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The epidemic and outbreaks of influenza B Victoria lineage (Bv) during 2019–2022 led to an analysis of genetic, epitopes, charged amino acids and Bv outbreaks. Based on the National Influenza Surveillance Network (NISN), the Bv 72 strains isolated during 2019–2022 were selected by spatio-temporal sampling, then were sequenced. Using the Compare Means, Correlate and Cluster, the outbreak data were analyzed, including the single nucleotide variant (SNV), amino acid (AA), epitope, evolutionary rate (ER), Shannon entropy value (SV), charged amino acid and outbreak. With the emergence of COVID-19, the non-pharmaceutical interventions (NPIs) made Less distant transmission and only Bv outbreak. The 2021–2022 strains in the HA genes were located in the same subset, but were distinct from the 2019–2020 strains (P < 0.001). The codon G → A transition in nucleotide was in the highest ratio but the transversion of C → A and T → A made the most significant contribution to the outbreaks, while the increase in amino acid mutations characterized by polar, acidic and basic signatures played a key role in the Bv epidemic in 2021–2022. Both ER and SV were positively correlated in HA genes (R = 0.690) and NA genes (R = 0.711), respectively, however, the number of mutations in the HA genes was 1.59 times higher than that of the NA gene (2.15/1.36) from the beginning of 2020 to 2022. The positively selective sites 174, 199, 214 and 563 in HA genes and the sites 73 and 384 in NA genes were evolutionarily selected in the 2021–2022 influenza outbreaks. Overall, the prevalent factors related to 2021–2022 influenza outbreaks included epidemic timing, Tv, Ts, Tv/Ts, P137 (B → P), P148 (B → P), P199 (P → A), P212 (P → A), P214 (H → P) and P563 (B → P). The preference of amino acid mutations for charge/pH could influence the epidemic/outbreak trends of infectious diseases. Here was a good model of the evolution of infectious disease pathogens. This study, on account of further exploration of virology, genetics, bioinformatics and outbreak information, might facilitate further understanding of their deep interaction mechanisms in the spread of infectious diseases. [ABSTRACT FROM AUTHOR]

Abstract The epidemic and outbreaks of influenza B Victoria lineage (Bv) during 2019–2022 led to an analysis of genetic, epitopes, charged amino acids and Bv outbreaks. Based on the National Influenza Surveillance Network (NISN), the Bv 72 strains isolated during 2019–2022 were selected by spatio-temporal sampling, then were sequenced. Using the Compare Means, Correlate and Cluster, the outbreak data were analyzed, including the single nucleotide variant (SNV), amino acid (AA), epitope, evolutionary rate (ER), Shannon entropy value (SV), charged amino acid and outbreak. With the emergence of COVID-19, the non-pharmaceutical interventions (NPIs) made Less distant transmission and only Bv outbreak. The 2021–2022 strains in the HA genes were located in the same subset, but were distinct from the 2019–2020 strains (P

