BMC Medical Genomics[JOURNAL]
Sun
200 papers
Molecular diagnosis of non-syndromic hearing loss in seven Iranian families using whole-exome sequencing.
Abghari FZ, Esmaeilzadeh E, Biglari S … +5 more , Ghasemi H, Mohseni M, Shahmohammad N, Khorshid HRK, Najafipour R
BMC Med Genomics · 2026 Jun · PMID 42231373 · Full text
BACKGROUND: Congenital hearing loss is a common and genetically diverse sensory disorder. Non-syndromic forms are often inherited in an autosomal recessive pattern, with the types and frequencies of clinically relevant v...
BACKGROUND: Congenital hearing loss is a common and genetically diverse sensory disorder. Non-syndromic forms are often inherited in an autosomal recessive pattern, with the types and frequencies of clinically relevant variants differing across populations. Studies of consanguineous families have been instrumental in identifying genes associated with autosomal recessive non-syndromic hearing loss (ARNSHL). The present study aimed to characterize candidate variants potentially underlying ARNSHL in seven unrelated Iranian families with consanguinity or from the same geographic region, as reported during genetic counseling. METHODS: We conducted GJB2 screening, whole-exome sequencing (WES), and copy-number variation (CNV) analysis in seven probands with sensorineural hearing loss in the absence of additional phenotypes. Bioinformatic filtering, in silico analysis, and segregation studies were applied to determine the potential clinical relevance of candidate variants. RESULTS: WES identified nine different candidate variants in five genes among the probands and their affected family members, including six missense variants, two affecting canonical splice sites, and one nonsense variant. Previously reported variants included TMC1 (NM_138691.3:c.100 C > T), SLC26A4 (NM_000441.2:c.1229 C > T, c.716T > A, c.2027T > A), MYO7A (NM_000260.4:c.247 C > T), LOXHD1 (NM_001384474.1:c.4940 C > A), and CABP2 (NM_016366.3:c.637 + 1G > T). Additionally, two novel variants were detected in two unrelated families: LOXHD1 (NM_001384474.1:c.1136T > A) and TMC1 (NM_138691.3:c.1567-1G > A). CONCLUSION: This study contributes to the current understanding of the genetic spectrum of ARNSHL in a small cohort of Iranian families by identifying rare variants in known hearing loss genes, including a novel missense variant in LOXHD1 and a novel splice-site variant in TMC1. However, due to lack of functional validation, their clinical significance remains uncertain. Further functional and large-cohort studies are needed to confirm pathogenicity and clarify genotype-phenotype relationships.
SomaScan proteomics reveals novel biomarkers in the progression of liver cirrhosis to hepatocellular carcinoma.
Huang L, Guo J, Liu W … +9 more , Xie S, Yan Q, Pu W, Zeng Z, Lai L, Wang B, Dai Y, Tang D, Chen H
BMC Med Genomics · 2026 Jun · PMID 42219486 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) typically develops from liver cirrhosis (LC), however early diagnosis is difficult due to a lack of reliable biomarkers. The goal of this study was to use SomaScan proteomics te...
BACKGROUND: Hepatocellular carcinoma (HCC) typically develops from liver cirrhosis (LC), however early diagnosis is difficult due to a lack of reliable biomarkers. The goal of this study was to use SomaScan proteomics technology to find plasma protein profiles that differentiated LC and HCC from healthy controls in order to develop novel biomarkers for HCC early detection and targeted therapy. METHODS: We used SomaScan technology to evaluate 10,893 plasma proteins from LC, HCC, and normal populations. Differentially expressed proteins (DEPs) were discovered and functionally annotated using HPA, GO/KEGG, and PPI networks. Venn analysis was used to identify DEPs that were expressed in both LC and HCC. RESULTS: There were 402 DEPs in LC and 389 in HCC, with MAPK signaling and neutrophil extracellular trap generation being the primary dysregulated pathways in LC and HCC, respectively. In addition, 38 co-expressed DEPs (e.g., SSX7, HIP1R, SLC25A18) were discovered in LC and HCC, including 9 previously unknown potential DEPs. PPI network analysis revealed that FLT4 and PDGFA were key drivers of LC progression to HCC. ELISA experiments confirmed that FLT4 and PDGFA are consistently down-regulated in the progression of LC to HCC (P < 0.05). CONCLUSIONS: This investigation described the plasma proteomes of LC and HCC and identified FLT4 and PDGFA as possible early screening targets for HCC, establishing a scientific foundation for HCC detection in high-risk LC populations.
Integrative single-cell and bulk transcriptomics define cell death patterns and ZDHHC22 in gastric cancer progression.
Wu J, Chen C, Dou G … +7 more , Huang L, Zhu Y, Chen Z, Mao Q, Jia J, Wang P, Li J
BMC Med Genomics · 2026 May · PMID 42218517 · Full text
INTRODUCTION: Gastric cancer remains a major global health burden with high incidence and mortality. Despite therapeutic advances, long-term survival remains unsatisfactory. Reliable biomarkers to predict therapeutic ef...
