Exome sequencing in extreme altitude mountaineers identifies pathogenic variants in RTEL1 and COL6A1 previously associated with respiratory failure.

Adaptation of humans to challenging environmental conditions, such as extreme temperature, malnutrition, or hypoxia, is an interesting phenomenon for both basic and applied research. Identification of the genetic factors contributing to human adaptation to these conditions enhances our understanding of the underlying molecular and physiological mechanisms. In our study, we analyzed the exomes of 22 high altitude mountaineers to uncover genetic variants contributing to hypoxic adaptation. To our surprise, we identified two putative loss-of-function variants, rs1385101139 in RTEL1 and rs1002726737 in COL6A1 in two extremely high altitude (personal record of more than 8500 m) professional climbers. Both variants can be interpreted as pathogenic according to medical geneticists' guidelines, and are linked to inherited conditions involving respiratory failure (late-onset pulmonary fibrosis and severe Ullrich muscular dystrophy for rs1385101139 and rs1002726737, respectively). Our results suggest that a loss of gene function may act as an important factor of human adaptation, which is corroborated by previous reports in other human subjects.

Establishment of a Pilot Newborn Screening Program for Spinal Muscular Atrophy in Saint Petersburg.

Spinal muscular atrophy 5q (SMA) is one of the most common neuromuscular inherited diseases and is the most common genetic cause of infant mortality. SMA is associated with homozygous deletion of exon 7 in the SMN1 gene. Recently developed drugs can improve the motor functions of infants with SMA when they are treated in the pre-symptomatic stage. With aim of providing an early diagnosis, newborn screening (NBS) for SMA using a real-time PCR assay with dried blood spots (DBS) was performed from January 2022 through November 2022 in Saint Petersburg, which is a representative Russian megapolis. Here, 36,140 newborns were screened by the GenomeX real-time PCR-based screening test, and three genotypes were identified: homozygous deletion carriers (4 newborns), heterozygous carriers (772 newborns), and wild-type individuals (35,364 newborns). The disease status of all four newborns that screened positive for the homozygous SMN1 deletion was confirmed by alternate methods. Two of the newborns had two copies of SMN2, and two of the newborns had three copies. We determined the incidence of spinal muscular atrophy in Saint Petersburg to be 1 in 9035 and the SMA carrier frequency to be 1 in 47. In conclusion, providing timely information regarding SMN1, confirmation of disease status, and SMN2 copy number as part of the SMA newborn-screening algorithm can significantly improve clinical follow-up, testing of family members, and treatment of patients with SMA.

Assessment of Nuclear Gem Quantity for Evaluating the Efficacy of Antisense Oligonucleotides in Spinal Muscular Atrophy Cells.

Spinal muscular atrophy is a neuromuscular disorder caused by mutations in both copies of the survival motor neuron gene 1 (SMN1), which lead to reduction in the production of the SMN protein. Currently, there are several therapies that have been approved for SMA, with many more undergoing active research. While various biomarkers have been proposed for assessing the effectiveness of SMA treatment, a universally accepted one still has not been identified. This study aimed to describe a fast and reliable method using the number of gems in cell nuclei as a potential tool for assessment of splicing correction of oligonucleotide efficacy in SMA cells. To gain insight into whether the number of gems in cell nuclei varies based on their SMN genotype and whether the increase in gem number is associated with therapeutic response, we utilized fibroblast cell cultures obtained from a patient with SMA type II and from a healthy individual. We discovered a remarkable difference in the number of gems found in the nuclei of these cells, specifically when counting gems per 100 nuclei. The SMA fibroblasts treated with antisense oligonucleotide showed beneficial effects in correcting the abnormal splicing of SMN2 exon 7. It was observed that there was a significant increase in the number of gems in the treated cells compared to the intact SMA cells. The results obtained significantly correlate with an increase of full-length SMN transcript sharing. Based on our findings, we propose using the quantity of gems as a reliable biomarker for SMA drug development.

Case report: Preimplantation genetic testing for infantile GM1 gangliosidosis.