In 2022, an unprecedented outbreak of mpox raged in several nations. Sequences from the 2022 outbreak reveal a higher nucleotide substitution if compared with the estimated rate for orthopoxviruses. Recently, intra-lesion SNVs (single nucleotide variants) have been described, and these have been suggested as possible sources of genetic variation. Until now, it has not been clear if the presence of several SNVs could represents the result of local mutagenesis or a possible co-infection. We investigated the significance of SNVs through whole-genome sequencing analysis of four unrelated mpox cases. In addition to the known mutations harboured by the circulating strains of virus (MPXV), 7 novel mutations were identified, including SNVs located in genes that are involved in immune evasion mechanisms and/or viral fitness, six of these appeared to be APOBEC3-driven. Interestingly, three patients exhibited the coexistence of mutated and wild-type alleles for five non-synonymous variants. In addition, two patients, apparently unrelated, showed an analogous pattern for two novel mutations, albeit with divergent frequencies. The coexistence of mixed viral populations, harbouring non-synonymous mutations in patients, supports the hypothesis of possible co-infection. Additional investigations of larger clinical cohorts are essential to validating intra-patient viral genome heterogeneity and determining the possibility of co-presence events of slightly divergent MPXV strains. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition with complete age-dependent penetrance, variable expressivity and a global prevalence of ~1/3,000. It is characteriszed by numerous café-au-lait macules, skin freckling in the inguinal or axillary regions, Lisch nodules of the iris, optic gliomas, neurofibromas, and tumour predisposition. The diagnostic testing strategy for NF1 includes testing for DNA single nucleotide variants (SNVs), copy number variants (CNVs) as well as RNA analysis for deep intronic and splice variants, which can cumulatively identify the causative variant in 95% of patients. In the present study, NF1 patients were screened using a next-generation sequencing (NGS) assay targeting NF1 exons and intron/exon boundaries for SNV and NF1 multiple ligation-dependent probe amplification (MLPA) analysis for CNV detection. Twenty-six unrelated Southern African patients clinically suspected of having NF1, based on the clinical diagnostic criteria developed by the National Institute of Health (NIH), were included in the current study. A detection rate of 58% (15/26) was obtained, with SNVs identified in 80% (12/15) using a targeted gene panel and NF1 gene deletion in 20% (3/15) identified using MLPA. Ten patients (38%) had no variants identified, although they met NF1 diagnostic criteria. One VUS was identified in this study in a patient that met NF1 diagnostic criteria, however there was no sufficient information to classify variant as pathogenic. The clinical features of Southern African patients with NF1 are similar to that of the known NF1 phenotype, with the exception of a lower frequency of plexiform neurofibromas and a higher frequency of developmental/intellectual disability compared to other cohorts. This is the first clinical and molecular characterisation of a Southern African ancestry NF1 cohort using both next-generation sequencing and MLPA analysis. A significant number of patients remained without a diagnosis following DNA-level testing. The current study offers a potential molecular testing strategy for our low resource environment that could benefit a significant proportion of patients who previously only received a clinical diagnosis without molecular confirmation. [ABSTRACT FROM AUTHOR]

Abstract Background Premature ovarian insufficiency (POI) is a highly heterogeneous disease, and up to 25% of the cases can be explained by genetic causes. G protein-coupled receptor 3 (GPR3) plays an important role in oocyte arrest, and Gpr3-deficient mice exhibited POI-like phenotypes. Case presentation We identified two heterozygous missense variants of GPR3: NM_005281: c.C973T (p.R325C) and c.G772A (p.A258T) in two sporadic Han Chinese POI cases through whole exome sequencing and genetic analysis. The two patients were diagnosed as POI in their late 20s, presenting elevated serum levels of follicle stimulating hormone and secondary amenorrhea. Both variants are very rare in the population databases of ExAC, gnomAD and PGG.Han. The affected amino acids are conserved across species and the mutated amino acids are predicted deleterious with bioinformatics prediction tools and the protein three-dimensional structure analysis. Conclusions It is the first report of rare GPR3 variants associated with POI women, providing an important piece of evidence for GPR3 as a candidate gene which should be screened in POI. This finding suggested the necessity of including GPR3 in etiology study and genetic counseling of POI patients.

Autism spectrum disorder (ASD) comprises a group of complex neurodevelopmental features seen in many different forms due to variable causes. Highly impactful ASD-susceptibility genes are involved in pathways associated with brain development, chromatin remodeling, and transcription regulation. In this study, we investigate a proband with complex ASD. Whole genome sequencing revealed a novel de novo missense mutation of a highly conserved amino acid residue (NP_001289981.1:p.His516Gln; chr2:1917275; hg38) in the MYT1L neural transcription factor gene. In combination with in silico analysis on gene effect and pathogenicity, we described the proband's phenotype and made comparisons with previously reported cases to explore the spectrum of clinical features in MYT1L single nucleotide variant (SNV) cases. The phenotype–genotype correlation showed a high degree of clinical similarity with previously reported cases of missense variants in MYT1L, indicating MYT1L as the causal gene for the observed phenotype in our proband. The variant was also predicted to be damaging according to multiple in silico pathogenicity predicting tools. This study expands the clinical description of SNVs on the MYT1L gene and provides insight into its contribution to ASD. [ABSTRACT FROM AUTHOR]

