetic factors related to taste preference in the Lithuanian population. Besides, this study reproduces, supports, and complements results of previous limited taste genetic studies or ones that lack comprehensive results concerning distinct (ethnic) human populations.

CYP2C19 polymorphisms are associated with severity of depression at initial evaluation and after the treatment independently of the prescribed medications: 4 weeks prospective study.

BACKGROUND: The cytochrome P-450 2C19 (CYP2C19) enzyme is involved in the metabolism of numerous antidepressants. It also metabolises some endogenous substrates, which could also confer to vulnerability. We aimed to establish whether the severity of depression and treatment response are associated with the genetically predicted CYP2C19 phenotype. METHODS: We assessed the CYP2C19 genotype-predicted metabolic phenotypes (normal, intermediate or ultrarapid, there were no poor metabolisers) in patients with moderate or severe depression. We used the self-rated Beck Depression Inventory-II (BDI-II) scale and the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, after 2 and 4 weeks of an empirical treatment trial. Patients and clinicians were blind to the genetic testing results. RESULTS: Seventy-six patients participated in the present study. At baseline, impaired CYP2C19 metabolisers, compared to normal metabolisers, had higher BDI-II (P = 0.046; ηp2 = 0.08) but not MADRS score. Intermediate metabolisers more often had a diagnosis of severe depression than normal metabolisers (P = 0.003). After 4 weeks of empirical treatment, intermediate metabolisers had significantly higher MADRS and BDI-II scores than normal metabolisers (P = 0.006; ηp2 = 0.131 and P = 0.030; ηp2 = 0.091). These differences were independent of the use of CYP2C19-metabolised medications in the treatment trial, as well as the treatment discrepancy status. CONCLUSIONS: Intermediate CYP2C19 polymorphism-predicted activity was associated with more severe depression after an empirical treatment trial. The lack of association between the prescription of CYP2C19-metabolised drugs and treatment response calls for a further look into the role of endogenous substrates of CYP2C19.

Dysregulation of microRNAs as the risk factor of lymph node metastasis in papillary thyroid carcinoma: systematic review.

Papillary thyroid carcinoma (PTC) has an excellent prognosis with a relatively low mortality rate, but a small portion of PTC patients suffer from an aggressive form of the disease. In such cases early detection of lymph node metastasis (LNM) is as paramount as it is problematic. The routine use of central neck lymph node dissection is not recommended. New methods to detect LNM are needed. MicroRNAs are a potential biomarker for diagnosis and prognosis of PTC. In this review we summarise the current knowledge regarding dysregulated miRNAs and their association with LNM in PTS patients. The PubMed and EBSCO databases were searched using terms for "microRNA", "thyroid carcinoma", and "prognosis" by using Boolean operators. Based on eligibility and exclusion criteria, articles were screened and reviewed in full, methodological data of included studies were extracted, and risk of bias analysis performed. In total, 446 unique studies were extracted from the mentioned databases, and based on inclusion and exclusion criteria 27 studies were included in this review. Of them 17 analysed tissue microRNAs, 5 analysed circulating microRNAs, and 5 studies analysed both tissue and circulating samples. MiRNA-146B, miRNA-221, miRNA-222, miRNA-21, miRNA-204, miRNA-451, miRNA-199a-3p, and miRNA-30a-3p were dysregulated in at least 2 separate studies. A sizable portion of studies failed to show statistically significant differences in miRNA expression between LNM-positive and -negative patients. Different methodologies and disparities of patient populations could explain these discrepancies.\ This research supports the statement that specific up- and downregulated miRNAs are associated with LNM in PTC patients. However, the prognostic value of these miRNAs is limited. Additional targeted cohort studies are required to elucidate the role of miRNAs in defining individualised treatment strategies for thyroid cancer patients.

One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver-Russell syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented. MAIN BODY: We analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS. CONCLUSIONS: WES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

HMGA2 Variants in Silver-Russell Syndrome: Homozygous and Heterozygous Occurrence.

CONTEXT: Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about one-half of patients currently remain without a molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling. OBJECTIVE: The aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and reevaluate its mode of inheritance. DESIGN, SETTING, PATIENTS: Patients were part of an ongoing study aiming on SRS-causing genes. They were classified according to the Netchine-Harbison clinical scoring system, and DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before. RESULTS: Three novel pathogenic HMGA2 variants were identified in 5 patients from 3 SRS families, and fulfilling diagnostic criteria of SRS. For the first time, homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. Treatment with recombinant growth hormone led to a catch-up growth in 1 patient, whereas all others did not receive growth hormone and stayed small. One patient developed type 2 diabetes at age 30 years. CONCLUSIONS: Identification of novel pathogenic variants confirms HMGA2 as an SRS-causing gene; thus, HMGA2 testing should be implemented in molecular SRS diagnostic workup. Furthermore, inheritance of HMGA2 is variable depending on the severity of the variant and its consequence for protein function.

A de novo 13q31.3 microduplication encompassing the miR-17 ~ 92 cluster results in features mirroring those associated with Feingold syndrome 2.

Hemizygosity of the MIR17HG gene encoding the miR-17 ~ 92 cluster is associated with Feingold syndrome 2 characterized by intellectual disability, skeletal abnormalities, short stature, and microcephaly. Here, we report on a female with a de novo 13q31.3 microduplication encompassing MIR17HG but excluding GPC5. She presented developmental delay, skeletal and digital abnormalities, and features such as tall stature and macrocephaly mirroring those of Feingold syndrome 2 patients. The limited extent of the proband's rearrangement to the miR cluster and the corresponding normal expression level of the neighboring GPC5 in her cells, together with previously described data on affected individuals of two families carrying overlapping duplications of the miR-17 ~ 92 cluster that comprise part of GPC5, who likewise presented macrocephaly, developmental delay, as well as skeletal, digital and stature abnormalities, allow to define a new syndrome due to independent microduplication of the miR-17 ~ 92 cluster.