MYH7 mutation is associated with mitral valve leaflet elongation in patients with obstructive hypertrophic cardiomyopathy.

Mitral valve (MV) leaflet elongation is recognized as a primary phenotypic expression of hypertrophic cardiomyopathy (HCM) that contributes to obstruction. This study investigates the correlation between MV length and genotype mutations in the two predominant genes, myosin-binding protein C (MYBPC3), and the ß-myosin heavy chain (MYH7) in patients with obstructive HCM (OHCM). Among the 402 OHCM patients, there were likely pathogenic or pathogenic variations in MYH7 (n = 94) and MYBPC3 (n = 76), along with a mutation-negative group (n = 212). Compared to genotype-negative patients, genotype-positive individuals exhibited elongated MV length, thicker interventricular septum, and increased instances of late gadolinium enhancement. Notably, MYH7 mutations were associated with a more severe disease trajectory than MYBPC3 mutations. After adjusting for potential confounders, multivariate linear regression analysis revealed that MYH7 gene mutations and left ventricular volume were independently associated with MV leaflet elongation. The study indicates that mutations in MYH7 and hemodynamics factors are significant risk factors for elongated MV leaflet. Consequently, regular assessment of MV length, especially in patients with MYH7 mutation and enlarged LV volume, is crucial for timely preoperative strategic planning and improved prognosis.

TNFRSF11A variants contribute to systemic autoinflammatory diseases: A case series of 12 patients.

BACKGROUND: Limited evidence suggests that variants in TNFRSF11A gene, encoding RANK, may contribute to systemic autoinflammatory disease (SAID). AIM/METHODS: To estimate the prevalence of TNFRSF11A variants in a cohort of patients with SAIDs screened for 26 related genes and describe the disease phenotypic expression. RESULTS: A total of 12 out of 167 patients, 7 males, aged (median) 38 years at disease onset, yielded at least one TNFRSF11A rare variant. All patients carried a coexisting variant in at least one other SAID-related gene, most frequently MEFV (6 patients), but also TNFRSF1A, NOD2, NLRP3, NLRP7, MVK, IL36RN, RBCK1, PLCG2 and PSMB8. SAID episodes lasting (median) 9 days manifested with high grade fever (91%), myalgias (75%), malaise (67%), serositis (58%), arthralgias/arthritis (58%), gastrointestinal involvement (33%), and rash (25%), and responded to corticosteroids. The most common initial clinical diagnosis was TNF-associated periodic fever syndrome (TRAPS), which was, however, confirmed, in only one patient. The emergence of MEFV variations supported the diagnosis of atypical Familial Mediterranean Fever in two cases, whereas the diagnosis of Yao syndrome was speculated in two patients with NOD2 variants. The presence of atypical disease and the inability of defining diagnosis in the remaining 7 patients, supported the possible involvement of TNFRSF11A variants in the phenotypic expression of SAIDs. CONCLUSION: TNFRSF11A variants, occurring in 7% of SAID patients always in combination with other SAID-related gene variants, contribute to the development of an autoinflammatory syndrome resembling to TRAPS. Additional studies to confirm novel pathogenic SAID pathways are clearly warranted.

A novel variation in DEPDC5 causing familial focal epilepsy with variable foci.

Background: Disheveled, EGL-10, and pleckstrin (DEP) domain-containing protein 5 (DEPDC5) is a component of GTPase-activating protein (GAP) activity toward the RAG complex 1 (GATOR1) protein, which is an inhibitor of the amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. GATOR1 complex variations were reported to correlate with familial focal epilepsy with variable foci (FFEVF). With the wide application of whole exome sequencing (WES), more and more variations in DEPDC5 were uncovered in FFEVF families. Methods: A family with a proband diagnosed with familial focal epilepsy with variable foci (FFEVF) was involved in this study. Whole exome sequencing (WES) was performed in the proband, and Sanger sequencing was used to confirm the variation carrying status of the family members. Mini-gene splicing assay was performed to validate the effect on the alternative splicing of the variation. Results: A novel variant, c.1217 + 2T>A, in DEPDC5 was identified by WES in the proband. This splicing variant that occurred at the 5' end of intron 17 was confirmed by mini-gene splicing assays, which impacted alternative splicing and led to the inclusion of an intron fragment. The analysis of the transcribed mRNA sequence indicates that the translation of the protein is terminated prematurely, which is very likely to result in the loss of function of the protein and lead to the occurrence of FFEVF. Conclusion: The results suggest that c.1217 + 2T>A variations in DEPDC5 might be the genetic etiology for FFEVF in this pedigree. This finding expands the genotype spectrum of FFEVF and provides new etiological information for FFEVF.

