A pangenome reference of 36 Chinese populations.

Human genomics is witnessing an ongoing paradigm shift from a single reference sequence to a pangenome form, but populations of Asian ancestry are underrepresented. Here we present data from the first phase of the Chinese Pangenome Consortium, including a collection of 116 high-quality and haplotype-phased de novo assemblies based on 58 core samples representing 36 minority Chinese ethnic groups. With an average 30.65× high-fidelity long-read sequence coverage, an average contiguity N50 of more than 35.63 megabases and an average total size of 3.01 gigabases, the CPC core assemblies add 189 million base pairs of euchromatic polymorphic sequences and 1,367 protein-coding gene duplications to GRCh38. We identified 15.9 million small variants and 78,072 structural variants, of which 5.9 million small variants and 34,223 structural variants were not reported in a recently released pangenome reference1. The Chinese Pangenome Consortium data demonstrate a remarkable increase in the discovery of novel and missing sequences when individuals are included from underrepresented minority ethnic groups. The missing reference sequences were enriched with archaic-derived alleles and genes that confer essential functions related to keratinization, response to ultraviolet radiation, DNA repair, immunological responses and lifespan, implying great potential for shedding new light on human evolution and recovering missing heritability in complex disease mapping.

Ancestral Origins and Admixture History of Kazakhs.

Kazakh people, like many other populations that settled in Central Asia, demonstrate an array of mixed anthropological features of East Eurasian (EEA) and West Eurasian (WEA) populations, indicating a possible scenario of biological admixture between already differentiated EEA and WEA populations. However, their complex biological origin, genomic makeup, and genetic interaction with surrounding populations are not well understood. To decipher their genetic structure and population history, we conducted, to our knowledge, the first whole-genome sequencing study of Kazakhs residing in Xinjiang (KZK). We demonstrated that KZK derived their ancestries from 4 ancestral source populations: East Asian (∼39.7%), West Asian (∼28.6%), Siberian (∼23.6%), and South Asian (∼8.1%). The recognizable interactions of EEA and WEA ancestries in Kazakhs were dated back to the 15th century BCE. Kazakhs were genetically distinctive from the Uyghurs in terms of their overall genomic makeup, although the 2 populations were closely related in genetics, and both showed a substantial admixture of western and eastern peoples. Notably, we identified a considerable sex-biased admixture, with an excess of western males and eastern females contributing to the KZK gene pool. We further identified a set of genes that showed remarkable differentiation in KZK from the surrounding populations, including those associated with skin color (SLC24A5, OCA2), essential hypertension (HLA-DQB1), hypertension (MTHFR, SLC35F3), and neuron development (CNTNAP2). These results advance our understanding of the complex history of contacts between Western and Eastern Eurasians, especially those living or along the old Silk Road.

Comparative Genomic and Transcriptomic Analyses Reveal the Impacts of Genetic Admixture in Kazaks, Uyghurs, and Huis.

Population admixture results in the combinations of genetic components derived from distinct ancestral populations, which may impact diversity at the genetic, transcriptomic, and phenotypic levels, as well as postadmixture adaptive evolution. Here, we systematically investigated the genomic and transcriptomic diversity in Kazaks, Uyghurs, and Huis-three admixed populations of various Eurasian ancestries living in Xinjiang, China. All three populations showed elevated genetic diversity and closer genetic distance compared with the reference populations across the Eurasian continent. However, we also observed differentiated genomic diversity and inferred different demographic histories among the three populations. Varying ancestry proportions observed in both the global and local aspects corresponded to the population-differentiated genomic diversity, with the most representative signals observed in the genes EDAR, SULT1C4, and SLC24A5. The varying local ancestry partly resulted from the postadmixture local adaptation, with the most significant signals observed in immunity- and metabolism-related pathways. Admixture-shaped genomic diversity further influenced the transcriptomic diversity in the admixed populations; in particular, population-specific regulatory effects were associated with immunity- and metabolism-involved genes such as MTHFR, FCER1G, SDHC, and BDH2. Furthermore, differentially expressed genes between the populations were identified, many of which could be explained by the population-specific regulatory properties, including genes related to health concerns (e.g., AHI1 between Kazak and Uyghurs [P < 6.92 × 10-5] and CTRC between Huis and Uyghurs [P < 2.32 × 10-4]). Our results demonstrate genetic admixture as a driving force in shaping the genomic and transcriptomic diversity of human populations.

