Genetic Phenotype Research Articles

Network-based transfer of pan-cancer immunotherapy responses to guide breast cancer prognosis

Breast cancer prognosis is complicated by tumor heterogeneity. Traditional methods focus on cancer-specific gene signatures, but cross-cancer strategies that provide deeper insights into tumor homogeneity are rarely used. Immunotherapy, particularly immune checkpoint inhibitors, results from variable responses across cancers, offering valuable prognostic insights. We introduced a network-based transfer (NBT) of pan-cancer immunotherapy responses to enhance breast cancer prognosis using node embedding and heat diffusion algorithms, identifying gene signatures netNE and netHD. Our results showed that netHD and netNE outperformed seven established breast cancer signatures in prognostic metrics, with netHD excelling. All nine gene signatures were grouped into three clusters, with netHD and netNE enriching the immune-related interferon-gamma pathway. Stratifying TCGA patients into two groups based on netHD revealed significant immunological differences and variations in 20 of 50 cancer hallmarks, emphasizing immune-related markers. This approach leverages pan-cancer insights to enhance breast cancer prognosis, facilitating insight transfer and improving tumor homogeneity understanding. graph of network-based insights translating pan-cancer immunotherapy responses to breast cancer prognosis. This abstract graph illustrates the conceptual framework for transferring immunotherapy response insights from pan-cancer studies to breast cancer prognosis. It highlights the integration of PPI networks to bridge genetic data and clinical phenotypes. The network-based method facilitates the identification of prognostic gene signatures in breast cancer by leveraging immunotherapy response information, providing a novel perspective on tumor homogeneity and its implications for clinical outcomes.

Tandem mass spectrometry screening and genetic analysis of neonates with Urea cycle disorders

To explore the results of four types of Urea cycle disorders (UCDs) in newborns from the Xuzhou region, assess the efficacy of newborn screening by tandem mass spectrometry (MS/MS), and analyze their genetic characteristics. A retrospective analysis was performed using tandem mass spectrometry to screen for inherited metabolic disorders in 691 712 newborns at the Maternal and Child Health Care Hospital of Xuzhou from November 2015 to December 2023. Ten children (cases 1-10) were diagnosed with Ornithine transcarbamylase deficiency (OTCD), Carbamoylphosphate synthase 1 deficiency (CPS1D), Arginase deficiency (ARGD), and Argininosuccinate synthase deficiency (ASSD) based on MS/MS and genetic testing. This study was approved by the Medical Ethics Committee of Xuzhou Maternity and Child Health Care Hospital (Ethics No.XZFY2024-051K-01J). A total of 691 712 neonates were screened for UCDs using MS/MS, which identified 1 237, 1 237, 510, and 1 009 initial positive cases for OTCD, CPS1D, ASSD, and ARGD, respectively. After genetic testing, 1 case of OTCD, 1 case of CPS1D, 1 case of ASSD, and 7 cases of ARGD were confirmed. The overall positive predictive value for these four UCDs was 0.362%. Among the 10 diagnosed UCD cases, four novel variants were identified, which included OTC: c.1024C>A (p.L342M) and ASS1: c.826A>G (p.M276V), c.695C>T (p.P232L) and c.694C>T (p.P232S). Bioinformatic analysis has rated these as variants of uncertain clinical significance or likely pathogenic based on guidelines from the American College of Medical Genetics and Genomics (ACMG). The incidence of four UCDs in neonates from the Xuzhou area is relatively low, and there is a correlation between genetic variants and clinical phenotypes. For novel variants with uncertain clinical significance or suspected pathogenicity, their pathogenicity should be clarified in conjunction with clinical and biochemical indicators. The four novel pathogenic variants of UCDs identified in this study have enriched the mutational spectrum of UCDs-associated genes in the Xuzhou region.

International Symposium on Ruminant Physiology: The immunometabolism of transition dairy cows from dry-off to early lactation: lights and shadows.