Parapoxvirus species revisited by whole genome sequencing: A retrospective analysis of bovine virus isolates.

Parapoxviruses (PPV) of animals are spread worldwide. While the Orf virus (ORFV) species is a molecularly well-characterized prototype pathogen of small ruminants, the genomes of virus species affecting large ruminants, namely Bovine papular stomatitis virus (BPSV) and Pseudocowpox virus (PCPV), are less well known. Using Nanopore sequencing we retrospectively show the whole genome sequences (WGS) of six BPSV, three PCPV isolates and an attenuated ORFV strain, originating from different geographic locations. A phylogenetic tree shows that the de novo assembled genomes belong to PPV species including WGS of reference PPV. Remarkably, Nanopore sequencing allowed the molecular resolution of inverted terminal repeats (ITR) and the hairpin loop within the de novo assembled WGS. Additionally, peculiarities regarding map location of two genes and the heterogeneity of a genomic region were noted. Details for the molecular variability of an interferon response modulatory gene (ORF116) and the PCPV specificity of gene 073.5 are reported. In summary, WGS gained by Nanopore sequencing allowed analysis of complete PPV genomes and confident virus species attribution within a phylogenetic tree avoiding uncertainty of limited gene-based diagnostics. Nanopore-based WGS provides robust comparison of PPV genomes and reliable identity determination of new Poxviruses.

Molecular and phenotypic characteristics of Bardet-Biedl syndrome in Chinese patients.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a type of non-motile ciliopathy. To date, 26 genes have been reported to be associated with BBS. However, BBS is genetically heterogeneous, with significant clinical overlap with other ciliopathies, which complicates diagnosis. Disability and mortality rates are high in BBS patients; therefore, it is urgent to improve our understanding of BBS. Thus, our study aimed to describe the genotypic and phenotypic spectra of BBS in China and to elucidate genotype-phenotype correlations. METHODS: Twenty Chinese patients diagnosed with BBS were enrolled in this study. We compared the phenotypes of Chinese BBS patients in this study with those from other countries to analyze the phenotypic differences across patients worldwide. In addition, genotype-phenotype correlations were described for our cohort. We also summarized all previously reported cases of BBS in Chinese patients (71 patients) and identified common and specific genetic variants in the Chinese population. RESULTS: Twenty-eight variants, of which 10 are novel, in 5 different BBS-associated genes were identified in 20 Chinese BBS patients. By comparing the phenotypes of BBSome-coding genes (BBS2,7,9) with those of chaperonin-coding genes (BBS10,12), we found that patients with mutations in BBS10 and 12 had an earlier age of onset (1.10 Vs. 2.20, p < 0.01) and diagnosis (4.64 Vs. 13.17, p < 0.01), whereas patients with mutations in BBS2, 7, and 9 had a higher body mass index (28.35 Vs. 24.21, p < 0.05) and more vision problems (p < 0.05). Furthermore, in 91 Chinese BBS patients, mutations were predominant in BBS2 (28.89%) and BBS7 (15.56%), and the most frequent variants were in BBS2: c.534 + 1G > T (10/182 alleles) and BBS7: c.1002delT (7/182 alleles), marking a difference from the genotypic spectra of BBS reported abroad. CONCLUSIONS: We recruited 20 Chinese patients with BBS for genetic and phenotypic analyses, and identified common clinical manifestations, pathogenic genes, and variants. We also described the phenotypic differences across patients worldwide and among different BBS-associated genes. This study involved the largest cohort of Chinese patients with BBS, and provides new insights into the distinctive clinical features of specific pathogenic variants.