MultiWaverX: modeling latent sex-biased admixture history.

Sex-biased gene flow has been common in the demographic history of modern humans. However, the lack of sophisticated methods for delineating the detailed sex-biased admixture process prevents insights into complex admixture history and thus our understanding of the evolutionary mechanisms of genetic diversity. Here, we present a novel algorithm, MultiWaverX, for modeling complex admixture history with sex-biased gene flow. Systematic simulations showed that MultiWaverX is a powerful tool for modeling complex admixture history and inferring sex-biased gene flow. Application of MultiWaverX to empirical data of 17 typical admixed populations in America, Central Asia, and the Middle East revealed sex-biased admixture histories that were largely consistent with the historical records. Notably, fine-scale admixture process reconstruction enabled us to recognize latent sex-biased gene flow in certain populations that would likely be overlooked by much of the routine analysis with commonly used methods. An outstanding example in the real world is the Kazakh population that experienced complex admixture with sex-biased gene flow but in which the overall signature has been canceled due to biased gene flow from an opposite direction.

Borderline personality traits mediate the relationship between negative life events and nonsuicidal self-injury in a clinical sample with youth depression.

BACKGROUND: Borderline personality traits play a significant role in nonsuicidal self-injury (NSSI), particularly in depressed youths. NSSI is also highly correlated with negative life events. This research aimed to explore the connections between negative life events, borderline personality traits, and NSSI. METHODS: The study included 338 depressed youth aged 13 to 25 years. Self-reported measures and clinical interviews were utilized to evaluate the depressive symptoms, borderline personality traits, negative life events, and NSSI behaviours of these participants. Identifying variables linked to NSSI was the aim of our analysis, and we also conducted a mediation analysis to look into the influence of borderline traits on the connection between negative life events and NSSI. RESULTS: Of the 338 depressed youth, approximately 59.47% (201/338) displayed NSSI, which was associated with greater clinical severity. Borderline traits had an independent influence on NSSI and it partially explained the connection between negative life events and NSSI, even when accounting for depression symptoms. Depressed youth who were more vulnerable to NSSI behaviours often experienced negative life events such as interpersonal relationships, academic pressure, being punished, and loss. CONCLUSIONS: Our research suggests that depressed youth who experience more negative life events are more likely to experience NSSI, and negative life events indirectly influence nonsuicidal self-injury through borderline personality traits. Implementing interventions focused on mitigating borderline symptoms could be a promising therapeutic approach for addressing NSSI in young people.

Quantitative DNA Methylation Analysis and Epigenotype-Phenotype Correlations in Taiwanese Patients with Silver-Russell Syndrome.

Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.

Genetic Connections and Convergent Evolution of Tropical Indigenous Peoples in Asia.

Tropical indigenous peoples in Asia (TIA) attract much attention for their unique appearance, whereas their genetic history and adaptive evolution remain mysteries. We conducted a comprehensive study to characterize the genetic distinction and connection of broad geographical TIAs. Despite the diverse genetic makeup and large interarea genetic differentiation between the TIA groups, we identified a basal Asian ancestry (bASN) specifically shared by these populations. The bASN ancestry was relatively enriched in ancient Asian human genomes dated as early as ∼50,000 years before the present and diminished in more recent history. Notably, the bASN ancestry is unlikely to be derived from archaic hominins. Instead, we suggest it may be better modeled as a survived lineage of the initial peopling of Asia. Shared adaptations inherited from the ancient Asian ancestry were detected among the TIA groups (e.g., LIMS1 for hair morphology, and COL24A1 for bone formation), and they are enriched in neurological functions either at an identical locus (e.g., NKAIN3), or different loci in an identical gene (e.g., TENM4). The bASN ancestry could also have formed the substrate of the genetic architecture of the dark pigmentation observed in the TIA peoples. We hypothesize that phenotypic convergence of the dark pigmentation in TIAs could have resulted from parallel (e.g., DDB1/DAK) or genetic convergence driven by admixture (e.g., MTHFD1 and RAD18), new mutations (e.g., STK11), or notably purifying selection (e.g., MC1R). Our results provide new insights into the initial peopling of Asia and an advanced understanding of the phenotypic convergence of the TIA peoples.

Profiling and integrated analysis of differentially expressed circRNAs in cervical cancer.

