Bi-allelic loss-of-function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental syndrome.

Over two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WW domain-binding protein 4 (WBP4) is part of the early spliceosomal complex and has not been previously associated with human pathologies in the Online Mendelian Inheritance in Man (OMIM) database. Through GeneMatcher, we identified ten individuals from eight families with a severe neurodevelopmental syndrome featuring variable manifestations.

The prevalence of congenital anomalies: nationwide study in 2020 in Estonia.

Objective: To assess the prevalence of congenital anomalies (CAs), chromosomal abnormalities and monogenic diseases among births and terminated pregnancies due to fetal anomalies (TOPFA) in 2020 in Estonia. Up to 2020 no data on prevalence of CAs in Estonia is reported.

Methods: For retrospective observational study data of all births and terminations of pregnancies after 12th gestational week from (i) the Estonian Medical Birth Registry, (ii) Abortion Registy, (iii) Health Insurance Fund and (iv) hospital records were linked.

DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with / variants.

Accurate diagnosis for patients living with neurodevelopmental disorders is often met with numerous challenges, related to the ambiguity of findings and lack of specificity in genetic variants leading to pathology. Genome-wide DNA methylation analysis has been used to develop highly sensitive and specific 'episignatures' as biomarkers capable of differentiating and classifying complex neurodevelopmental disorders. In this study we describe distinct episignatures for KAT6A syndrome, caused by pathogenic variants in the lysine acetyltransferase A gene (), and for the two neurodevelopmental disorders associated with lysine acetyl transferase B ().

Untargeted metabolomics profiling in pediatric patients and adult populations indicates a connection between lipid imbalance and epilepsy.

Introduction: Epilepsy is a common central nervous system disorder characterized by abnormal brain electrical activity. We aimed to compare the metabolic profiles of plasma from patients with epilepsy across different etiologies, seizure frequency, seizure type, and patient age to try to identify common disrupted pathways.

Material And Methods: We used data from three separate cohorts.

AXIN2-related oligodontia-colorectal cancer syndrome with cleft palate as a possible new feature.

Background: Pathogenic variants in AXIN2 have been associated with tooth agenesis, colon polyps, and colon cancer. Given the rare nature of this phenotype, we set out to collect additional genotypic and phenotypic information.

Methods: Data were collected via a structured questionnaire.

The prevalence of inherited metabolic disorders in Estonian population over 30 years: A significant increase during study period.

Inherited metabolic disorders (IMD) are a group of hereditary diseases wherein the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease. Estonia's small population and nationwide digitalised healthcare system make it possible to perform an epidemiological study that covers the whole population. A study was performed in Tartu University Hospital, which is the only tertiary care unit in Estonia for diagnosing patients with IMD, to define the prevalence and live birth prevalence of IMDs and the effectiveness of new diagnostic methods on the diagnosis of IMD.

The Birth Prevalence of Spinal Muscular Atrophy: A Population Specific Approach in Estonia.

Rare diseases are an important population health issue and many promising therapies have been developed in recent years. In light of novel genetic treatments expected to significantly improve spinal muscular atrophy (SMA) patients' quality of life and the urgent need for SMA newborn screening (NBS), new epidemiological data were needed to implement SMA NBS in Estonia. We aimed to describe the birth prevalence of SMA in the years 1996-2020 and to compare the results with previously published data.

Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5.

The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the STX5 mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identify a human disorder caused by a single missense substitution in the second starting methionine (p.

Total Synthesis of a Chimeric Glycolipid Bearing the Partially Acetylated Backbone of Sponge-Derived Agminoside E.

We describe the total synthesis of a chimeric glycolipid bearing both the partially acetylated backbone of sponge-derived agminoside E and the ()-3-hydroxydecanoic acid chain of bacterial rhamnolipids. The branched pentaglucolipid skeleton was achieved using a [3 + 2] disconnection approach. The β-(1 → 2) and β-(1 → 4)-glycosidic bonds were synthesized through a combination of NIS/Yb(OTf)- and TMSOTf-mediated stereoselective glycosylations of thiotolyl, -phenyltrifluoroacetimidate, and trichloroacetimidate donors.

A two-year prospective study assessing the performance of fetal chromosomal microarray analysis and next-generation sequencing in high-risk pregnancies.

Background: Introduction of cell-free fetal DNA (cff-DNA) testing in maternal blood opened possibilities to improve the performance of combined first-trimester screening (cFTS) in terms of better detection of trisomies and lowering invasive testing rate. The use of new molecular methods, such as chromosomal microarray analysis (CMA) and next-generation sequencing (NGS), has shown benefits in prenatal diagnosis of chromosomal and genetic diseases, which are not detectable with cff-DNA screening, but require an invasive procedure.

Methods: The objective of this study was to evaluate prospectively during two years performance of CMA and NGS in high-risk pregnancies.

Glycosylation and Protecting Group Strategies Towards the Synthesis of Saponins and Bacterial Oligosaccharides: A Personal Account.