Ganglioside-monosialic acid (GM1) gangliosidosis (ICD-10: E75.1; OMIM: 230500, 230600, 230650) is a rare autosomal recessive hereditary disease, lysosomal storage disorder caused by mutations in the GLB1 gene that lead to the absence or insufficiency of ß-galactosidase. In this study, we report a case of a Russian family with a history of GM1 gangliosidosis. The family had a child who, from the age of 6 months, experienced a gradual loss of developmental skills, marked by muscle flaccidity, psychomotor retardation, hepatosplenomegaly, and the onset of tonic seizures by the age of 8 months. Funduscopic examination revealed a «cherry red spot¼ in the macula, which is crucial for the diagnosis of lipid storage disorders. To find the pathogenic variants responsible for these clinical symptoms, the next-generation sequencing approach was used. The analysis revealed two variants in the heterozygous state: a frameshift variant c.699delG (rs1452318343, ClinVar ID 928700) in exon 6 and a missense variant c.809A>C (rs371546950, ClinVar ID 198727) in exon 8 of the GLB1 gene. The spouses were advised to plan the pregnancy with assisted reproductive technology (ART), followed by preimplantation genetic testing for monogenic disorder (PGT-M) on the embryos. Trophectoderm biopsy was performed on 8 out of 10 resulting embryos at the blastocyst stage. To perform PGT-M, we developed a novel testing system, allowing for direct analysis of disease-causing mutations, as well as haplotype analysis based on the study of polymorphic markers-short tandem repeats (STR), located upstream and downstream of the GLB1 gene. The results showed that four embryos were heterozygous carriers of pathogenic variants in the GLB1 gene (#1, 2, 5, 8). Two embryos had a compound heterozygous genotype (#3, 4), while the embryos #7 and 9 did not carry disease-causing alleles of the GLB1 gene. The embryo #7 without pathogenic variants was transferred after consideration of its morphology and growth rate. Prenatal diagnosis in the first trimester showed the absence of the variants analyzed in the GLB1 gene in the fetus. The pregnancy resulted in the delivery of a female infant who did not inherit the disease-causing variants in the GLB1 gene.

Assessment of quadrivalent characteristics influencing chromosome segregation by analyzing human preimplantation embryos from reciprocal translocation carriers.

Patterns of meiotic chromosome segregation were analyzed in cleavage stage and blastocyst stage human embryos from couples with autosomal reciprocal translocations (ART). The influence of quadrivalent asymmetry degree, the presence of terminal breakpoints, and the involvement of acrocentric chromosomes in the rearrangement were analyzed to evaluate their contribution to the formation of non-viable embryos with significant chromosomal imbalance due to pathological segregation patterns and to assess the selection of human embryos by the blastocyst stage. A selection of viable embryos resulting from alternate and adjacent-1 segregation and a significant reduction in the detection frequency of the 3 : 1 segregation pattern were observed in human embryos at the blastocyst stage. The presence of terminal breakpoints increased the frequency of 3 : 1 segregation and was also associated with better survival of human embryos resulting from adjacent-1 mode, reflecting the process of natural selection of viable embryos to the blastocyst stage. The demonstrated patterns of chromosome segregation and inheritance of a balanced karyotype in humans will contribute to optimizing the prediction of the outcomes of in vitro fertilization programs and assessing the risks of the formation of unbalanced embryos for ART carriers.

Diagnostics of preeclampsia based on Congo red binding to urinary components: Rationales and limitations.