Background: Premature ovarian insufficiency (POI) is a highly heterogeneous disease, and up to 25% of the cases can be explained by genetic causes. G protein-coupled receptor 3 (GPR3) plays an important role in oocyte arrest, and Gpr3-deficient mice exhibited POI-like phenotypes. Case presentation: We identified two heterozygous missense variants of GPR3: NM_005281: c.C973T (p.R325C) and c.G772A (p.A258T) in two sporadic Han Chinese POI cases through whole exome sequencing and genetic analysis. The two patients were diagnosed as POI in their late 20s, presenting elevated serum levels of follicle stimulating hormone and secondary amenorrhea. Both variants are very rare in the population databases of ExAC, gnomAD and PGG.Han. The affected amino acids are conserved across species and the mutated amino acids are predicted deleterious with bioinformatics prediction tools and the protein three-dimensional structure analysis. Conclusions: It is the first report of rare GPR3 variants associated with POI women, providing an important piece of evidence for GPR3 as a candidate gene which should be screened in POI. This finding suggested the necessity of including GPR3 in etiology study and genetic counseling of POI patients. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition with complete age-dependent penetrance, variable expressivity and a global prevalence of ∼1/3,000. It is characteriszed by numerous café-au-lait macules, skin freckling in the inguinal or axillary regions, Lisch nodules of the iris, optic gliomas, neurofibromas, and tumour predisposition. The diagnostic testing strategy for NF1 includes testing for DNA single nucleotide variants (SNVs), copy number variants (CNVs) as well as RNA analysis for deep intronic and splice variants, which can cumulatively identify the causative variant in 95% of patients. In the present study, NF1 patients were screened using a next-generation sequencing (NGS) assay targeting NF1 exons and intron/exon boundaries for SNV and NF1 multiple ligation-dependent probe amplification (MLPA) analysis for CNV detection. Twenty-six unrelated Southern African patients clinically suspected of having NF1, based on the clinical diagnostic criteria developed by the National Institute of Health (NIH), were included in the current study. A detection rate of 58% (15/26) was obtained, with SNVs identified in 80% (12/15) using a targeted gene panel and NF1 gene deletion in 20% (3/15) identified using MLPA. Ten patients (38%) had no variants identified, although they met NF1 diagnostic criteria. One VUS was identified in this study in a patient that met NF1 diagnostic criteria, however there was no sufficient information to classify variant as pathogenic. The clinical features of Southern African patients with NF1 are similar to that of the known NF1 phenotype, with the exception of a lower frequency of plexiform neurofibromas and a higher frequency of developmental/intellectual disability compared to other cohorts. This is the first clinical and molecular characterisation of a Southern African ancestry NF1 cohort using both next-generation sequencing and MLPA analysis. A significant number of patients remained without a diagnosis following DNA-level testing. The current study offers a potential molecular testing strategy for our low resource environment that could benefit a significant proportion of patients who previously only received a clinical diagnosis without molecular confirmation.

In 2022, an unprecedented outbreak of mpox raged in several nations. Sequences from the 2022 outbreak reveal a higher nucleotide substitution if compared with the estimated rate for orthopoxviruses. Recently, intra-lesion SNVs (single nucleotide variants) have been described, and these have been suggested as possible sources of genetic variation. Until now, it has not been clear if the presence of several SNVs could represents the result of local mutagenesis or a possible co-infection. We investigated the significance of SNVs through whole-genome sequencing analysis of four unrelated mpox cases. In addition to the known mutations harboured by the circulating strains of virus (MPXV), 7 novel mutations were identified, including SNVs located in genes that are involved in immune evasion mechanisms and/or viral fitness, six of these appeared to be APOBEC3-driven. Interestingly, three patients exhibited the coexistence of mutated and wild-type alleles for five non-synonymous variants. In addition, two patients, apparently unrelated, showed an analogous pattern for two novel mutations, albeit with divergent frequencies. The coexistence of mixed viral populations, harbouring non-synonymous mutations in patients, supports the hypothesis of possible co-infection. Additional investigations of larger clinical cohorts are essential to validating intra-patient viral genome heterogeneity and determining the possibility of co-presence events of slightly divergent MPXV strains.