Understanding the Mechanisms of Diminished Ovarian Reserve: Insights from Genetic Variants and Regulatory Factors.

Delaying childbearing age has become a trend in modern times, but it has also led to a common challenge in clinical reproductive medicine-diminished ovarian reserve (DOR). Since the mechanism behind DOR is unknown and its clinical features are complex, physicians find it difficult to provide targeted treatment. Many factors affect ovarian reserve function, and existing studies have shown that genetic variants, upstream regulatory genes, and changes in protein expression levels are present in populations with reduced ovarian reserve function. However, existing therapeutic regimens often do not target the genetic profile for more individualized treatment. In this paper, we review the types of genetic variants, mutations, altered expression levels of microRNAs, and other related factors and their effects on the regulation of follicular development, as well as altered DNA methylation. We hope this review will have significant implications for the future treatment of individuals with reduced ovarian reserve.

Novel variations in TENT5D lead to teratozoospermia in infertile patients.

PURPOSE: Teratozoospermia is the main pathogenic factor of male infertility. However, the genetic etiology of teratozoospermia is largely unknown. This study aims to clarify the relationship between novel variations in TENT5D and teratozoospermia in infertile patients. MATERIALS AND METHODS: Two infertile patients were enrolled. Routine semen analysis of patients and normal controls was conducted with the WHO guidelines. Whole-exome sequencing (WES) was conducted to identify pathogenic variants in the two patients. Morphology and ultrastructure analysis of spermatozoa in the two patients was determined by Papanicolaou staining, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The functional effect of the identified variants was analyzed by immunofluorescence staining and western blotting. The expression of TENT5D in different germ cells was detected by immunofluorescence staining. RESULTS: Two new hemizygous variations, c.101C > T (p.P34L) and c.125A > T (p.D42V), in TENT5D were detected in two patients with male infertility. Morphology analysis showed abnormalities in spermatozoa morphology in the two patients, including multiple heads, headless, multiple tails, coiled, and/or bent flagella. Ultrastructure analysis showed that most of the spermatozoa exhibited missing or irregularly arranged '9+2' structures. Further functional experiments confirmed the abrogated TENT5D protein expression in patients. In addition, both p.P34L and p.D42V substitutions resulted in a conformational change of the TENT5D protein. We precisely analyzed the subcellular localization of TENT5D in germ cells in humans and mice. And we found that TENT5D was predominantly detected in the head and flagellum of elongating spermatids and epididymal spermatozoa. CONCLUSIONS: Our results showed further evidence of a relationship between TENT5D mutation and human male infertility, providing new genetic insight for use in the diagnosis and treatment of male infertility.

Peripheral immune profile and gene variations of 11 immunodeficiency virus-negative children with Talaromyces marneffei infection / 中华实用儿科临床杂志

Objective:To explore the immunological characteristics of peripheral blood and genetic variations of 11 immunodeficiency virus(HIV)-negative children with Talaromyces marneffei(TM) infection, thus enhancing the diagnostic and therapeutic levels of TM infection in children. Methods:Clinical data of 11 HIV-negative children with TM infection who presented to Guangzhou Women and Children′s Medical Center, Guangzhou Medical University from January 2010 to December 2022 were retrospectively analyzed, including clinical characteristics, peripheral immune profile and genetic test results.Results:A total of 11 HIV-negative children with TM infections were recruited, involving 9 males and 2 females with a median age of 19 months.The main clinical manifestations were fever (10/11, 90.91%), cough (10/11, 90.91%) and hepatomegaly (7/11, 63.64%). Common severe complications included acute respiratory distress syndrome (7/11, 63.64%) and septic shock (5/11, 45.45%). Finally, 2 children died.Transient neutropenia occurred in 6 cases (6/11, 54.55%), and lymphocytopenia combined with serum immunoglobulin (Ig) G decrease was observed in 4 cases (4/11, 36.36%). IgA decrease, IgM decrease, IgE decrease, IgM increase and IgE increase were observed in 6 cases, 3 cases, 5 cases, 3 cases, and 2 cases, respectively.Both T-lymphocyte and B-lymphocyte counts decreases was observed in 1 case.Genetic testing was performed in all recruited children, and genetic variations were detected in all of them.Inborn errors of immunity (IEIs) were diagnosed in 8 cases, including 4 diagnosed as CD 40 ligand deficiency with CD40LG variation, 1 of severe combined immunodeficiency with IL2RG variation, 1 of Signal transduction and activator of transcription 3(STAT3)-hyper-IgE syndrome with STAT3 variation and 1 of familial candidiasis type 2 with CARD9 compound heterozygous mutations.In the other 3 cases, 2 carried genetic variations that were likely pathogenic, and 1 case was considered uncertain. Conclusions:The clinical manifestations of HIV-negative children with TM infection are atypical, which is characterized as serious complications and high mortality.Early identification and gene testing to detect potential IEIs can improve the prognosis of TM infection.