Carbohydrates and their conjugates are not only involved in important biological processes but are also regarded as promising therapeutics and prophylactics. Over the last century, several glycosylation methodologies, glycosyl donors, and protecting groups have been developed and some of them have found broad synthetic applications in carbohydrate chemistry. In this Personal Account, we describe how glycosylation and protecting group strategies have been implemented in our as well as in other research groups as to synthesize bioactive glycans, more specifically naturally occurring lupane-type saponins as well as oligosaccharides related to Burkholderia species.

Melioidosis patient serum-reactive synthetic tetrasaccharides bearing the predominant epitopes of Burkholderia pseudomallei and Burkholderia mallei O-antigens.

Melioidosis and glanders, respectively caused by the Gram-negative bacteria Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm), are considered as urgent public health issues in developing countries and potential bioterrorism agents. Bp and Bm lipopolysaccharides (LPS) have been identified as attractive vaccine candidates for the development of prophylactic measures against melioidosis and glanders. Bp and Bm express structurally similar LPSs wherein the O-antigen (OAg) portion consists of a heteropolymer whose repeating unit is a disaccharide composed of d-glucose and 6-deoxy-l-talose residues, the latter being diversely acetylated and methylated.

FLAD1-associated multiple acyl-CoA dehydrogenase deficiency identified by newborn screening.

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria type II, is a mitochondrial fatty acid oxidation disorder caused by variants in ETFA, ETFB, and ETFDH. Recently, riboflavin transporter genes and the mitochondrial FAD transporter gene have also been associated with MADD-like phenotype.

Methods: We present a case of MADD identified by newborn biochemical screening in a full-term infant suggestive of both medium-chain acyl-CoA dehydrogenase deficiency and MADD.

PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene.

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland.

The evaluation of phenylalanine levels in Estonian phenylketonuria patients during eight years by electronic laboratory records.

Blood phenylalanine (Phe) values from the dried blood spots of all Estonian phenylketonuria (PKU) patients have been deposited into a unified electronic laboratory database for eight years, providing an opportunity to assess the adherence of the patients to dietary recommendations over time and to observe patient practices both individually and collectively. Our results demonstrate generally good adherence to clinical and dietary recommendations during the first six years of life, as the percentage of patients with median Phe values fitting under the national recommendation levels were 95%, 84% and 70% in age groups 0-1, 1-2 and 2-6 years, respectively. Conversely, significant deviations occur in the group of 6 to 12 year-olds, mildly decreasing in adolescence and increasing in adulthood (43%, 53% and 57%, respectively).

Polysaccharides from Burkholderia species as targets for vaccine development, immunomodulation and chemical synthesis.

Covering: up to 2018 Burkholderia species are a vast group of human pathogenic, phytopathogenic, and plant- or environment-associated bacteria. B. pseudomallei, B.

Hyperphenylalaninaemias in Estonia: Genotype-Phenotype Correlation and Comparative Overview of the Patient Cohort Before and After Nation-Wide Neonatal Screening.

The present study provides a retrospective overview of the cohort of phenylketonuria (PKU) patients in Estonia. Based on the available data, the patients clearly cluster into two distinct groups: the patients with late diagnosis and start of therapy (N = 46), who were born before 1993 when the national newborn screening programme was launched, and the screened babies (N = 48) getting their diagnoses at least in a couple of weeks after birth.Altogether 153 independent phenylalanine hydroxylase (PAH) alleles from 92 patients were analysed in the study, wherein 80% of them were carrying the p.

Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies.

Objective: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations.

Methods: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected.

Competitive intramolecular C-C vs. C-O bond coupling reactions toward C6 ring-fused 2-pyridone synthesis.

An interesting competitive C-C vs. C-O bond coupling reaction on N,3,5-trisubstituted pyridones is reported. These coupling reactions provided selective access to C- or O-ring-fused pyridones, both at the challenging C6-pyridone position.

Familial 1.3-Mb 11p15.5p15.4 Duplication in Three Generations Causing Silver-Russell and Beckwith-Wiedemann Syndromes.

Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 opposite growth-affecting disorders. The common molecular cause for both syndromes is an abnormal regulation of genes in chromosomal region 11p15, where 2 imprinting control regions (ICR) control fetal and postnatal growth. Also, many submicroscopic chromosomal disturbances like duplications in 11p15 have been described among SRS and BWS patients.

The Frequency of Methylation Abnormalities Among Estonian Patients Selected by Clinical Diagnostic Scoring Systems for Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome.

Aims: To study the frequency of methylation abnormalities among Estonian patients selected according to published clinical diagnostic scoring systems for Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS).

Materials And Methods: Forty-eight patients with clinical suspicion of SRS (n = 20) or BWS (n = 28) were included in the study group, to whom methylation-specific multiplex ligation-dependant probe amplification analysis of 11p15 region was made. In addition, to patients with minimal diagnostic score for either SRS or BWS, multilocus methylation-specific single nucleotide primer extension assay was performed.

Leopard syndrome: a report of five cases from one family in two generations.

Unlabelled: This is the first reported family with Leopard syndrome (LS) from Bosnia and Herzegovina. We report five cases of LS from two generations of the same family. In the present series of patients from one family, all patients carry the same recurrent mutation Y279C in the PTPN11 gene, exhibiting different phenotypes and a variable expression of multiple lentigines.