Preeclampsia is a disorder that can occur during pregnancy and is one of the leading causes of death among pregnant women. This disorder occurs after the 20th week of pregnancy and is characterized by arterial hypertension, proteinuria, fetoplacental, and multiple organ dysfunctions. Despite the long history of studying preeclampsia, its etiology and pathogenesis remain poorly understood, and therapy is symptomatic. One of the factors of the disorder is believed to be misfolded proteins that are prone to form amyloid aggregates. The CRD tests, utilizing the binding of the amyloid-specific dye Congo red to urine components, demonstrate high efficiency in diagnosing preeclampsia. However, these tests have also been found to be positive in other disorders with proteinuria, presumably associated with concomitant amyloidosis. To assess the limitations of the CRD tests, we examined urine congophilia and protein components mediating Congo red positivity in patients with proteinuria, including preeclampsia, amyloid and non-amyloid nephropathies. We stained the urine samples and calculated congophilia levels. We also assessed the contribution of large protein aggregates to congophilia values using ultracentrifugation and determined the molecular weights of congophilic urinary proteins using centrifugal concentrators. All proteinuric groups demonstrate positive results in the CRD tests and congophilia levels were more than two times higher compared with the control non-proteinuric groups (p <0.01). There was a strong correlation between urine protein excretion and congophilia in amyloid nephropathy (rs = 0.76), non-amyloid nephropathies (rs = 0.90), and preeclampsia (rs = 0.90). Removal of large aggregates from urine did not affect the congophilia levels. Separation of urine protein fractions revealed congophilic components in the range of 30-100 kDa, including monomeric serum albumin. Our results indicate limitations of CRD tests in preeclampsia diagnostics in women with renal disorders and underscore the need for further research on the mechanisms of Congo red binding with urine components.

Bioinformatics of germline variant discovery for rare disease diagnostics: current approaches and remaining challenges.

Next-generation sequencing (NGS) has revolutionized the field of rare disease diagnostics. Whole exome and whole genome sequencing are now routinely used for diagnostic purposes; however, the overall diagnosis rate remains lower than expected. In this work, we review current approaches used for calling and interpretation of germline genetic variants in the human genome, and discuss the most important challenges that persist in the bioinformatic analysis of NGS data in medical genetics. We describe and attempt to quantitatively assess the remaining problems, such as the quality of the reference genome sequence, reproducible coverage biases, or variant calling accuracy in complex regions of the genome. We also discuss the prospects of switching to the complete human genome assembly or the human pan-genome and important caveats associated with such a switch. We touch on arguably the hardest problem of NGS data analysis for medical genomics, namely, the annotation of genetic variants and their subsequent interpretation. We highlight the most challenging aspects of annotation and prioritization of both coding and non-coding variants. Finally, we demonstrate the persistent prevalence of pathogenic variants in the coding genome, and outline research directions that may enhance the efficiency of NGS-based disease diagnostics.

Hybrid laparo-endoscopic access: New approach to surgical treatment for giant fibrovascular polyp of esophagus: A case report and review of literature.

BACKGROUND: Fibrovascular polyps are rare type of esophageal submucosal neoplasms. They are highly vascularized and can cause difficulty swallowing and even fatal complications such as uncontrolled bleeding and death caused by asphyxiation in case of tumor migration to oropharynx. In the article we describe a novel hybrid technique to surgical treatment - an endoscopic submucosal dissection with laparoscopic removal of the tumor. CASE SUMMARY: The patient with a giant fibrovascular esophageal polyp presented with cough, discomfort in the throat, difficulty swallowing, and an episode of tumor migration into oropharynx. The patient was investigated with several imaging studies and was diagnosed with a giant highly vascularized esophageal fibrovascular polyp. The follow-up period of eight months accompanied with no complications. CONCLUSION: This method has been shown to have comparable rates of recurrence and a low risk of complications.

Plasma microRNA Profiling in Type 2 Diabetes Mellitus: A Pilot Study.

Type 2 diabetes mellitus (T2D) is a chronic metabolic disease characterized by insulin resistance and ß-cell dysfunction and leading to many micro- and macrovascular complications. In this study we analyzed the circulating miRNA expression profiles in plasma samples from 44 patients with T2D and 22 healthy individuals using next generation sequencing and detected 229 differentially expressed miRNAs. An increased level of miR-5588-5p, miR-125b-2-3p, miR-1284, and a reduced level of miR-496 in T2D patients was verified. We also compared the expression landscapes in the same group of patients depending on body mass index and identified differential expression of miR-144-3p and miR-99a-5p in obese individuals. Identification and functional analysis of putative target genes was performed for miR-5588-5p, miR-125b-2-3p, miR-1284, and miR-496, showing chromatin modifying enzymes and apoptotic genes being among the significantly enriched pathways.