Analysis of drug resistance gene variation of influenza A（H1N1） pdm09 virus in Huzhou City，Zhejiang Province / 上海预防医学

ObjectiveTo investigate the mutation and genetic evolution of drug resistance gene of A（H1N1） pdm09 influenza pandemic strain in 2023 in Huzhou City， Zhejiang Province. MethodsRespiratory tract specimens from 2 influenza monitoring hospitals were collected forA（H1N1） pdm09 influenza virus nucleic acid detection. Positive specimens were inoculated with MDCK cells for influenza virus isolation and sequencing. DNA Star 7.1 software and Mega 4.0 software were used to analyze the neuraminidase （NA） enzyme active site and the amino acid sites related to drug resistance in M2 protein. ResultsNucleotide homology and amino acid homology of NA between the isolated and the vaccine strains were 98.87%‒99.22% and 98.94%‒99.36%， respectively. The nucleotide homology range of M gene was 99.07% to 99.85%， and the amino acid homology range was 99.02%‒99.94%. The isolates and vaccine strains belong to the evolutionary clades of 6B.1A.5a.2a. The amino acids at the key sites of the enzyme activity center of NA were still highly conserved， and the 9 key amino acid sites related to NA inhibitor resistance did not change， but some mutations occurred at the non-enzyme active sites in some popular strains. The 5 amino acid sites related to drug resistance of M2 protein were not replaced， but the 31st amino acid sites changed from serine to asparagine. ConclusionThe A（H1N1） pdm09 pandemic strain in Huzhou in 2023 has high homology with the 2023‒2024 vaccine strain recommended by WHO. All endemic strains are resistant to amantadines.

Gut microbiome and metabolic profiles of mouse model for MeCP2 duplication syndrome.

The extra copy of the methyl-CpG-binding protein 2 (MeCp2) gene causes MeCP2 duplication syndrome (MDS), a neurodevelopmental disorder characterized by intellectual disability and autistic phenotypes. However, the disturbed microbiome and metabolic profiling underlying the autistic-like behavioral deficits of MDS are rarely investigated. Here we aimed to understand the contributions of microbiome disruption and associated metabolic alterations, especially the disturbed neurotransmitters in MDS employing a transgenic mouse model with MeCP2 overexpression. We analyzed metabolic profiles of plasma, urine, and cecum content and microbiome profiles by both 16 s RNA and shotgun metagenomics sequence technology. We found the decreased levels of Firmicutes and increased levels of Bacteroides in the single MeCP2 gene mutation autism-like mouse model, demonstrating the importance of the host genome in a selection of microbiome, leading to the heterogeneity characteristics of microbiome in MDS. Furthermore, the changed levels of several neurotransmitters (such as dopamine, taurine, and glutamate) implied the excitatory-inhibitory imbalance caused by the single gene mutation. Concurrently, a range of microbial metabolisms of aromatic amino acids (such as tryptophan and phenylalanine) were identified in different biological matrices obtained from MeCP2 transgenic mice. Our investigation revealed the importance of genetic variation in accounting for the differences in microbiomes and confirmed the bidirectional regulatory axis of microbiota-gut-brain in studying the role of microbiome on MDS, which could be useful in deeply understanding the microbiome-based treatment in this autistic-like disease.