The aim of this study was to screen potential susceptibility genes using whole-exome sequencing (WES) in 15 Han Chinese patients with stage III or IV periodontitis and to evaluate the quantity and quality of genomic DNA extracted from saliva. DNA was extracted from saliva epithelial cells, quality-tested, and then subjected to WES and bioinformatics analyses. All variation loci were analyzed and interpreted following the American College of Medical Genetics and Genomics (ACMG) criteria. Candidate pathogenic variation loci were identified and verified using Sanger sequencing. Correlation and functional analyses of the candidate genes were used to identify potential susceptibility genes in patients with severe periodontitis. LFNG, LENG8, NPHS1, HFE, ILDR1, and DMXL2 genes were identified in over two cases each with shared mutations. Following these analyses, the DMXL2 gene was identified as being associated with stage III and IV periodontitis. These results suggest a potential pathophysiological risk mechanism for periodontitis, but need to be verified through larger clinical studies and mechanistic experiments to determine the pathogenicity of these gene mutations and their generalizability to a wider population of periodontitis patients. By screening candidate pathogenic variation loci using WES in 15 Han Chinese patients with stage III or IV periodontitis, our study could provide a pipeline and feasibility support for the identification of susceptibility genes in patients with stage III and IV periodontitis.

Primary open-angle glaucoma (POAG), the world's main cause of irreversible blindness, is an asymptomatic and neurodegenerative disease of multifactorial etiology with ethnic and geographic disparities. Multiethnic genome-wide association studies (GWAS) identified single nucleotide variants (SNVs) in ATXN2, FOXC1, and TXNRD2 loci as risk factors for POAG pathophysiology and/or endophenotypes. The aim of this case–control study was to investigate the association of the variants rs7137828 (ATXN2), rs2745572 (FOXC1), and rs35934224 (TXNRD2), as risk factors for POAG development, additionally to rs7137828 association with glaucoma clinical parameters in a Brazilian cohort from the Southeast and South regions. This investigation comprised 506 cases and 501 controls. Variants rs2745572 and rs35934224 were genotyped through TaqMan® assays and validated by Sanger sequencing. Variant rs7137828 was genotyped exclusively by Sanger sequencing. The primary research outcome revealed that the variant rs7137828 (ATXN2) was associated with an increased risk for the development of POAG in the presence of the TT genotype compared to the CC genotype (p = 0.006; Odds Ratio [OR] = 1.717; Confidence Interval [CI] 95% = 1.169–2.535). There was no significant association of rs2745572 and rs35934224 genotypes with POAG. The CT genotype of the rs7137828 was associated with the vertical cup-to-disk ratio (VCDR) (p =.023) but not with the age at diagnosis or the mean deviation. Our data indicate the rs7137828 associated with increased risk for the development of POAG and VCDR in a Brazilian cohort. If validated in additional populations, these findings may enable the development of relevant strategies for early diagnosis of glaucoma in the future. [ABSTRACT FROM AUTHOR]