INTRODUCTION: Gastric cancer remains a major global health burden with high incidence and mortality. Despite therapeutic advances, long-term survival remains unsatisfactory. Reliable biomarkers to predict therapeutic efficacy and clinical outcomes are urgently needed. This study aimed to elucidate the heterogeneity of gastric cancer using an integrative bioinformatics approach that combines single-cell RNA-sequencing (scRNA-seq) and bulk RNA-seq data. METHODS: scRNA-seq datasets were obtained from the GEO database, and bulk RNA-seq data were obtained from the TCGA. Cell communication, pseudotime analysis, and cell death scoring (cuproptosis, ferroptosis, autophagy, and pyroptosis) were performed on the basis of the scRNA-seq datasets. Stemness, survival, drug sensitivity and posttranslational modification (PTM) analyses were conducted using TCGA data. RESULTS: Cancer cells were clustered into three molecular subtypes with distinct molecular characteristics, pathway activation profiles and cell death patterns. Cell-cell communication analysis revealed subtype-specific regulatory interactions, whereas pseudotime and cell death scoring demonstrated dynamic cellular states. Bulk RNA-seq revealed five cell death patterns, among which "cell death 2" and high cuproptosis scores emerged as independent risk factors for poor prognosis. Genes such as LMF1-AS1, CAMKV, ERVW-1, ACLY, GAS2L2, RGS8, and RASSF8-AS1 were differentially expressed in the high-risk group. Samples with low stemness and elevated pyroptosis showed enhanced inferred drug resistance, particularly to LBH589. Additionally, ZDHHC22 was identified as a potential protective prognostic factor, and in vitro assays suggested its association with cell death modulation in gastric cancer. CONCLUSION: This study highlights the molecular heterogeneity of gastric cancer, demonstrating how distinct cell death patterns and PTM features shape prognosis and drug sensitivity. The identified biomarkers and resistance profiles may provide valuable guidance for personalized therapeutic strategies.
Identification of serum miR‑320a in gestational diabetes mellitus for predicting macrosomia and in vitro mechanistic investigation.
Yu R, Liu X, Zhang S
BMC Med Genomics · 2026 May · PMID 42210203 · Full text
BACKGROUND: Gestational diabetes mellitus (GDM) significantly elevates the risk for a spectrum of adverse pregnancy outcomes. The expression pattern and regulatory mechanism of microRNA-320a (miR-320a) in GDM remain poor...
BACKGROUND: Gestational diabetes mellitus (GDM) significantly elevates the risk for a spectrum of adverse pregnancy outcomes. The expression pattern and regulatory mechanism of microRNA-320a (miR-320a) in GDM remain poorly elucidated. METHODS: The study enrolled 40 GDM patients along with 40 healthy controls. Serum expression levels of miR-320a were quantified using reverse transcription quantitative polymerase chain reaction (RT-qPCR). ROC curve analysis and binary logistic regression were applied to evaluate its diagnostic performance for GDM and predictive value for fetal macrosomia, respectively. In HTR-8/SVneo trophoblast cells, CCK-8 assay and flow cytometry were used to assess the influence of miR-320a on cell proliferation and apoptosis. Dual-luciferase reporter assay validated the direct targeting relationship between miR-320a and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD). Western blot was performed to detect PIK3CD protein expression, and rescue experiments further explored the biological function of the miR-320a/PIK3CD axis in trophoblast proliferation and apoptosis. RESULTS: Serum miR-320a was significantly downregulated in GDM patients and exhibited good diagnostic capability to distinguish GDM from healthy pregnancies. Lower miR-320a expression was correlated with a higher risk of fetal macrosomia. In addition, overexpression of miR-320a promoted cell proliferation and suppressed apoptosis in HTR‑8/SVneo cells. PIK3CD was identified as a direct downstream target of miR‑320a, and miR‑320a overexpression inhibited PIK3CD expression. Furthermore, the effects of miR‑320a on cell proliferation and apoptosis were markedly reversed by co‑transfection with pcDNA‑PIK3CD. CONCLUSIONS: Circulating miR-320a has promising potential for GDM diagnosis and fetal macrosomia prediction. Increased miR-320a expression facilitates proliferation and restricts apoptosis in HTR-8/SVneo trophoblast cells by directly targeting PIK3CD.
Early-onset hereditary spastic paraplegia type 56 (SPG56): clinical-molecular correlations and functional validation of CYP2U1 variants.
Sustrova E, Rihova K, Pokorna P … +11 more , Havlova V, Stiborek M, Simek Z, Damborsky J, Horak O, Kozelkova K, Hlouskova E, Demlova R, Kubatova J, Slaby O, Slaba K
BMC Med Genomics · 2026 May · PMID 42204580 · Full text
BACKGROUND: Hereditary spastic paraplegia type 56 (SPG56) is a rare autosomal recessive neurodegenerative disorder caused by biallelic variants in the CYP2U1 gene, which encodes a cytochrome P450 enzyme involved in fatty...