A Rare Case Report of Neonatal Neurofibromatosis Type 1 Presented with Giant Faciocervical Mass and Complicated with HIE.

A newborn with giant faciocervical mass and presented with asphyxia during birth was admitted to the hospital. After stabilizing her vital sign, we provided the patient with image examinations and whole-exome sequencing, which revealed a heterozygous variation of neurofibromatosis type 1 (NF1). The final diagnosis of the patient was NF1 complicated with neonatal hypoxic-ischemic encephalopathy (NHIE). During hospitalization, the patient received comprehensive and systematic care. There was no reports of similar cases in the literature. So, this report aimed to elucidate the special clinical manifestations, diagnosis, treatment and prognosis of NF1 complicated with NHIE by analyzing the clinical data of the patient and her family and reviewing relevant literature.

Results of neonatal screening for congenital hypothyroidism and hyperphenylalaninemia in Zhejiang province from 1999 to 2022. / 浙江省1200ä¸‡ä¾‹æ–°ç”Ÿå„¿å ˆå¤©æ€§ç”²çŠ¶è ºåŠŸèƒ½å‡é€€ç—‡ã€é«˜è‹¯ä¸™æ°¨é ¸è¡€ç—‡ç­›æŸ¥ç»“æžœåˆ†æž.

OBJECTIVES: To analyze the results of neonatal screening for congenital hypothyroidism (CH) and hyperphenylalaninemia (HPA) in Zhejiang province from 1999 to 2022. METHODS: A total of 11 922 318 newborns were screened from September 1999 and December 2022 in Zhejiang province. The blood thyroid stimulating hormone (TSH) levels were measured by a fluorescence method and blood phenylalanine (Phe) levels were measured by fluorescence method or tandem mass spectrometry. TSH≥9 µIU/mL was considered positive for CH, while Phe>120 µmol/L and/or Phe/Tyr ratio>2.0 were considered positive for HPA. The positive newborns in screening were recalled, and the gene variations were detected by high-throughput sequencing and MassARRAY tests. RESULTS: The overall neonatal screening rate during 1999-2022 was 89.41% (11 922 318/13 333 929) and the screening rate was increased from 6.46% in 1999 to 100.0% in 2022. A total of 8924 cases of CH were diagnosed among screened newborns with an incidence rate of 1/1336. A total of 563 cases of HPA were diagnosed, including 508 cases of classic phenylketonuria (cPKU) and 55 cases of tetrahydrobiopterin deficiency (BH4D), with an incidence rate of 1/21 176. Ninety-seven out of 8924 cases of CH underwent genetic analysis. Gene mutations were detected in 9 CH related genes, the highest frequency mutations were found in DUOX2 gene (69.0%) with c.3329G>A (p.R1110Q) (18.2%) and c.1588A>T (p.K530X) (17.3%) as the hotspot mutations. There were 81 PAH gene variants detected in a total of 250 cases of cPKU, and c728G>A (p.R243Q) (24.4%), c.721C>T (p.R241C) (15.0%) were the hotspot mutations. Meanwhile 7 novel variants in PAH gene were detected: c.107C>A (p.S36*), c.137G>T (p.G46V), c.148A>G(p.K50E), c.285C>T (p.I95I), c.843-10delTTCC, exon4-7del and c.1066-2A>G. There were 12 PTS gene variants detected in 36 cases of BH4D, and c.259C>T (p.P87S) (31.9%) was the hotspot mutation. CONCLUSIONS: The incident of CH has increased from 1999 to 2022 in Zhejiang province, and it is higher than that of national and global levels; while the incidence of HPA is similar to the national average. DUOX2 gene variation is the most common in CH patients; c.728G>A (p.R243Q) is the hotspot mutation in cPKU patients, while c.259C>T (p.P87S) is the hotspot mutation in BH4D patients.