The mismatch between the nutrient intake from the diet and the output by the mammary gland causes a negative energy balance in transition dairy cows, that, if excessive, can promote several metabolic disorders. Other relevant phenomena occur during transition, such as inflammation at calving and changes in immunocompetence, redox balance, and mineral metabolism. Despite the efforts, some aspects of the adaptive mechanisms observed in the transition period still need to be clarified. For instance, alterations of physiological responses even before the dry-off or during the dry period can affect the success of the whole transition period in certain cows. In this context, the mechanism regulating the inflammatory response around calving may play a pivotal role, as suggested by the variety of factors influencing it and its consequences, particularly feed intake depression, that can amplify and anticipate the negative energy balance. When this mechanism derails is still unclear, but detecting the triggers of diverted or abnormal physiological responses and where they stem (e.g., liver, rumen and gut epithelia, uterus, or mammary gland) will help to discover the weak points in the immune system and the possible ways of restoring it. Furthermore, the postpartum healthy cow appears to have an acute phase response at the liver level, despite a decrease in circulating proinflammatory cytokines. What is physiological and what is pathological in this context? To understand the latter, finding markers of an unsuccessful transition period that go beyond the energy deficit would be advisable. Future efforts should be dedicated to clarifying the causes of the acute phase response at calving, exploiting the potential of the system biology. Moreover, it would be helpful, for both basic and applied research, to define biomarkers associated with pathological responses (i.e., cytokines and acute phase proteins) and to introduce in the genetic selection phenotypes related to the ability of cows to adapt to the immunometabolic stress typical of the transition period.

Genetic Mapping by 55K Single-Nucleotide Polymorphism Array Reveals Candidate Genes for Tillering Trait in Wheat Mutant dmc.

The tiller number is a key agronomic trait for increasing the yield potential of wheat (Triticum aestivum L.). A number of quantitative trait loci (QTLs) and key genes controlling tillering have been identified, but the regulatory mechanisms remain unclear. In this study, we utilized the dwarf-monoculm mutant (dmc) obtained from the ethyl methane sulfonate (EMS)-treated wheat cultivar Guomai 301. The F2 populations were constructed using the dmc mutant crossed to multiple tiller parents. The F2 populations were surveyed for tillering traits at the critical fertility stage for genetic analyses. The extreme-tillering-phenotype plants from the F2 population were used to construct mixing pools that were analyzed by a wheat 55K SNP array. The tillering genes of dmc were mapped using the wheat 55K SNP array combined with transcriptomic data. The results showed that the genetic phenotype of dmc is controlled by two dominant genes. The tillering genes of dmc were mapped on the 60-100 Mb region of chromosome 5B and the 135-160 Mb region of chromosome 7A. A total of sixteen candidate genes associated with the tillering trait of dmc were identified. Two candidate genes, TraesCS5B02G058800 and TraesCS7A02G184200, were predicted to be involved in indole acetic acid (IAA) response and transport, which were considered as potential regulatory genes. This study elucidated the genetic basis of the dmc mutant and provided two valuable reference genes for studying the development and regulatory mechanisms of wheat tillering.

Genetic variation and clinical phenotype analysis of hypermethioninemia caused by MAT1A gene mutation: Case report.