Estrogen receptor α (ERα), encoded by the ESR1 gene, is a key prognostic and predictive biomarker firmly established in routine diagnostics and as a therapeutic target of breast cancer, and it has a central function in breast cancer biology. Genetic variants at 6q25.1, containing the ESR1 gene, were found to be associated with breast cancer susceptibility. The rs2046210 and rs9383590 single nucleotide variants (SNVs) are located in the same putative enhancer region upstream of ESR1 and were separately identified as candidate causal variants responsible for these associations. Here, both SNVs were genotyped in a hospital-based case-control study of 409 female breast cancer patients and 422 female controls of a Central European (Austrian) study population. We analyzed the association of both SNVs with the risk, age at onset, clinically and molecularly relevant characteristics and prognosis of breast cancer. We also assessed the concordances between both SNVs and the associations of each SNV conditional on the other SNV. The minor alleles of both SNVs were found to be non-significantly associated with an increased breast cancer risk. Significant associations were found in specific subpopulations, particularly in patients with an age younger than 55 years. The minor homozygotes of rs2046210 and the minor homozygotes plus heterozygotes of rs9383590 exhibited a several-years-younger age at onset than the common homozygotes, which was more pronounced in ER-positive and luminal patients. Importantly, the observed associations of each SNV were not consistently nullified upon correction for the other SNV nor upon analyses in common homozygotes for the other SNV. We conclude that both SNVs remain independent candidate causal variants. [ABSTRACT FROM AUTHOR]

Collectively, rare genetic disorders affect a substantial portion of the world’s population. In most cases, those affected face difficulties in receiving a clinical diagnosis and genetic characterization. The understanding of the molecular mechanisms of these diseases and the development of therapeutic treatments for patients are also challenging. However, the application of recent advancements in genome sequencing/analysis technologies and computer-aided tools for predicting phenotype-genotype associations can bring significant benefits to this field. In this review, we highlight the most relevant online resources and computational tools for genome interpretation that can enhance the diagnosis, clinical management, and development of treatments for rare disorders. Our focus is on resources for interpreting single nucleotide variants. Additionally, we present use cases for interpreting genetic variants in clinical settings and review the limitations of these results and prediction tools. Finally, we have compiled a curated set of core resources and tools for analyzing rare disease genomes. Such resources and tools can be utilized to develop standardized protocols that will enhance the accuracy and effectiveness of rare disease diagnosis.

Abstract Background Genome-wide association studies (GWAS) aim to correlate phenotypic changes with genotypic variation. Upon transcription, single nucleotide variants (SNVs) may alter mRNA structure, with potential impacts on transcript stability, macromolecular interactions, and translation. However, plant genomes have not been assessed for the presence of these structure-altering polymorphisms or “riboSNitches.” Results We experimentally demonstrate the presence of riboSNitches in transcripts of two Arabidopsis genes, ZINC RIBBON 3 (ZR3) and COTTON GOLGI-RELATED 3 (CGR3), which are associated with continentality and temperature variation in the natural environment. These riboSNitches are also associated with differences in the abundance of their respective transcripts, implying a role in regulating the gene's expression in adaptation to local climate conditions. We then computationally predict riboSNitches transcriptome-wide in mRNAs of 879 naturally inbred Arabidopsis accessions. We characterize correlations between SNPs/riboSNitches in these accessions and 434 climate descriptors of their local environments, suggesting a role of these variants in local adaptation. We integrate this information in CLIMtools V2.0 and provide a new web resource, T-CLIM, that reveals associations between transcript abundance variation and local environmental variation. Conclusion We functionally validate two plant riboSNitches and, for the first time, demonstrate riboSNitch conditionality dependent on temperature, coining the term “conditional riboSNitch.” We provide the first pan-genome-wide prediction of riboSNitches in plants. We expand our previous CLIMtools web resource with riboSNitch information and with 1868 additional Arabidopsis genomes and 269 additional climate conditions, which will greatly facilitate in silico studies of natural genetic variation, its phenotypic consequences, and its role in local adaptation.

