X-linked juvenile retinoschisis: phenotypic and genetic characterization

Juvenile X-linked retinoschisis (XLRS, MIM#312700) belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-domain optical coherence tomography (SD-OCT) images. The mean central foveal thickness was 569.7 µm. Two patients presented with peripheral retinoschisis. Flash electroretinogram demonstrated a reduced b/a ratio (T (p.R200L) mutation was detected in one case, showing to be pathogenic in silico analysis. c. (92_97) insC (p.W33fs) mutation was identified for another patient, indicating the variant is possibly damaging in silico analysis. The third case was identified with a pathogenic mutation c.422C>G (p.R141H), HGMD CM981753. These are the first cases of XLRS in the Lithuanian population confirmed by molecular genotyping. Presented patients had a different genotype but similar phenotypic traits

Association of BMP4 polymorphisms with non-syndromic cleft lip with or without cleft palate and isolated cleft palate in Latvian and Lithuanian populations

Cleft lip with or without cleft palate (CLP and CL, respectively) and isolated cleft palate (CP) represent one of the most common human birth defects, with a prevalence of approximately 1 in 300-2500 depending on the population. Formation of non-syndromic CL/CLP and CP arises from the interaction of environmental and genetic factors. The objective of this study was to investigate the association between the BMP4 gene (encoding bone morphogenetic protein 4) and non-syndromic CL/CLP and CP in order to clarify the role of this gene in the aetiology of the malformation in Latvian and Lithuanian populations. We genotyped three markers of the BMP4 gene (rs17563, rs2071047 and rs1957860) in order to perform single marker and haplotype association analyses for Latvian and Lithuanian non-syndromic CL/CLP and CP patients and controls. Transmission disequilibrium test was also conducted for Latvian and Lithuanian proband-parent trios. The case-control analysis revealed that SNP rs2071047 allele A was associated with a decreased risk of CL/CLP in the Latvian population, which was confirmed by the haplotype analysis. A modest association was detected between SNP rs1957860 and CP in the Lithuanian population, where allele C was associated with a decreased risk of this cleft phenotype, corroborating haplotype analysis data. Our findings support a role of the BMP4 gene in the aetiology of non-syndromic CL/CLP and CP in the studied populations.publishersversionPeer reviewe

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.publishedVersio

Determination of genomic variants of the complex aetiology cleft lip and (or) palate in Lithuanian patient group

The incidence of cleft lip and (or) palate (CL/P) varies from 0.4 to 2.0 in 1000 live births across populations. More and more CL/P candidate loci are being confirmed using novel genome-wide methods of molecular genetics and tools of statistical analysis. The aim of this study was to identify the alleles of the candidate genes for cleft lip with or without cleft palate and isolated cleft palate in the Lithuanian patient group, applying the molecular genotyping of the genomic markers in 42 CL/P candidate genes and association analysis using transmission disequilibrium test approach. Using families’ studies and case – control studies approach CL/P candidate genes TIMP2, BMP2, FN1 variants were confirmed for cleft lip with or without cleft palate and COL11A1, COL11A2, COL2A1 for cleft palate only in the population of Lithuania. Estimating the association analysis results of the CL/P patients of Lithuania, Latvia and Estonia, FGF1, TIMP2 were identified as candidate genes for cleft lip with or without cleft palate and COL2A1, COL11A2 for isolated cleft palate in the North East European populations. Different genomic risk variants have influence for cleft lip with or without cleft palate and for cleft palate only, which confirms the hypothesis of different mechanisms for these two phenotypes

Genominių veiksnių įtaka daugiaveiksnės etiologijos lūpos ir (arba) gomurio nesuaugimams Lietuvos pacientų grupėje

The incidence of cleft lip and (or) palate (CL/P) varies from 0.4 to 2.0 in 1000 live births across populations. More and more CL/P candidate loci are being confirmed using novel genome-wide methods of molecular genetics and tools of statistical analysis. The aim of this study was to identify the alleles of the candidate genes for cleft lip with or without cleft palate and isolated cleft palate in the Lithuanian patient group, applying the molecular genotyping of the genomic markers in 42 CL/P candidate genes and association analysis using transmission disequilibrium test approach. Using families’ studies and case – control studies approach CL/P candidate genes TIMP2, BMP2, FN1 variants were confirmed for cleft lip with or without cleft palate and COL11A1, COL11A2, COL2A1 for cleft palate only in the population of Lithuania. Estimating the association analysis results of the CL/P patients of Lithuania, Latvia and Estonia, FGF1, TIMP2 were identified as candidate genes for cleft lip with or without cleft palate and COL2A1, COL11A2 for isolated cleft palate in the North East European populations. Different genomic risk variants have influence for cleft lip with or without cleft palate and for cleft palate only, which confirms the hypothesis of different mechanisms for these two phenotypes

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

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 con-duction anomalies. In most cases KSS is caused by spontaneous heteroplasmic single large- scale mitochondrial DNA (mtDNA) deletions. Long- range polymer-ase 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 conflict-ing. 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

Insights Into de novo Mutation Variation in Lithuanian Exome

In the last decade, one of the biggest challenges in genomics research has been to distinguish definitive pathogenic variants from all likely pathogenic variants identified by next-generation sequencing. This task is particularly complex because of our lack of knowledge regarding overall genome variation and pathogenicity of the variants. Therefore, obtaining sufficient information about genome variants in the general population is necessary as such data could be used for the interpretation of de novo mutations (DNMs) in the context of patient’s phenotype in cases of sporadic genetic disease. In this study, data from whole-exome sequencing of the general population in Lithuania were directly examined. In total, 84 (VarScan) and 95 (VarSeqTM) DNMs were identified and validated using different algorithms. Thirty-nine of these mutations were considered likely to be pathogenic based on gene function, evolutionary conservation, and mutation impact. The mutation rate estimated per position pair per generation was 2.74 × 10-8 [95% CI: 2.24 × 10-8–3.35 × 10-8] (VarScan) and 2.4 × 10-8 [95% CI: 1.96 × 10-8–2.99 × 10-8] (VarSeqTM), with 1.77 × 10-8 [95% CI: 6.03 × 10-9–5.2 × 10-8] de novo indels per position per generation. The rate of germline DNMs in the Lithuanian population and the effects of the genomic and epigenetic context on DNM formation were calculated for the first time in this study, providing a basis for further analysis of DNMs in individuals with genetic diseases. Considering these findings, additional studies in patient groups with genetic diseases with unclear etiology may facilitate our ability to distinguish certain pathogenic or adaptive DNMs from tolerated background DNMs and to reliably identify disease-causing DNMs by their properties through direct observation