The Landscape of Point Mutations in Human Protein Coding Genes Leading to Pregnancy Loss.

Pregnancy loss is the most frequent complication of a pregnancy which is devastating for affected families and poses a significant challenge for the health care system. Genetic factors are known to play an important role in the etiology of pregnancy loss; however, despite advances in diagnostics, the causes remain unexplained in more than 30% of cases. In this review, we aggregated the results of the decade-long studies into the genetic risk factors of pregnancy loss (including miscarriage, termination for fetal abnormality, and recurrent pregnancy loss) in euploid pregnancies, focusing on the spectrum of point mutations associated with these conditions. We reviewed the evolution of molecular genetics methods used for the genetic research into causes of pregnancy loss, and collected information about 270 individual genetic variants in 196 unique genes reported as genetic cause of pregnancy loss. Among these, variants in 18 genes have been reported by multiple studies, and two or more variants were reported as causing pregnancy loss for 57 genes. Further analysis of the properties of all known pregnancy loss genes showed that they correspond to broadly expressed, highly evolutionary conserved genes involved in crucial cell differentiation and developmental processes and related signaling pathways. Given the features of known genes, we made an effort to construct a list of candidate genes, variants in which may be expected to contribute to pregnancy loss. We believe that our results may be useful for prediction of pregnancy loss risk in couples, as well as for further investigation and revealing genetic etiology of pregnancy loss.

Massive Localized Abdominal Lymphedema: A Case Report with Literature Review.

Massive localized lymphedema (MLL) is a rare disease caused by the obstruction of lymphatic vessels with specific clinical morphological and radiological characteristics. People with morbid obesity are mainly affected by MLL. Lymphedema is easily confused with soft tissue sarcoma and requires differential diagnosis, both the possibility of an MLL and also carcinoma manifestations in the soft tissues. The possible causes of massive lymphedema include trauma, surgery, and hypothyroidism. This report is the first case of MLL treated surgically in the Russian Federation. Detailed computed tomography (CT) characteristics and an electron microscope picture of MLL are discussed. A 50-year-old woman (body mass index of 43 kg/m 2 ) with MLL arising from the anterior abdominal wall was admitted to the hospital for surgical treatment. Its mass was 22.16 kg. A morphological study of the resected mass confirmed the diagnosis of MLL. We review etiology, clinical presentation, diagnosis, and treatment of MLL. We also performed an electron-microscopic study that revealed interstitial Cajal-like cells telocytes not previously described in MLL cases. We did not find similar findings in the literature. It is possible that the conduction of an ultrastructural examination of MLL tissue samples will further contribute to the understanding of MLL pathogenesis.

Development of 2'-O-Methyl and LNA Antisense Oligonucleotides for SMN2 Splicing Correction in SMA Cells.

Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease caused by mutations in the SMN1 gene. Existing therapies demonstrate positive results on SMA patients but still might be ameliorated in efficacy and price. In the presented study we designed antisense oligonucleotides (AONs), targeting intronic splicing silencer sites, some were modified with 2'-O-methyl, others with LNA. The AONs have been extensively tested in different concentrations, both individually and combined, in order to effectively target the ISS-N1 and A+100G splicing silencer regions in intron 7 of the SMN2 gene. By treating SMA-cultured fibroblasts with certain AONs, we discovered a remarkable increase in the levels of full-length SMN transcripts and the number of nuclear gems. This increase was observed to be dose-dependent and reached levels comparable to those found in healthy cells. When added to cells together, most of the tested molecules showed a remarkable synergistic effect in correcting splicing. Through our research, we have discovered that the impact of oligonucleotides is greatly influenced by their length, sequence, and pattern of modification.

Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases.