Circular RNAs (circRNAs) are a new type of regulatory RNAs, which have been identified to play critical role in various tumors. However, the profiles and roles of circRNAs in cervical cancer (CCa) have not been fully understood and need to be further explored. In the present study, we performed circRNA array and mRNA-sequencing (mRNA-Seq) to profile the differentially expressed circRNAs and mRNAs in CCa tissues. A total of 397 differentially expressed circRNAs and 2138 differentially expressed mRNAs were detected, respectively. Subsequently, a circRNA-miRNA-mRNA regulatory network was constructed and indicated that hsa_circ_0026377 was downregulated in CCa. Overexpression of hsa_circ_0026377 inhibited HeLa and SiHa cells proliferation, migration and invasion. Collectively, this study provided new insights into the circRNA profiles in CCa and suggested that hsa_circ_0026377 might play important roles in CCa development.

Transport model simulation prediction and environmental risk assessment of pyrethroid insecticides in urban artificial lakes caused by rainfall: A case study of Cloud Mountain Park in subhumid climate zone.

Pyrethroid insecticides are among urban parks' most widely used and harmful insecticides. The advanced prediction method is the key to studying the pollution and diffusion risk of plant conservation insecticides in parks. A two-dimensional advection-dispersion model was established for the North Lake of Cloud Mountain Park in the subhumid area of Hebei Province. The temporal and spatial distribution of lambda-cyhalothrin pollution required by plant growth in artificial lakes under different rainfall intensities and the time of water renewal after rainfall was simulated and predicted. According to the model efficiency (E: 0.98), mean absolute error (MAE: 0.016-0.064 cm), and root mean square error (RMSE: 0.014-0.041 cm), the prediction results showed that the model fits well. The results showed that the concentration of lambda-cyhalothrin in the artificial lake was positively correlated with the increase in rainfall intensity. Under the three scenarios of moderate rain, heavy rain, and rainstorm, the variation of total pollutants into the lake over time conformed to the first-order dynamic equation (R2＞0.97), and the cumulative rates were 0.013 min-1, 0.019 min-1 and 0.022 min-1, respectively. Under light rain, the accumulation rate of lambda-cyhalothrin showed a double-linear relationship, which was in accordance with the second-order kinetic equation (R2＞0.97). The rapid accumulation rate of early-stage rainfall was 0.0024 min-1, and the slow accumulation rate of late-stage rainfall was 0.0019 min-1. The human health risk assessment predicted by the simulation was lower than the hazard value (Rtgn(a-1): 9.65 E-11-1.12 E-10 a-1). However, the potential risk value to aquatic species was higher (RQ: 0.33-23.05). In addition, the increase in rainfall intensity has no significant effect on the acceleration of water renewal time. The two-dimensional dispersion model of pollutants driven by water dynamics provided relevant examples for evaluating the impact of runoff on pesticide scour in parks and supplied scientific support for improving the management of artificial lakes in urban parks.

Genetic Origins and Sex-Biased Admixture of the Huis.

The Hui people are unique among Chinese ethnic minorities in that they speak the same language as Han Chinese (HAN) but practice Islam. However, as the second-largest minority group in China numbering well over 10 million, the Huis are under-represented in both global and regional genomic studies. Here, we present the first whole-genome sequencing effort of 234 Hui individuals (NXH) aged over 60 who have been living in Ningxia, where the Huis are mostly concentrated. NXH are genetically more similar to East Asian than to any other global populations. In particular, the genetic differentiation between NXH and HAN (FST = 0.0015) is only slightly larger than that between northern and southern HAN (FST = 0.0010), largely attributed to the western ancestry in NXH (∼10%). Highly differentiated functional variants between NXH and HAN were identified in genes associated with skin pigmentation (e.g., SLC24A5), facial morphology (e.g., EDAR), and lipid metabolism (e.g., ABCG8). The Huis are also distinct from other Muslim groups such as the Uyghurs (FST = 0.0187), especially, NXH derived much less western ancestry (∼10%) compared with the Uyghurs (∼50%). Modeling admixture history indicated that NXH experienced an episode of two-wave admixture. An ancient admixture occurred ∼1,025 years ago, reflecting the intensive west-east contacts during the late Tang Dynasty, and the Five Dynasties and Ten Kingdoms period. A recent admixture occurred ∼500 years ago, corresponding to the Ming Dynasty. Notably, we identified considerable sex-biased admixture, that is, excess of western males and eastern females contributing to the NXH gene pool. The origins and the genomic diversity of the Hui people imply the complex history of contacts between western and eastern Eurasians.

PGG.Han: the Han Chinese genome database and analysis platform.