The aim of this study was to identify mRNA isoforms and small genetic variants that may be affecting marbling and beef color in Nellore cattle. Longissimus thoracis muscle samples from 20 bulls with different phenotypes (out of 80 bulls set) for marbling (moderate (n = 10) and low (n = 10) groups) and beef color (desirable (n = 10) and undesirable (n = 9) group) traits were used to perform transcriptomic analysis using RNA sequencing. Fourteen and 15 mRNA isoforms were detected as differentially expressed (DE) (P-value ≤ 0.001) between divergent groups for marbling and meat color traits, respectively. Some of those DE mRNA isoforms have shown sites of splicing modified by small structural variants as single nucleotide variant (SNV), insertion, and/or deletion. Enrichment analysis identified metabolic pathways, such as O2/CO2 exchange in erythrocytes, tyrosine biosynthesis, and phenylalanine degradation. The results obtained suggest potential key regulatory genes associated with these economically important traits for the beef industry and for the consumer. [ABSTRACT FROM AUTHOR]

Estrogen receptor α (ERα), encoded by the ESR1 gene, is a key prognostic and predictive biomarker firmly established in routine diagnostics and as a therapeutic target of breast cancer, and it has a central function in breast cancer biology. Genetic variants at 6q25.1, containing the ESR1 gene, were found to be associated with breast cancer susceptibility. The rs2046210 and rs9383590 single nucleotide variants (SNVs) are located in the same putative enhancer region upstream of ESR1 and were separately identified as candidate causal variants responsible for these associations. Here, both SNVs were genotyped in a hospital-based case-control study of 409 female breast cancer patients and 422 female controls of a Central European (Austrian) study population. We analyzed the association of both SNVs with the risk, age at onset, clinically and molecularly relevant characteristics and prognosis of breast cancer. We also assessed the concordances between both SNVs and the associations of each SNV conditional on the other SNV. The minor alleles of both SNVs were found to be non-significantly associated with an increased breast cancer risk. Significant associations were found in specific subpopulations, particularly in patients with an age younger than 55 years. The minor homozygotes of rs2046210 and the minor homozygotes plus heterozygotes of rs9383590 exhibited a several-years-younger age at onset than the common homozygotes, which was more pronounced in ER-positive and luminal patients. Importantly, the observed associations of each SNV were not consistently nullified upon correction for the other SNV nor upon analyses in common homozygotes for the other SNV. We conclude that both SNVs remain independent candidate causal variants.

Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as anhedonia and flat affect, and cognitive impairment. Recently, glucuronate (GlucA) levels were reported to be significantly higher in serum of patients with schizophrenia than those in healthy controls. The accumulation of GlucA is known to be related to treatment-resistant schizophrenia, since GlucA is known to promote drug excretion by forming conjugates with drugs. However, the cause of GlucA accumulation remains unclear. Aldo-keto reductase family one member A1 (AKR1A1) is an oxidoreductase that catalyzes the reduction of GlucA. Genetic loss of AKR1A1 function is known to result in the accumulation of GlucA in rodents. Here, we aimed to explore genetic defects in AKR1A1 in patients with schizophrenia, which may result in the accumulation of GlucA. We identified 28 variants of AKR1A1 in patients with schizophrenia and control subjects. In particular, we identified a silent c.753G > A (rs745484618, p. Arg251Arg) variant located at the first position of exon 8 to be associated with schizophrenia. Using a minigene assay, we found that the c.753G > A variant induced exon 8 skipping in AKR1A1, resulting in a frameshift mutation, which in turn led to truncation of the AKR1A1 protein. Using the recombinant protein, we demonstrated that the truncated AKR1A1 completely lost its activity. Furthermore, we showed that AKR1A1 mRNA expression in the whole blood cells of individuals with the c.753G > A variant tended to be lower than that in those without the variants, leading to lower AKR activity. Our findings suggest that AKR1A1 carrying the c.753G > A variant induces exon skipping, leading to a loss of gene expression and enzymatic activity. Thus, GlucA patients with schizophrenia with the c.753G > A variant may show higher GlucA levels, leading to drug-resistant schizophrenia, since drug excretion by GlucA is enhanced. [ABSTRACT FROM AUTHOR]

Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as anhedonia and flat affect, and cognitive impairment. Recently, glucuronate (GlucA) levels were reported to be significantly higher in serum of patients with schizophrenia than those in healthy controls. The accumulation of GlucA is known to be related to treatment-resistant schizophrenia, since GlucA is known to promote drug excretion by forming conjugates with drugs. However, the cause of GlucA accumulation remains unclear. Aldo-keto reductase family one member A1 (AKR1A1) is an oxidoreductase that catalyzes the reduction of GlucA. Genetic loss of AKR1A1 function is known to result in the accumulation of GlucA in rodents. Here, we aimed to explore genetic defects in AKR1A1 in patients with schizophrenia, which may result in the accumulation of GlucA. We identified 28 variants of AKR1A1 in patients with schizophrenia and control subjects. In particular, we identified a silent c.753G > A (rs745484618, p. Arg251Arg) variant located at the first position of exon 8 to be associated with schizophrenia. Using a minigene assay, we found that the c.753G > A variant induced exon 8 skipping in AKR1A1, resulting in a frameshift mutation, which in turn led to truncation of the AKR1A1 protein. Using the recombinant protein, we demonstrated that the truncated AKR1A1 completely lost its activity. Furthermore, we showed that AKR1A1 mRNA expression in the whole blood cells of individuals with the c.753G > A variant tended to be lower than that in those without the variants, leading to lower AKR activity. Our findings suggest that AKR1A1 carrying the c.753G > A variant induces exon skipping, leading to a loss of gene expression and enzymatic activity. Thus, GlucA patients with schizophrenia with the c.753G > A variant may show higher GlucA levels, leading to drug-resistant schizophrenia, since drug excretion by GlucA is enhanced.

• Levodopa-induced dyskinesia (LID) is a common and difficult to treat symptom found in patients with Parkinson's disease. • Prior animal studies indicated that D3 receptor (DRD3) may have a role in LID. • It is reported that the SNV rs6280 (AA or serine variant) polymorphism is associated with reduced dopamine binding affinity of D3 presynaptic auto-receptor. • In the current study, we found that the AA genotype was more frequently present in PD patients with LID and healthy controls in comparison to PD patients without LID. Levodopa-induced dyskinesia (LID) is a debilitating motor feature in a subset of patients with Parkinson's disease (PD) after prolonged therapeutic administration of levodopa. Preliminary animal and human studies are suggestive of a key role of dopamine type 3 (D3) receptor polymorphism (Ser9Gly; rs6280) in LID. Its contribution to development of LID among Indian PD patients has remained relatively unexplored and merits further investigation. 200 well-characterised PD patients (100 without LID and 100 with LID) and 100 age-matched healthy controls were recruited from the outpatient department of Institute of Neurosciences Kolkata. MDS-UPDRS (Unified Parkinson's Disease Rating Scale from International Movement Disorder Society) Part III and AIMS (abnormal involuntary movement scale) were performed for estimation of severity of motor features and LID respectively in the ON state of the disease. Participants were analysed for the presence of Ser9Gly single nucleotide variant (SNV) (rs6280) by polymerase chain reaction followed by restriction fragment length polymorphism techniques. The frequency of AA genotype (serine type) was more frequently present in PD patients with LID compared to PD patients without LID (50 % vs 28 %; P = 0.002; OR = 2.57, 95 % CI: 1.43 – 4.62). The abnormal involuntary movement scale score was significantly higher in PD patients with AA genotype compared to carriers of glycine allele (AG + GG) (4.08 ± 3.35; P = 0.002). We observed a significant association of serine type SNV (rs6280) in D3 receptor gene in a cohort of PD patients with LID from India. More severe motor severity was found in patients with glycine substitution of the same SNV. The current study emphasised the role of D3 receptor in the pathogenesis of LID. [ABSTRACT FROM AUTHOR]