Phenotypicheterogeneity is a phenomenon in which distinct phenotypes can develop in individuals bearing pathogenic variants in the same gene. Genetic factors, gene interactions, and environmental factors are usually considered the key mechanisms of this phenomenon. Phenotypic heterogeneity may impact the prognosis of the disease severity and symptoms. In our work, we used publicly available data on the association between genetic variants and Mendelian disease to investigate the genetic factors (such as the intragenic localization and type of a variant) driving the heterogeneity of gene-disease relationships. First, we showed that genes linked to multiple rare diseases (GMDs) are more constrained and tend to encode more transcripts with high levels of expression across tissues. Next, we assessed the role of variant localization and variant types in specifying the exact phenotype for GMD variants. We discovered that none of these factors is sufficient to explain the phenomenon of such heterogeneous gene-disease relationships. In total, we identified only 38 genes with a weak trend towards significant differences in variant localization and 30 genes with nominal significant differences in variant type for the two associated disorders. Remarkably, four of these genes showed significant differences in both tests. At the same time, our analysis suggests that variant localization and type are more important for genes linked to autosomal dominant disease. Taken together, our results emphasize the gene-level factors dissecting distinct Mendelian diseases linked to one common gene based on open-access genetic data and highlight the importance of exploring other factors that contributed to phenotypic heterogeneity.

Human Exome Sequencing and Prospects for Predictive Medicine: Analysis of International Data and Own Experience.

Today, whole-exome sequencing (WES) is used to conduct the massive screening of structural and regulatory genes in order to identify the allele frequencies of disease-associated polymorphisms in various populations and thus detect pathogenic genetic changes (mutations or polymorphisms) conducive to malfunctional protein sequences. With its extensive capabilities, exome sequencing today allows both the diagnosis of monogenic diseases (MDs) and the examination of seemingly healthy populations to reveal a wide range of potential risks prior to disease manifestation (in the future, exome sequencing may outpace costly and less informative genome sequencing to become the first-line examination technique). This review establishes the human genetic passport as a new WES-based clinical concept for the identification of new candidate genes, gene variants, and molecular mechanisms in the diagnosis, prediction, and treatment of monogenic, oligogenic, and multifactorial diseases. Various diseases are addressed to demonstrate the extensive potential of WES and consider its advantages as well as disadvantages. Thus, WES can become a general test with a broad spectrum pf applications, including opportunistic screening.

Prenatal Detection of Trisomy 2: Considerations for Genetic Counseling and Testing.

We report on the case of prenatal detection of trisomy 2 in placental biopsy and further algorithm of genetic counseling and testing. A 29-year-old woman with first-trimester biochemical markers refused chorionic villus sampling and preferred targeted non-invasive prenatal testing (NIPT), which showed low risk for aneuploidies 13, 18, 21, and X. A series of ultrasound examinations revealed increased chorion thickness at 13/14 weeks of gestation and fetal growth retardation, a hyperechoic bowel, challenging visualization of the kidneys, dolichocephaly, ventriculomegaly, increase in placental thickness, and pronounced oligohydramnios at 16/17 weeks of gestation. The patient was referred to our center for an invasive prenatal diagnosis. The patient's blood and placenta were sampled for whole-genome sequencing-based NIPT and array comparative genomic hybridization (aCGH), respectively. Both investigations revealed trisomy 2. Further prenatal genetic testing in order to confirm trisomy 2 in amniocytes and/or fetal blood was highly questionable because oligohydramnios and fetal growth retardation made amniocentesis and cordocentesis technically unfeasible. The patient opted to terminate the pregnancy. Pathological examination of the fetus revealed internal hydrocephalus, atrophy of brain structure, and craniofacial dysmorphism. Conventional cytogenetic analysis and fluorescence in situ hybridization revealed chromosome 2 mosaicism with a prevalence of trisomic clone in the placenta (83.2% vs. 16.8%) and a low frequency of trisomy 2, which did not exceed 0.6% in fetal tissues, advocating for low-level true fetal mosaicism. To conclude, in pregnancies at risk of fetal chromosomal abnormalities that refuse invasive prenatal diagnosis, whole-genome sequencing-based NIPT, but not targeted NIPT, should be considered. In prenatal cases of trisomy 2, true mosaicism should be distinguished from placental-confined mosaicism using cytogenetic analysis of amniotic fluid cells or fetal blood cells. However, if material sampling is impossible due to oligohydramnios and/or fetal growth retardation, further decisions should be based on a series of high-resolution fetal ultrasound examinations. Genetic counseling for the risk of uniparental disomy in a fetus is also required.