As the largest ethnic group in the world, the Han Chinese population is nonetheless underrepresented in global efforts to catalogue the genomic variability of natural populations. Here, we developed the PGG.Han, a population genome database to serve as the central repository for the genomic data of the Han Chinese Genome Initiative (Phase I). In its current version, the PGG.Han archives whole-genome sequences or high-density genome-wide single-nucleotide variants (SNVs) of 114 783 Han Chinese individuals (a.k.a. the Han100K), representing geographical sub-populations covering 33 of the 34 administrative divisions of China, as well as Singapore. The PGG.Han provides: (i) an interactive interface for visualization of the fine-scale genetic structure of the Han Chinese population; (ii) genome-wide allele frequencies of hierarchical sub-populations; (iii) ancestry inference for individual samples and controlling population stratification based on nested ancestry informative markers (AIMs) panels; (iv) population-structure-aware shared control data for genotype-phenotype association studies (e.g. GWASs) and (v) a Han-Chinese-specific reference panel for genotype imputation. Computational tools are implemented into the PGG.Han, and an online user-friendly interface is provided for data analysis and results visualization. The PGG.Han database is freely accessible via http://www.pgghan.org or https://www.hanchinesegenomes.org.

AdmixSim 2: a forward-time simulator for modeling complex population admixture.

BACKGROUND: Computer simulations have been widely applied in population genetics and evolutionary studies. A great deal of effort has been made over the past two decades in developing simulation tools. However, there are not many simulation tools suitable for studying population admixture. RESULTS: We here developed a forward-time simulator, AdmixSim 2, an individual-based tool that can flexibly and efficiently simulate population genomics data under complex evolutionary scenarios. Unlike its previous version, AdmixSim 2 is based on the extended Wright-Fisher model, and it implements many common evolutionary parameters to involve gene flow, natural selection, recombination, and mutation, which allow users to freely design and simulate any complex scenario involving population admixture. AdmixSim 2 can be used to simulate data of dioecious or monoecious populations, autosomes, or sex chromosomes. To our best knowledge, there are no similar tools available for the purpose of simulation of complex population admixture. Using empirical or previously simulated genomic data as input, AdmixSim 2 provides phased haplotype data for the convenience of further admixture-related analyses such as local ancestry inference, association studies, and other applications. We here evaluate the performance of AdmixSim 2 based on simulated data and validated functions via comparative analysis of simulated data and empirical data of African American, Mexican, and Uyghur populations. CONCLUSIONS: AdmixSim 2 is a flexible simulation tool expected to facilitate the study of complex population admixture in various situations.

Is Non-Stimulated C-Peptide at Diagnosis a Good Predictive Value for Insulin Use at Two Years after Diagnosis in Pediatric Diabetic Patients?

Background and Objectives: Insulin treatment may be initially required to stabilize patients presenting with metabolic crisis at type 1 and 2 diabetes mellitus (DM) onset. Some patients with type 2 DM may need persistent insulin treatment. This study aimed to examine the predictive performance of non-stimulated C-peptide level at the time of diagnosis for future insulin use in pediatric diabetic patients. Materials and Methods: We reviewed the medical charts of diabetic patients aged 18 years or younger in a medical center in southern Taiwan from January 2000 to December 2019. Clinical and individual data were collected at the time of DM diagnosis. Outcomes were persistent insulin use at the time of diagnosis, as well as at one and two years after diagnosis. Results: The final analysis included a total of 250 patients. The best cut-off point of non-stimulated C-peptide was 0.95 ng/mL, and the predictive indices for the insulin use were 0.84 for sensitivity and 0.94 for specificity at two years after DM diagnosis. Incorporating age at onset and presence of GAD antibodies can further increase the predictive power of non-stimulated C-peptide. Conclusions: The value of non-stimulated C-peptide at diabetic onset was feasible and effective for predicting future insulin treatment up to the time point of two years after diagnosis.

Identification of southern Taiwan genetic variants in thyroid dyshormonogenesis through whole-exome sequencing.