Analysis of genotypes and biochemical phenotypes of neonates with abnormal metabolism of butyrylcarnitine. / ä¸é °åŸºè‚‰ç¢±ä»£è°¢å¼‚å¸¸æ–°ç”Ÿå„¿çš„åŸºå› åž‹å’Œç”ŸåŒ–è¡¨åž‹åˆ†æž.

OBJECTIVES: To investigate the genotypes and biochemical phenotypes of neonates with abnormal metabolism of butyrylcarnitine (C4). METHODS: One hundred and twenty neonates with increased C4 levels detected by tandem mass spectrometry in the neonatal screening at Children's Hospital, Zhejiang University School of Medicine from January 2018 to June 2023 were included. The initial screening data and recalled data of C4 and C4/C3 were collected and converted into multiples of C4 reference range. Next generation sequencing was performed and the exons with adjacent 50 bp regions of ACAD8 and ACADS genes were captured by liquid phase capture technique. Variant information was obtained by bioinformatic analysis and the pathogenicity were classified according to the American College of Medical Genetics and Genomics criteria. The Wilcoxon rank sum test was used to analyze the differences in C4 levels among neonates with different variation types. RESULTS: In total, 32 variants in ACAD8 gene were detected, of which 7 variants were reported for the first time; while 41 variants of ACADS gene were detected, of which 17 variants have not been previously reported. There were 39 cases with ACAD8 biallelic variations and 3 cases with ACAD8 monoallelic variations; 34 cases with ACADS biallelic variations and 36 cases with ACADS monoallelic variations. Furthermore, 5 cases were detected with both ACAD8 and ACADS gene variations. Inter group comparison showed that the multiples of C4 reference range in initial screening and re-examination of the ACAD8 biallelic variations and ACADS biallelic variations groups were significantly higher than those of the ACADS monoallelic variations group (all P<0.01), while the multiples in the ACAD8 biallelic variations group were significantly higher than those in the ACADS biallelic variations group (all P<0.01). The multiples of C4 reference range in the initial screening greater than 1.5 times were observed in all neonates carrying ACAD8 or ACADS biallelic variations, while only 25% (9/36) in neonates carrying ACADS monoallelic variations. CONCLUSIONS: ACAD8 and/or ACADS gene variants are the main genetic causes for elevated C4 in newborns in Zhejiang region with high genotypic heterogeneity. The C4 levels of neonates with biallelic variations are significantly higher than those of neonates with monoallelic variations. The cut-off value for C4 level could be modestly elevated, which could reduce the false positive rate in tandem mass spectrometry neonatal screening.

A multi-layered computational structural genomics approach enhances domain-specific interpretation of Kleefstra syndrome variants in EHMT1.

This study investigates the functional significance of assorted variants of uncertain significance (VUS) in euchromatic histone lysine methyltransferase 1 (EHMT1), which is critical for early development and normal physiology. EHMT1 mutations cause Kleefstra syndrome and are linked to various human cancers. However, accurate functional interpretations of these variants are yet to be made, limiting diagnoses and future research. To overcome this, we integrate conventional tools for variant calling with computational biophysics and biochemistry to conduct multi-layered mechanistic analyses of the SET catalytic domain of EHMT1, which is critical for this protein function. We use molecular mechanics and molecular dynamics (MD)-based metrics to analyze the SET domain structure and functional motions resulting from 97 Kleefstra syndrome missense variants within the domain. Our approach allows us to classify the variants in a mechanistic manner into SV (Structural Variant), DV (Dynamic Variant), SDV (Structural and Dynamic Variant), and VUS (Variant of Uncertain Significance). Our findings reveal that the damaging variants are mostly mapped around the active site, substrate binding site, and pre-SET regions. Overall, we report an improvement for this method over conventional tools for variant interpretation and simultaneously provide a molecular mechanism for variant dysfunction.

Characteristics, differential diagnosis, individualized treatment, and prevention of hyperhomocysteinemia in newborns.