The high clinical heterogeneity of hypermethioninemia caused by MAT1A gene defects has resulted in a paucity of studies examining the association between clinical phenotypes, biochemical characteristics, and gene mutations in this patient group. Furthermore, the indications for therapeutic interventions in patients remain unclear. The objective of this study is to provide a foundation for clinical diagnosis, genetic counseling, and follow-up management of hypermethioninemia caused by MAT1A gene defects. A retrospective analysis of children with hypermethioninemia at Jinan Maternal and Child Health Hospital from January 2016 to December 2023 was performed using tandem mass spectrometry (MS/MS). The screened and diagnosed children were tested for gene mutations using second-generation sequencing technology and confirmed using Sanger sequencing. Newborn MS/MS screening for diseases demonstrated an elevated methionine level, which was outside the reference range. Upon recalling the newborns, the methionine levels remained elevated, necessitating further refinement of genetic testing. Ultimately, genetic testing confirmed hypermethioninemia, which was attributed to a mutation in the MAT1A gene. The intervention for the patients in this study took the following forms: regular follow-up without treatment (n = 3), intake of methionine-free milk powder without any medication (n = 4), intake of methionine-free milk powder with some medication, and eventually liver transplantation (n = 1). A total of 14 mutation types were detected, including 3 compound heterozygous mutation types (c.926G > T, c.37_38delCT, and c.316G > A) that have not been previously reported. One patient had monoheterozygous mutations, including the novel mutation c.550-1G > A. Eight cases were monitored over time, 7 of which demonstrated typical growth and development. One infant with growth retardation was fed a special formula lacking methionine. The patient underwent liver transplantation. Subsequent follow-up examinations showed methionine and homocysteine levels within normal limits and no further neurological manifestations. Compound heterozygous mutations c.874C > T and c.896G > A may result in higher levels of methionine, affecting the central nervous system. For newborns with initial methionine levels of >500 µmol/L, treatment with a low-Met diet is recommended. Liver transplantation may be beneficial for children with severe hypermethioninemia, particularly in preventing central nervous system damage.

Genetic and epigenetic factors shape phenotypes and outcomes in systemic lupus erythematosus - focus on juvenile-onset systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a severe autoimmune/inflammatory disease. Patients with juvenile disease-onset and those of non-European ancestry are most severely affected. While the exact pathophysiology remains unknown, common and rare gene variants in the context of environmental exposure and epigenetic alterations are involved. This manuscript summarizes the current understanding of genetic and epigenetic contributors to SLE risk, manifestations and outcomes. Though SLE is a mechanistically complex disease, we are beginning to understand the impact of rare and common gene variants on disease expression and associated outcomes. Recent trans-ancestral and multigenerational studies suggest that differential genetic and environmental impacts shape phenotypic variability between age-groups and ancestries. High genetic burden associates with young age at disease-onset, organ involvement, and severity. Additional epigenetic impact contributes to disease-onset and severity, including SLE-phenotypes caused by rare single gene variants. Studies aiming to identify predictors of organ involvement and disease outcomes promise future patient stratification towards individualized treatment and care. An improved understanding of genetic variation and epigenetic marks explain phenotypic differences between age-groups and ancestries, promising their future exploitation for diagnostic, prognostic and therapeutic considerations.

The genetic landscape of autism spectrum disorder in an ancestrally diverse cohort

Autism spectrum disorder (ASD) comprises neurodevelopmental disorders with wide variability in genetic causes and phenotypes, making it challenging to pinpoint causal genes. We performed whole exome sequencing on a modest, ancestrally diverse cohort of 195 families, including 754 individuals (222 with ASD), and identified 38,834 novel private variants. In 68 individuals with ASD (~30%), we identified 92 potentially pathogenic variants in 73 known genes, including BCORL1, CDKL5, CHAMP1, KAT6A, MECP2, and SETD1B. Additionally, we identified 158 potentially pathogenic variants in 120 candidate genes, including DLG3, GABRQ, KALRN, KCTD16, and SLC8A3. We also found 34 copy number variants in 31 individuals overlapping known ASD loci. Our work expands the catalog of ASD genetics by identifying hundreds of variants across diverse ancestral backgrounds, highlighting convergence on nervous system development and signal transduction. These findings provide insights into the genetic underpinnings of ASD and inform molecular diagnosis and potential therapeutic targets.

Effects of CYP3A4 Variants on Methadone Metabolism InVitro.