Thyroid dyshormonogenesis (TDH) is responsible for 15%-25% of congenital hypothyroidism (CH) cases. Pathogenetic variants of this common inherited endocrine disorders vary geographically. Unraveling the genetic underpinnings of TDH is essential for genetic counseling and precise therapeutic strategies. This study aims to identify genetic variants associated with TDH in Southern Taiwan using whole exome sequencing (WES). We included CH patients diagnosed through newborn screening at a tertiary medical center from 2011 to 2022. Permanent TDH was determined based on imaging evidence of bilateral thyroid structure and the requirement for continuous medication beyond 3 years of age. Genomic DNA extracted from blood was used for exome library construction, and pathogenic variants were detected using an in-house algorithm. Of the 876 CH patients reviewed, 121 were classified as permanent, with 47 (40%) confirmed as TDH. WES was conducted for 45 patients, and causative variants were identified in 32 patients (71.1%), including DUOX2 (15 cases), TG (8 cases), TSHR (7 cases), TPO (5 cases), and DUOXA2 (1 case). Recurrent variants included DUOX2 c.3329G>A, TSHR c.1349G>A, TG c.1348delT, and TPO c.2268dupT. We identified four novel variants based on genotype, including TSHR c.1135C>T, TSHR c.1349G>C, TG c.2461delA, and TG c.2459T>A. This study underscores the efficacy of WES in providing definitive molecular diagnoses for TDH. Molecular diagnoses are instrumental in genetic counseling, formulating treatment, and developing management strategies. Future research integrating larger population cohorts is vital to further elucidate the genetic landscape of TDH.

Syndromic ciliopathy: a taiwanese single-center study.

BACKGROUND: Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes. METHODS: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment. RESULTS: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation. CONCLUSIONS: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.

Fatty Acid Oxidation Supports Lymph Node Metastasis of Cervical Cancer via Acetyl-CoA-Mediated Stemness.

Accumulating evidence indicates that metabolic reprogramming of cancer cells supports the energy and metabolic demands during tumor metastasis. However, the metabolic alterations underlying lymph node metastasis (LNM) of cervical cancer (CCa) have not been well recognized. In the present study, it is found that lymphatic metastatic CCa cells have reduced dependency on glucose and glycolysis but increased fatty acid oxidation (FAO). Inhibition of carnitine palmitoyl transferase 1A (CPT1A) significantly compromises palmitate-induced cell stemness. Mechanistically, FAO-derived acetyl-CoA enhances H3K27 acetylation (H3K27Ac) modification level in the promoter of stemness genes, increasing stemness and nodal metastasis in the lipid-rich nodal environment. Genetic and pharmacological loss of CPT1A function markedly suppresses the metastatic colonization of CCa cells in tumor-draining lymph nodes. Together, these findings propose an effective method of cancer therapy by targeting FAO in patients with CCa and lymph node metastasis.

Correlates of disordered eating and insulin restriction behavior and its association with psychological health in Taiwanese youths with diabetes mellitus.

BACKGROUND: Adolescents and young adults (AYAs) with diabetes mellitus (DM) are prone to eating disorders that may worsen metabolic control. This study investigated the clinical and behavioral correlates of disordered eating and insulin restriction (DE/IR) behavior and its association with psychological health among AYAs with DM. METHODS: We enrolled patients with DM aged 10-30 years receiving insulin treatment in a tertiary medical center from 2019 to 2021. After obtaining informed consent, we assessed various visit-to-visit HbA1c measures indicating glycemic control, DE/IR behavior using the modified SCOFF questionnaire, weight-control practices (e.g., self-medication, induced vomiting, and over-exercising), and anxious and depressive symptoms using the Hospital Anxiety and Depression Scale. Correlation and hierarchical regression analyses were applied to understand the clinical and behavioral correlates of DE/IR behavior and its association with anxiety and depression. RESULTS: Among the 110 patients with type 1 and type 2 DM recruited, we found 17.6% restricting insulin use and 6.3% self-medicating for weight control (higher in type 2 DM than type 1 DM). Hierarchical regression analyses showed HbA1c standard deviation (odds ratio = 2.18, [95% confidence interval 1.07-4.42]), body image (1.83, [1.05-3.20]), and dieting (4.74, [1.70-13.23]) associated with DE/IR behavior. Moreover, DE/IR behavior was further associated with anxiety (1.17 [1.08-1.27]) and depression (1.12 [1.03-1.22]). CONCLUSION: DE/IR behavior is not uncommon among AYAs with DM, particularly those with type 2 DM, and may be associated with anxiety and depressive symptoms. In addition, HbA1c variability is correlated with DE/IR behavior, and the clinical implications need further exploration.

Role of the tripartite motif (TRIM) family in female genital neoplasms.