Circulating tumor DNA (ctDNA) in blood carries genetic variations associated with tumors. There is evidence indicating that the abundance of single nucleotide variant (SNV) in ctDNA is correlated well with cancer progression and metastasis. Thus, accurate and quantitative detection of SNVs in ctDNA may benefit clinical practice. However, most current methods are unsuitable for the quantification of SNV in ctDNA that usually differentiates from wild-type DNA (wtDNA) only by a single base. In this setting, ligase chain reaction (LCR) coupled with mass spectrometry (MS) was developed to simultaneously quantify multiple SNVs using PIK3CA ctDNA as a model. Mass-tagged LCR probe set for each SNV including mass-tagged probe and three DNA probes was firstly designed and prepared. Then, LCR was initiated to discriminate SNVs specifically and amplify the signal of SNVs in ctDNA selectively. Afterward, a biotin-streptavidin reaction system was used to separate the amplified products, and photolysis was initiated to release mass tags. Finally, mass tags were monitored and quantified by MS. After optimizing conditions and verifying performance, this quantitative system was applied for blood samples from breast cancer patients, and risk stratification for breast cancer metastasis was also performed. This study is among the first to quantify multiple SNVs in ctDNA in a signal amplification and conversion manner, and also highlights the potential of SNV in ctDNA as a liquid biopsy marker to monitor cancer progression and metastasis. [Display omitted] • Combination of MS with LCR for quantification of SNVs in ctDNA. • Sensitive detection and specific discrimination of multiple SNVs via LCR amplification. • Capture smaller fragments of ctDNA via LCR. • Simultaneous quantification of multiple SNVs via mass-tagged probes. • The levels of specific SNVs in ctDNA may be a good indicator of cancer metastasis. [ABSTRACT FROM AUTHOR]

Collectively, rare genetic disorders affect a substantial portion of the world's population. In most cases, those affected face difficulties in receiving a clinical diagnosis and genetic characterization. The understanding of the molecular mechanisms of these diseases and the development of therapeutic treatments for patients are also challenging. However, the application of recent advancements in genome sequencing/analysis technologies and computer-aided tools for predicting phenotype-genotype associations can bring significant benefits to this field. In this review, we highlight the most relevant online resources and computational tools for genome interpretation that can enhance the diagnosis, clinical management, and development of treatments for rare disorders. Our focus is on resources for interpreting single nucleotide variants. Additionally, we present use cases for interpreting genetic variants in clinical settings and review the limitations of these results and prediction tools. Finally, we have compiled a curated set of core resources and tools for analyzing rare disease genomes. Such resources and tools can be utilized to develop standardized protocols that will enhance the accuracy and effectiveness of rare disease diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Licata, Via, Turina, Babbi, Benevenuta, Carta, Casadio, Cicconardi, Facchiano, Fariselli, Giordano, Isidori, Marabotti, Martelli, Pascarella, Pinelli, Pippucci, Russo, Savojardo, Scafuri, Valeriani and Capriotti.)

In the past two decades since the first sequencing of the human genome, clinical genomics has undergone a renaissance with the advent of next generation sequencing (NGS) technologies. Whole genome sequencing is now increasingly available in the clinical setting at a fraction of the cost of the human genome reference sequence, and with turnaround times as short as 7-10days. Clinical genetics-based management has become more tractable with improved payer reimbursement and increased availability of targeted therapies, especially in the oncology space. Precision diagnostics in cancer allow clinicians to assess a patient's risk of developing cancers, detect and classify tumors, predict prognoses, select targeted therapies when available, and monitor their patient's disease burden longitudinally. This approach ushers in a new era of predictive and preventive oncology care that can be personalized to the genetics of the individual patient, the patient's tumor, and their clinical presentation. Within oncology, there are global collaborative efforts including the International Cancer Genome Consortium (ICGC), Pan-Cancer Analysis of Whole Genomes (PCAWG) and The Cancer Genome Atlas (TCGA) that have archived thousands of cancer genomes. In collaboration with databases including but not limited to cancer cataloging variant association with disease risk (ClinVar and others) and drug responses (PharmGKB and others), the study of somatic and germline genomic variation provides a wealth of information on cancer development, evolution, heterogeneity, and treatment response. Although many challenges still exist for defining all possible actionable genomic variants, we have unprecedented opportunity to gain mechanistic and clinical insights into human neoplastic diseases., (Copyright © 2022 Elsevier Inc. All rights reserved.)