In hepatic drug metabolism, cytochrome P450 (CYP450) enzymes, particularly CYP3A4, catalyze the majority of drug biotransformations, accounting for over 50% of the CYP450 family's metabolic capacity. This study aimed to assess the catalytic efficiency of 22 CYP3A4 allelic variants on the invitro oxidative metabolism of methadone. We utilized a baculovirus-insect cell expression system to produce recombinant CYP3A4 variants and subsequently assessed their catalytic activity in the N-demethylation of methadone. Of the 23 tested CYP3A4 allelic variants, CYP3A4*1 represents the wild type. Compared with CYP3A4*1, 12 variants displayed significantly lower intrinsic clearance of methadone, while 3 variants showed increased intrinsic clearance of methadone. Additionally, six variants demonstrated no significant difference in intrinsic clearance of methadone compared to CYP3A4*1, and one variant showed no detectable expression. Our evaluation of the enzymatic activity of CYP3A4 gene polymorphisms on methadone can aid in the personalized clinical use of methadone and facilitate the investigation into the relationship between genetic variations and clinical phenotypes.

Recent advances in autoimmune encephalitis.

Since the description of autoimmune encephalitis (AE) associated with N-methyl-D-aspartate receptor antibodies (anti-NMDARE) in 2007, more than 12 other clinical syndromes and antibodies have been reported. In this article, we review recent advances in pathophysiology, genetics, diagnosis pitfalls, and clinical phenotypes of AE associated with cell surface antibodies and anti-GAD associated neurological syndromes. Genetic studies reported human leukocyte antigen (HLA) associations for anti-LGI1, anti-Caspr2, anti-IgLON5, and anti-GAD. Follow-up studies characterized cognitive dysfunction, psychiatric symptoms, sleep disorders, and adaptative behavior dysfunction, mainly for anti-NMDARE. Late-onset anti-NMDARE and anti- GABA-B receptor (GABA-BR) encephalitis patients were described to have worse prognoses and different tumor associations. Additionally, the clinical spectrum of anti-LGI1, anti-AMPAR, anti-CASPR2, and anti-IgLON5 was expanded, comprising new differential diagnoses. The diagnostic criteria for AE were adapted to the pediatric population, and a diagnostic algorithm was proposed, considering potential mimics and misdiagnosis. We also review the limitations of commercial assays for AE and treatment recommendations, as well as clinical scales for short and long-term assessment of AE patients, along with cognitive evaluation.

Whole-genome sequencing analysis of Japanese autism spectrum disorder trios.

Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis. WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS). Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS. Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology.

Dynamic changes in gut microbiota and production phenotypes driven by host genetic background in large yellow croaker

The gut microbiota is becoming increasingly important in enhancing aquaculture productivity. However, there are fewer studies on the effect of host genetic background on the gut microbiota of cultured fish. In the current study, we aimed to determine whether the genetic background of large yellow croaker influences differences in gut microbial composition and growth. To address this objective, we conducted a comparative experiment involving the nearshore cage culture of a selected line (SL) of large yellow croaker, which was subjected to genetic selection for swimming performance, alongside a control line (CL). Both lines were reared under identical environmental and dietary conditions for a duration of six weeks. We employed 16S rRNA gene sequencing technology to analyze the gut microbial composition of the large yellow croaker, and utilized bioinformatics methods to assess the abundance and diversity of the gut microbiota. The findings revealed that the core gut microbiota of both lines primarily comprised Proteobacteria, Firmicutes, and Bacteroidetes. However, a significant disparity in gut microbiota abundance was observed between SL and CL following nearshore cage culture. Additionally, the survival rate of SL reached 64.8 %, significantly higher than the 37.3 % observed in CL. The feed conversion efficiency of SL reached 47.7 %, significantly higher than that of CL (28.6 %). These results underscore the influence of host genetic background on driving differences in gut microbial community composition and production phenotypes. This research offers intriguing insights into the interconnectedness of gut microbiota, fish genetics, and production phenotypes.