OBJECTIVES: This study aimed to investigate the incidence rate, clinical phenotype, gene variation spectrum, and prognosis of neonatal hyperhomocysteinemia (HHcy) and explore its diagnosis, individualised treatment, and prevention strategies. METHODS: We screened 84722 neonates for HHcy using liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with biochemical detection, urine gas chromatography-mass spectrometry (GC-MS), and next-generation sequencing (NGS) for gene analysis to comprehensively differentiate and diagnose diseases. RESULTS: 18 children (P1-P18) were diagnosed with methylmalonic acidemia (MMA) and HHcy, and fourteen known and one new variant of the MMACHC gene were found. Five children showed poor mental reactions, brain dysplasia, lethargy, hyperbilirubinemia, and jaundice, whereas the other 13 children had no evident abnormalities. These children were all cobalamin- and folic acid-reactive types, and they were mainly supplemented with cobalamin, L-carnitine, betaine, and folic acid. The mother of P12 had a prenatal diagnosis at the next pregnancy; the results showed that MMACHC gene was not pathogenic and she gave birth to a healthy baby. One child (P19) was diagnosed with methylenetetrahydrofolate reductase (MTHFR) deficiency, and one new mutation was detected in the MTHFR gene. Patient P19 showed congenital brain dysplasia, neonatal anaemia, and hyperbilirubinemia, and treatment consisted mainly of betaine and cobalamin supplementation. One child (P20) was confirmed to have methionine adenosyltransferase I (MAT I) deficiency but had no clinical manifestations. After treatment, all the children had a good prognosis. CONCLUSION: The incidence of neonatal HHcy in the Zibo area was 1/4236, and the common pathogenic variants were c.609G>A, c.80A>G, and c.482G>A in the MMACHC gene. Patients with HHcy can achieve a good prognosis if pathogenic factors and targeted treatment are identified. Gene analysis and prenatal diagnosis contribute to the early prevention of HHcy.

Case report: A Chinese patient with glutathione synthetase deficiency and a novel glutathione synthase mutation.

Glutathione synthetase deficiency (GSSD) is an autosomal-recessive metabolic disorder caused by glutathione synthetase (GSS) gene mutations. No more than 90 cases of GSSD have been reported worldwide; thus, the spectrum of GSS mutations and the genotype-phenotype association remain unclear. Here, we present a severely affected infant carrying a compound heterozygous GSS variation, c.491G > A, and a novel variant of c.1343_1348delTACTTC. We also summarize the clinical manifestations, treatment protocol, prognosis, and genetic characteristics of previously reported GSSD cases in China. In this case study, our patient presented with tachypnea, jaundice, intractable metabolic acidosis, and hemolytic anemia. Urinary-organic acid analysis revealed elevated 5-oxoproline levels. Further, this patient showed improved outcomes owing to early diagnosis and the timely administration of vitamins C and E. Therefore, our study indicates that in clinical cases of unexplained hemolytic anemia and metabolic acidosis, GSSD should be considered. Additionally, genetic testing and antioxidant application might help identify GSSD and improve the prognosis.

Imprinted Genes: Genomic Conservation, Transcriptomic Dynamics and Phenomic Significance in Health and Diseases.

Since its discovery in 1991, genomic imprinting has been the subject of numerous studies into its mechanisms of establishment and regulation, evolution and function, and presence in multiple genomes. Disturbance of imprinting has been implicated in a range of diseases, ranging from debilitating syndromes to cancers to fetal deficiencies. Despite this, studies done on the prevalence and relevance of imprinting on genes have been limited in scope, tissue types available, and focus, by both availability and resources. This has left a gap in comparative studies. To address this, we assembled a collection of imprinted genes available in current literature covering five species. Here we sought to identify trends and motifs in the imprinted gene set (IGS) in three distinct arenas: evolutionary conservation, across-tissue expression, and health phenomics. Overall, we found that imprinted genes displayed less conservation and higher proportions of non-coding RNA while maintaining synteny. Maternally expressed genes (MEGs) and paternally expressed genes (PEGs) occupied distinct roles in tissue expression and biological pathway use, while imprinted genes collectively showed a broader tissue range, notable preference for tissue specific expression and limited gene pathways than comparable sex differentiation genes. Both human and murine imprinted genes showed the same clear phenotypic trends, that were distinct from those displayed by sex differentiation genes which were less involved in mental and nervous system disease. While both sets had representation across the genome, the IGS showed clearer clustering as expected, with PEGs significantly more represented than MEGs.