The tripartite motif proteins (TRIMs) family represents a class of highly conservative proteins which play a large regulatory role in molecular processes. Recently, increasing evidence has demonstrated a role of TRIMs in female genital neoplasms. Our review thereby aimed to provide an overview of the biological involvement of TRIMs in female genital neoplasms, to provide a better understanding of its role in the development and progression of such diseases, and emphasize its potential as targeted cancer therapy. Overall, our review highlighted that the wide-ranging roles of TRIMs, in not only target protein ubiquitination, tumor migration and/or invasion, epithelial-mesenchymal transition, stemness, cell adhesion, proliferation, cell cycle regulation, and apoptosis, but also in influencing estrogenic, and chemotherapy response.

A boy with a progressive neurologic decline harboring two coexisting mutations in KMT2D and VPS13D.

INTRODUCTION: Kabuki syndrome (KS) and spinocerebellar ataxia (SCA) are both rare conditions with neurodevelopmental abnormalities. Approaching a patient with complex phenotypes and differentiating the role of mutations may be beneficial but challenging in predicting the disease prognosis. CASE PRESENTATION: A boy presented with progressive ataxia, developmental regression, and myoclonus since 4 years of age. Additional features included growth hormone deficiency, excessive body hair, dysmorphic facies, hypoparathyroidism, and bilateral sensorineural hearing impairment. Brain magnetic resonance imaging depicted T2-weighted hyperintensities over bilateral globus pallidus, thalamus, subcortical white matter, and brainstem. The results of tandem mass spectrometry, mitochondrial deletion, and mitochondrial DNA sequencing were inconclusive. Whole-exome sequencing (WES) on genomic DNA obtained from peripheral blood cells revealed a known pathogenic variant at KMT2D gene (c.5993A > G, p.Tyr1998Cys) related to KS and two compound heterozygous, likely pathogenic variants at VPS13D gene (c.908G > A, p.Arg303Gln and c.8561T > G, p.Leu2854Arg) related to autosomal recessive SCA type 4 (SCAR4). DISCUSSION: SCAR4 is mainly adult-onset, but a few pediatric cases have recently been reported with progressive gait instability and developmental delay. The VPS13D gene has been suggested to play a role in mitochondrial size, autophagy, and clearance, thus explaining the clinical and imaging phenotypes. CONCLUSION: Our case showed a rare co-existence of KS and SCAR4, highlighting the utility of WES in atypical cases that a single-gene disease cannot fully explain.

Enzyme replacement therapy for children with acid sphingomyelinase deficiency in the real world: A single center experience in Taiwan.

Background: Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease with multi-systemic involvement, with no disease-modifying treatment available. Olipudase alfa is an investigational enzyme product developed to replace the deficient acid sphingomyelinase in ASMD patients. Several clinical trials have reported promising safety and efficacy results in adult and pediatric patients. However, no data have been reported outside of the clinical trial setting yet. This study aimed to evaluate major outcomes in pediatric chronic ASMD patients receiving olipudase alfa in the real-world setting. Materials and methods: Two children with type A/B (chronic neuropathic) ASMD have received olipudase alfa treatment since May 2021. Clinical parameters, including height, weight, complete blood count, liver function tests, lipid profiles, biomarkers, abdominal ultrasonography with shear wave elastography, chest computed tomography, nerve conduction studies, neurodevelopmental evaluations, and six-minute walk tests, were checked at baseline and every three to six months in the first year of enzyme replacement therapy (ERT) to assess its efficacy and safety. Results: The two patients in our study started olipudase alfa treatment at the age of 5 years and 8 months and 2 years and 6 months. During the first year of treatment, both patients saw a reduction in their hepatic and splenic volumes as well as liver stiffness. Height z-score, weight z-score, lipid profiles, biomarker levels, interstitial lung disease scores, and bone mineral densities also improved over time. The six-minute walk test showed a gradual increase in walking distance in both patients. There were no obvious improvements or deterioration in neurocognitive function and peripheral nerve conduction velocities after treatment. No severe infusion-associated reactions were noted during the first year of treatment. One patient had two episodes of transient but significantly elevated liver enzymes during the dose-escalation phase. The patient was asymptomatic, and the impaired liver function resolved spontaneously within two weeks. Conclusion: Our results provide real-world experience that olipudase alfa is safe and effective in improving major systemic clinical outcomes for pediatric chronic ASMD patients. Monitoring of liver stiffness by shear wave elastography is a noninvasive procedure that can monitor treatment efficacy during ERT.