Genetic, Metabolic, and Proteomic Polymorphisms and Clinical Phenotypes of Sepsis

The heterogeneity of sepsis patient populations remains an unresolved issue, hindering the development of effective therapeutic strategies and disease prognostic tools. Classification of diverse sepsis patients by molecular endotypes, together with multi-omics profiling, enables a more personalized treatment approach. Studying the immune response, genomic, metabolomic and proteomic profiles of sepsis patients will enable clinical phenotyping of this diverse population and the development of a precision approach to the diagnosis, prognosis and treatment of sepsis and septic shock. The aim of the review was to discuss sepsis subtypes as identified by profiling of patient genomic, metabolic, and proteomic data and present the latest approaches addressing the heterogeneity of sepsis patient populations, such as multi-omics endotyping and clinical phenotyping, which may aid in targeted therapy and optimization of diagnosis and therapy. The keywords «sepsis omics», «sepsis endotypes», and «sepsis heterogeneity» were used to search PubMed databases without language restrictions. From over 300 sources, 120 were selected for analysis as being most relevant to the aim of the review. More than half of these were published within the last five years. Criteria for excluding sources were their inconsistency with the aims of the review and their low informativeness. This review discusses the different types of immune responses, the impact of patient population heterogeneity on therapeutic interventions, and current perspectives on phenotyping sepsis patients. Despite the limitations of centralized collection of clinical information, cluster analysis of large data sets and the role of immune response genomics, metabolomics, and proteomics are beginning to dominate the prognosis and treatment of sepsis. Establishing links between all these elements and attempting clinical phenotyping of sepsis, including subtype analysis, appear to be critical in the search for personalized treatment approaches in the near future. Conclusion. Currently, the widely accepted goal in sepsis management is early detection and initiation of therapy to prevent the development of irreversible septic shock and multiorgan failure syndrome. Personalized genetic, metabolomic and proteomic profiling of the patient seems to be an intriguing and promising avenue in the search for new treatment strategies in sepsis.

Identification of genomic biomarkers of disease progression and survival in primary CNS lymphoma

AbstractThe determination of the genetic subtypes of primary central nervous system lymphoma (PCNSL) and their relationship to differential chemoimmunotherapeutic response has not been established. There is a particular need for genomic biomarkers that identify patients with newly diagnosed PCNSL at high risk of early progression and death. We applied targeted next-generation sequencing for detection of recurrent single-nucleotide variants, copy number alterations, and zygosity abnormalities in diagnostic specimens from 78 patients with PCNSL treated with a standard methotrexate-based regimen, to identify prognostically significant molecular subgroups. All patients received induction immunochemotherapy, and 44 proceeded to dose-intensive consolidation. Genomic aberrations at 4 loci were associated with 91% of lymphoma progression events and all 15 deaths: (1) chromosome 6p copy-neutral loss of heterozygosity (CN-LOH) or focal homozygous deletion (HD) at 6p21.3, and mutations of tumor suppressor genes (2) BTG1, (3) ETV6, and (4) TP53. Cox regression multivariate analysis demonstrated a high risk of progression in patients with aberrations at these loci. Genomic aberrations at these loci were also associated with significantly shorter survival. Lower expression of HLA-DR was associated with 6p CN-LOH/6p21.3 HD and inferior prognosis. These genomic aberrations identify a high-risk molecular subgroup that may inform risk stratification in PCNSL. Further elucidation of the mechanisms of therapeutic resistance associated with the high-risk genetic phenotype is requisite to facilitate precision medicine and progress in therapy.

The Correlation Patterns of miRNA Expression with Targeted mRNA Transcripts in Glioma Patients with Wild-Type and Mutated Isocitrate Dehydrogenase (IDH) Genotypes.