Variation of insulin-related peptides accompanying the differentiation of Aphis gossypii biotypes and their expression profiles.

Insulin signaling plays a critical role in regulating various aspects of insect biology, including development, reproduction, and the formation of wing polyphenism. This leads to differentiation among insect populations at different levels. The insulin family exhibits functional variation, resulting in diverse functional pathways. Aphis gossypii Glover, commonly known as the cotton-melon aphid, is a highly adaptable aphid species that has evolved into multiple biotypes. To understand the genetic structure of the insulin family and its evolutionary diversification and expression patterns in A. gossypii, we conducted studies using genome annotation files and RNA-sequencing data. Consequently, we identified 11 insulin receptor protein (IRP) genes in the genomes of the examined biotypes. Among these, eight AgosIRPs were dispersed across the X chromosome, while two were found in tandem on the A1 chromosome. Notably, AgosIRP2 exhibited alternative splicing, resulting in the formation of two isoforms. The AgosIRP genes displayed a high degree of conservation between Hap1 and Hap3, although some variations were observed between their genomes. For instance, a transposon was present in the coding regions of AgosIRP3 and AgosIRP9 in the Hap3 genome but not in the Hap1 genome. RNA-sequencing data revealed that four AgosIRPs were expressed ubiquitously across different morphs of A. gossypii, while others showed specific expression patterns in adult gynopara and adult males. Furthermore, the expression levels of most AgosIRPs decreased upon treatment with the pesticide acetamiprid. These findings demonstrate the evolutionary diversification of AgosIRPs between the genomes of the two biotypes and provide insights into their expression profiles across different morphs, developmental stages, and biotypes. Overall, this study contributes valuable information for investigating aphid genome evolution and the functions of insulin receptor proteins.

Genetic variability and mutation of Epstein‒Barr virus (EBV)-encoded LMP-1 and BHRF-1 genes in EBV-infected patients: identification of precise targets for development of personalized EBV vaccines.

The critical Epstein‒Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) and BamHI fragment H rightward open reading frame 1 (BHRF-1) genes affect EBV-mediated malignant transformation and virus replication during EBV infection. Therefore, these two genes are considered ideal targets for EBV vaccine development. However, gene mutations in LMP-1 and BHRF-1 in different cohorts may affect the biological functions of EBV, which would seriously hinder development of personalized vaccines for EBV. In the present study, by performing nested polymerase chain reaction (nested PCR) and DNA sequence techniques, we analyzed the nucleotide variability and phylogeny of LMP-1 containing a 30 bp deletion region (del-LMP-1) and BHRF-1 in EBV-infected patients (N = 382) and healthy persons receiving physical examination (N = 98; defined as the control group) in Yunnan Province, China. Three BHRF-1 subtypes were identified in this study: 79V88V, 79L88L, and 79V88L, with mutation frequencies of 58.59%, 24.24%, and 17.17%, respectively. Compared with the control group, the distribution of BHRF-1 subtypes of the three groups showed no significant difference, suggesting that BHRF-1 is highly conserved in EBV-related samples. In addition, a short fragment of del-LMP-1 was found in 133 cases, and the nucleotide variation rate was 87.50% (133/152). For del-LMP-1, a significant distribution in three groups was detected, as characterized by a high mutation rate. In conclusion, our study illustrates gene variability and mutations of EBV-encoded del-LMP-1 and BHRF-1 in clinical samples. Highly mutated LMP-1 might be associated with various types of EBV-related diseases, indicating that BHRF-1 combined with LMP-1 may be used as an ideal target for development of EBV personalized vaccines.