Current Status and Prospects of the Single-Cell Sequencing Technologies for Revealing the Pathogenesis of Pregnancy-Associated Disorders.

Single-cell RNA sequencing (scRNA-seq) is a method that focuses on the analysis of gene expression profile in individual cells. This method has been successfully applied to answer the challenging questions of the pathogenesis of multifactorial diseases and open up new possibilities in the prognosis and prevention of reproductive diseases. In this article, we have reviewed the application of scRNA-seq to the analysis of the various cell types and their gene expression changes in normal pregnancy and pregnancy complications. The main principle, advantages, and limitations of single-cell technologies and data analysis methods are described. We discuss the possibilities of using the scRNA-seq method for solving the fundamental and applied tasks related to various pregnancy-associated disorders. Finally, we provide an overview of the scRNA-seq findings for the common pregnancy-associated conditions, such as hyperglycemia in pregnancy, recurrent pregnancy loss, preterm labor, polycystic ovary syndrome, and pre-eclampsia.

Russian Regional Differences in Allele Frequencies of CFTR Gene Variants: Genetic Monitoring of Infertile Couples.

A male factor, commonly associated with poor semen quality, is revealed in about 50% of infertile couples. CFTR gene (Cystic Fibrosis Transmembrane Conduction Regulator) variants are one of the common genetic causes of azoospermia-related male infertility. Notably, the spectrum and frequency of pathogenic CFTR variants vary between populations and geographical regions. In this work, we made an attempt to evaluate the allele frequency (AF) of 12 common CFTR variants in infertile Russian men and healthy individuals from different districts of Russia. Because of the limited number of population-based studies on Russian individuals, we characterized the population AFs based on data from the Registry of Russian cystic fibrosis (CF) patients. In addition to the CF patient registry, we estimated the local frequencies of the same set of variants based on the results of genotyping of CF patients in local biocollections (from St. Petersburg and Yugra regions). AFs of common CFTR variants calculated based on registry and biocollection data showed good concordance with directly measured population AFs. The estimated region-specific frequencies of CFTR variants allowed us to uncover statistically significant regional differences in the frequencies of the F508del (c.1521_1523del; p.Phe508del) and CFTRdele2,3(21kb) (c.54-5940_273+10250del21kb; p.Ser18ArgfsX) variants. The data from population-based studies confirmed previous observations that F508del, CFTRdele2,3(21kb), and L138ins (c.413_415dup; p.Leu138dup)variants are the most abundant among infertile patients, and their frequencies are significantly lower in healthy individuals and should be taken into account during genetic monitoring of the reproductive health of Russian individuals.

bioGWAS: A Simple and Flexible Tool for Simulating GWAS Datasets.

Genome-wide association studies (GWAS) have proven to be a powerful tool for the identification of genetic susceptibility loci affecting human complex traits. In addition to pinpointing individual genes involved in a particular trait, GWAS results can be used to discover relevant biological processes for these traits. The development of new tools for extracting such information from GWAS results requires large-scale datasets with known biological ground truth. Simulation of GWAS results is a powerful method that may provide such datasets and facilitate the development of new methods. In this work, we developed bioGWAS, a simple and flexible pipeline for the simulation of genotypes, phenotypes, and GWAS summary statistics. Unlike existing methods, bioGWAS can be used to generate GWAS results for simulated quantitative and binary traits with a predefined set of causal genetic variants and/or molecular pathways. We demonstrate that the proposed method can recapitulate complete GWAS datasets using a set of reported genome-wide associations. We also used our method to benchmark several tools for gene set enrichment analysis for GWAS data. Taken together, our results suggest that bioGWAS provides an important set of functionalities that would aid the development of new methods for downstream processing of GWAS results.