Low-grade gliomas are divided into two main genetic phenotypes based on the presence or absence of mutations in the isocitrate dehydrogenase (IDH) genes. The mutated IDH phenotype (IDHmut), in contrast to the wild-type phenotype (IDHwt), is characterized by a more positive response to pharmacological intervention and a significantly longer survival time. In this study, we analyzed the differential co-expression of 225,000 microRNA-mRNA pairs at the level of correlations between microRNA levels and their potential mRNA targets. Analysis of the associative relationships of individual representatives of the selected pairs revealed that the level of mRNAs encoded by the ELN, ARL4C, C9orf64, PLAT, and FKBP9 genes associated with aggressive progression of glioma was increased in the IDHwt group. Meanwhile, the levels of miRNA-182, miRNA-455, and miRNA-891a associated with the negative prognosis in glioma were generally increased in the IDHmut group. Most (16/21) of the detected 21 microRNA-mRNA pairs with significant difference in regulation between IDHwt and IDHmut glioma samples had a weak or moderate positive correlation in IDHmut samples and a negative correlation in IDHwt samples. Therefore, our findings indicate that glioma samples from the IDHmut group with a positive prognosis potentially have a significantly less pronounced ability to microRNA-mediated regulation. We further suggest that such physiological disorders can lead to reduced tumor viability, resulting in an increased ability of the host to resist the spread of a malignant transformation of this genetic phenotype.

Prenatal diagnosis and genetic analysis: rare familial chromosomal duplications larger than 5 Mb without disease phenotypes.

This study aimed to identify large duplications (>5 Mb) that are harmless through long-term clinical follow-ups of fetuses and phenotype analyses of carrier family members. We retrospectively analyzed fetuses undergoing prenatal diagnosis and who had >5 Mb chromosomal duplications. Routine karyotyping and single-nucleotide polymorphism array analysis were performed to identify the source and location information of the duplicated segments. Genotype-phenotype analyses were conducted based on genetic information and phenotypes during postnatal follow-up. Eight eligible cases were included. All fetuses carried maternal or paternal duplications ranging in length from 5.3 to 12.2 Mb. The locations were as follows: 2q32.3q33.1 (Chr2:192322509-199548704), 4q22.1 (Chr4: 88347368-93602855), 4q34.2q35.2 (Chr4:176956406-189189971), 4q34.3q35.2 (Chr4:180613345-189353740), 5p14.3p14.1 (Chr5:19093749-28557664), 10q22.2q23.2 (Chr10:77448435-88786593), 12q21.31q21.32 (Chr12:81983257-87322734), and 13q14.11q14.2 (Chr13: 40825382-47633710). Karyotyping revealed that these duplications occurred within their respective chromosomal regions, except in pedigrees 6 and 7. In the eight pedigrees, the coordinates and lengths of duplicated segments in family members were matched with those in fetuses. Neither the fetuses nor other carriers were clinically symptomatic. Our findings revealed that the eight pedigrees carrying duplications >5 Mb were asymptomatic, providing new data to inform genetic counseling for the observed segments. We focused on unrelated fetuses among eight pedigrees who carried duplications of different chromosomal segments. These duplications had been stably transmitted through 2 or 3 generations of normal individuals. Importantly, phenotypic abnormalities were lacking, which was unexpected given that the maximum segment size was approximately 12.2 Mb. We found that duplications in these regions were benign in the context of prenatal genetic counseling. These results provide a foundation for addressing genotype-phenotype correlations. To our knowledge, this is the first description of normal phenotypes in individuals with duplications in these regions.

Clinical and genetic analysis of a case of Triadin knockout syndrome due to variant of TRDN gene and a literature review

To explore the genetic etiology and clinical phenotype of a child with Triadin knockout syndrome (TKOS), and to review the relevant literature of TKOS patients due to variants of TRDN gene. A child who was admitted to the Children's Hospital of Xi'an Jiaotong University on March 19, 2023 due to sudden cardiac arrest 3 days earlier was selected as the study subject. Peripheral blood samples (2 to 3 mL) were collected from the child and her parents for the extraction of genomic DNA and whole exome sequencing (WES). Pathogenic variants were searched from databases such as the Genome Aggregation Database (gnomAD) and Online Mendelian Inheritance in Man (OMIM), and were assessed based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Sanger sequencing was carried out for family validation of the pathogenic variants. Using keywords such as "arrhythmias" "TRDN" and "Triadin" both in Chinese and English, relevant literature on TKOS patients due to variants of the TRDN gene was retrieved from the CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases, and the time of literature retrieval was set from January 1, 2012 to December 1, 2023. This study has been approved by the Ethics Committee of the Affiliated Children's Hospital of Xi'an Jiaotong University (No. 20230097), and informed consent was obtained from the parents of the child. The child had experienced syncope and cardiac arrest after exercise. Electrocardiographic examination revealed QTc interval prolongation, T-wave inversion in precordial leads V1-V3, polymorphic ventricular premature beat (VPB), and ventricular tachycardia (VT) along with increased heart rate. WES and Sanger sequencing revealed that the child has harbored a homozygous c.463del(p.E155Kfs*20) variant of the TRDN gene, for which both of the parents were heterozygous. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+PM2+PM3). The child was ultimately diagnosed with TKOS. In total 12 publications on TOKS cases caused by TRDN gene variants were retrieved, which involved 30 patients and 28 carriers of single heterozygous variant of the TRDN gene. Among the 30 TKOS patients, 20 had carried homozygous variants of the TRDN gene, and 10 had carried compound heterozygous variants, and all had exhibited significant clinical phenotype of arrhythmia, with most cases had experienced malignant arrhythmia induced by exercise and/or excitement during infancy or early childhood, leading to recurrent syncope and cardiac arrest. Of note, none of the 28 carriers of single heterozygous variant had abnormal clinical phenotype. The homozygous c.463del(p.E155Kfs20) variant of the TRDN gene probably underlay the pathogenesis of cardiac arrest in this child. Above discovery has enriched the mutational spectrum of the TRDN gene.

Development of Novel InDel Markers for Breeding Applications in Pomegranate (Punica granatum L.)

ABSTRACTThe present study aims to enrich the genetic marker resources that are amenable for future trait mapping and quality improvement programmes in pomegranate. We analysed 140 well‐characterized genes that belonged to seven important gene families involved in the growth and development of pomegranate. We retrieved 140 representative genes for seven gene families from four draft genomes of pomegranate, cvs. Tunisia, Dabenzi, Taishanhong and Bhagawa, using BLASTn homology search. A total of 245 InDel primers were designed based on the comparison among four pomegranate genomes for the representative gene sequences, focusing on a size difference of at least 8 base pairs (bp). One hundred forty‐eight (60.41%) markers were in silico verified through e‐PCR on the Tunisia genome and further confirmed on the other three genomes, and we identified 107 polymorphic markers with an average PIC value of 0.62. By using 148 InDel markers physically mapped on the genome, we found that Tunisia had the highest syntenic relations with the Bhagawa (100%), Dabenzi (97.97%) and Taishanhong (97.30%) genomes. Experimental validation of 54 InDel primers on six pomegranate genotypes identified a set of 37 (71.15%) polymorphic markers, 24 of which had PIC values of ≥ 0.48. An investigation on genetic diversity and phenotype correlations in 16 pomegranate genotypes using 16 InDel markers demonstrated the utility of these markers. The developed InDel markers are an excellent resource for diverse applications in pomegranate including genetic diversity, trait mapping, gene discovery and gene editing.

Comparison of Genetic, Auditory Features, and Systemic Clinical Phenotype in 14 Families with Syndromic Hearing Loss.