Altered Sphingolipid Hydrolase Activities and Alpha-Synuclein Level in Late-Onset Schizophrenia.

Recent data described that patients with lysosomal storage disorders (LSDs) may have clinical schizophrenia (SCZ) features. Disruption of lipid metabolism in SCZ pathogenesis was found. Clinical features of schizophrenia (SCZ) have been demonstrated in patients with several lysosomal storage disorders (LSDs). Taking into account the critical role of lysosomal function for neuronal cells' lysosomal dysfunction could be proposed in SCZ pathogenesis. The current study analyzed lysosomal enzyme activities and the alpha-synuclein level in the blood of patients with late-onset SCZ. In total, 52 SCZ patients with late-onset SCZ, 180 sporadic Parkinson's disease (sPD) patients, and 176 controls were recruited. The enzymatic activity of enzymes associated with mucopolysaccharidosis (alpha-L-Iduronidase (IDUA)), glycogenosis (acid alpha-glucosidase (GAA)) and sphingolipidosis (galactosylceramidase (GALC), glucocerebrosidase (GCase), alpha-galactosidase (GLA), acid sphingomyelinase (ASMase)) and concentration of lysosphingolipids (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), and lysosphingomyelin (LysoSM)) were measured using LC-MS/MS. The alpha-synuclein level was estimated in magnetically separated CD45+ blood cells using the enzyme-linked immunosorbent assay (ELISA). Additionally, NGS analysis of 11 LSDs genes was conducted in 21 early-onset SCZ patients and 23 controls using the gene panel PGRNseq-NDD. Decreased ASMase, increased GLA activities, and increased HexSpn, LysoGb3, and LysoSM concentrations along with an accumulation of the alpha-synuclein level were observed in late-onset SCZ patients in comparison to the controls (p < 0.05). Four rare deleterious variants among LSDs genes causing mucopolysaccharidosis type I (IDUA (rs532731688, rs74385837) and type III (HGSNAT (rs766835582)) and sphingolipidosis (metachromatic leukodystrophy (ARSA (rs201251634)) were identified in five patients from the group of early-onset SCZ patients but not in the controls. Our findings supported the role of sphingolipid metabolism in SCZ pathogenesis. Aberrant enzyme activities and compounds of sphingolipids associated with ceramide metabolism may lead to accumulation of alpha-synuclein and may be critical in SCZ pathogenesis.

Aggregation of Genome-Wide Association Data from FinnGen and UK Biobank Replicates Multiple Risk Loci for Pregnancy Complications.

Complications endangering mother or fetus affect around one in seven pregnant women. Investigation of the genetic susceptibility to such diseases is of high importance for better understanding of the disease biology as well as for prediction of individual risk. In this study, we collected and analyzed GWAS summary statistics from the FinnGen cohort and UK Biobank for 24 pregnancy complications. In FinnGen, we identified 11 loci associated with pregnancy hypertension, excessive vomiting, and gestational diabetes. When UK Biobank and FinnGen data were combined, we discovered six loci reaching genome-wide significance in the meta-analysis. These include rs35954793 in FGF5 (p=6.1×10-9), rs10882398 in PLCE1 (p=8.9×10-9), and rs167479 in RGL3 (p=5.2×10-9) for pregnancy hypertension, rs10830963 in MTNR1B (p=4.5×10-41) and rs36090025 in TCF7L2 (p=3.4×10-15) for gestational diabetes, and rs2963457 in the EBF1 locus (p=6.5×10-9) for preterm birth. In addition to the identified genome-wide associations, we also replicated 14 out of 40 previously reported GWAS markers for pregnancy complications, including four more preeclampsia-related variants. Finally, annotation of the GWAS results identified a causal relationship between gene expression in the cervix and gestational hypertension, as well as both known and previously uncharacterized genetic correlations between pregnancy complications and other traits. These results suggest new prospects for research into the etiology and pathogenesis of pregnancy complications, as well as early risk prediction for these disorders.