Syndromic hearing loss (SHL) is characterized by distinctive clinical phenotypes as well as genetic and phenotypic heterogeneity. More than 400 species of SHL have been described, the majority of which are autosomal dominant. 11 forms of SHL were obtained from 14 unrelated families with probands ranging in age from 5 to 78 months. The results of whole exome sequencing(WES), audiological characteristics, middle and inner ear radiological findings, and additional clinical phenotype characteristics were retrospectively analyzed. Fourteen people with SHL were found. Two of them had Waardenburg syndrome, two had Branchio-Oto-Renal syndrome, two had CHARGE syndrome, and one had Treacher Collins syndrome, Kleefstra syndrome, Muenke syndrome, Osteopathia Striata with Cranial Sclerosis, Ayme-Gripp syndrome, Tatton-Brown-Rahman syndrome, Stickler syndrome, or Stapes Ankylosis with Broad Thumbs and Toes. In this investigation, ten variants were first reported. The combination of a neonatal hearing screening and WES can diagnose syndrome-type hearing loss in infancy and childhood, according to our findings, expansion of the gene variant spectrum and phenotype for various age groups of SHL is essential and can provide valuable guidelines for clinical intervention decisions. It is imperative for medical practitioners to conduct diligent and prolonged patient monitoring due to the inherent variability in both the auditory impairment and the comprehensive clinical manifestation of SHL.

Differential expression and co-expression reveal cell types relevant to genetic disorder phenotypes.

Knowledge of the specific cell types affected by genetic alterations in rare diseases is crucial for advancing diagnostics and treatments. Despite significant progress, the cell types involved in the majority of rare disease manifestations remain largely unknown. In this study, we integrated scRNA-seq data from non-diseased samples with known genetic disorder genes and phenotypic information to predict the specific cell types disrupted by pathogenic mutations for 482 disease phenotypes. We found significant phenotype-cell type associations focusing on differential expression and co-expression mechanisms. Our analysis revealed that 13% of the associations documented in the literature were captured through differential expression, while 42% were elucidated through co-expression analysis, also uncovering potential new associations. These findings underscore the critical role of cellular context in disease manifestation and highlight the potential of single-cell data for the development of cell-aware diagnostics and targeted therapies for rare diseases. All code generated in this work is available at https://github.com/SergioAlias/sc-coex.

Intramuscular hemangioma capillary type with HRAS mutation: Expanding the molecular genetic spectrum with an emphasis on overlap with arteriovenous malformations and distinct from infantile hemangioma

AimsIntramuscular hemangioma capillary type (IHCT) is a rare entity that refers to fast-flow vascular lesions. This study aims to elucidate the relationships between clinicopathological, radiological, and molecular characteristics in IHCT patients. Methods and resultsWe reviewed all IHCT cases which were treated surgically in our pathology database from 2014 to 2023. Ten cases were analyzed via next-generation sequencing (NGS) and Sanger sequencing. The cohort consisted of 10 patients (6 males, 4 females) with a median age of 18 years (range: 1–37). Disease lesions were located in the trunk (n = 4), upper extremity (n = 2), lower extremity (n = 2), shoulder (n = 1), and neck (n = 1). IHCT is most commonly a progressively increasing painless mass. Histopathologically, all lesions exhibited aggregates, lobules, and anastomosing cords of capillary-type vessels separating or infiltrating the skeletal muscles. Four cases exhibited irregularly dilated vessels with thick walls, such as arteriovenous malformations (AVM) in the lesion's periphery. MRI findings commonly demonstrated a well-delineated, homogeneous mass. Somatic mutations were detected in seven of the ten IHCT cases. Four cases harbored mutations in MAP2K1 (p.Q58_E62del, p.K57_G61del, p.K57 N), two cases harbored mutations in KRAS (p.Q61R and p.L56V, p.G13R), and one case harbored a mutation in HRAS (p.D69_Q70insRWYSAMRD). Mutant allele frequencies detected by sequencing ranged from 9.98% to 15.97%. ConclusionsThe hemodynamic and molecular genetic phenotypes of IHCT closely resemble those observed in AVMs. Newly identified KRAS missense mutations, including cases with coexisting mutation types, and HRAS insertion mutations offer valuable insights into the genetic basis of vascular anomalies. These findings may also present potential targets for the development of novel pharmacotherapeutic interventions.