BACKGROUND: Hereditary spastic paraplegia type 56 (SPG56) is a rare autosomal recessive neurodegenerative disorder caused by biallelic variants in the CYP2U1 gene, which encodes a cytochrome P450 enzyme involved in fatty acid metabolism and mitochondrial function. The clinical spectrum includes progressive spasticity of the lower limbs, developmental delay or regression, cognitive impairment, and variable ophthalmological findings. Although several cases have been reported in recent years, the functional characterization of individual variants remains limited. CASE PRESENTATION: Here we describe a male patient with early-onset SPG56 carrying two CYP2U1 missense variants, NM_183075.3:c.1376 C > T p.(Pro459Leu) and NM_183075.3:c.557G > A p.(Arg186His). Combined genomic, cellular, and in silico analyses confirmed loss of enzymatic activity and protein instability, supporting the pathogenic classification of both variants. Functional validation led to reclassification of the p.(Arg186His) variant from uncertain significance to pathogenic. Further, we link specific CYP2U1 missense changes to convergent molecular defects, thereby refining genotype-phenotype correlations. From a therapeutic perspective, we highlight the relevance of experimental interventions such as folinic acid supplementation and multimodal spasticity management, while emphasizing the future promise of gene therapy for SPG56 patients. CONCLUSIONS: Our findings highlight the value of integrating genomic, biochemical, and structural approaches in the diagnostic evaluation of rare neurogenetic disorders, and provide functional evidence that the identified CYP2U1 variants are damaging, consistent with the observed early-onset complex SPG56 phenotype.
HMGA1 promotes the proliferation, migration, and invasion of uveal melanoma cells via the PI3K/Akt/MMP-9 pathway.
Ren W, Luo B
BMC Med Genomics · 2026 May · PMID 42174595 · Full text
BACKGROUND: Uveal melanoma (UM) was prone to metastasis and had an extremely poor prognosis. High-mobility group protein A1 (HMGA1) was known to promote proliferation and invasion in various tumors, but its molecular mec...
BACKGROUND: Uveal melanoma (UM) was prone to metastasis and had an extremely poor prognosis. High-mobility group protein A1 (HMGA1) was known to promote proliferation and invasion in various tumors, but its molecular mechanism in UM remained unclear. OBJECTIVE: The effect of HMGA1 on the proliferation, migration, and invasion of UM cells was investigated, and whether it functioned through the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/matrix metalloproteinase-9 (MMP-9) pathway was explored. METHODS: HMGA1 overexpression (OE) and knockdown (KD) models were established in two UM cell lines (C918, MUM-2B). Cell functions were assessed using MTT assay, EdU (5‑ethynyl‑2'‑deoxyuridine) incorporation assay, scratch wound healing assay, and Matrigel-Transwell assay. The expression of PI3K, phosphorylated PI3K (p-PI3K), Akt, phosphorylated Akt (p-Akt), and MMP-9 was detected by Western blot (WB). Pathway intervention was performed using the PI3K inhibitor LY294002. RESULTS: Compared with the control group, HMGA1 overexpression significantly up-regulated the proliferation, migration, and invasion abilities of both cell lines, and led to a fold-dependent up-regulation of PI3K/Akt pathway activation and MMP-9 expression. In contrast, HMGA1 knockdown significantly down-regulated the above indicators. After treatment with LY294002, the tumor-promoting effects induced by HMGA1 overexpression were significantly reversed. CONCLUSION: HMGA1 significantly promoted the proliferation, migration, and invasion of UM cells from different origins (primary C918, metastatic MUM-2B) by activating the PI3K/Akt pathway and upregulating MMP-9 expression, suggesting its potential as a target for molecular targeted therapy in UM.
Mitotic catastrophe-related six-gene signature predicts prognosis, tumor immune landscape, and therapeutic response in lung adenocarcinoma.
Luo M, Zhu G, Zhong W
BMC Med Genomics · 2026 May · PMID 42152077 · Full text
BACKGROUND: Lung adenocarcinoma (LUAD) exhibits significant molecular and immune heterogeneity, limiting the prognostic and therapeutic value of single biomarkers. Mitotic catastrophe (MC) is a key biological axis, but e...
BACKGROUND: Lung adenocarcinoma (LUAD) exhibits significant molecular and immune heterogeneity, limiting the prognostic and therapeutic value of single biomarkers. Mitotic catastrophe (MC) is a key biological axis, but externally validated MC-related gene (MCRG) signatures integrating immune and pharmacologic annotations remain lacking. METHODS: We obtained datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially expressed genes overlapping with mitotic catastrophe-related genes (MCRGs) were screened. GSVA-derived MCRG scores guided WGCNA to identify associated modules; after KEGG/GO-BP enrichment and mutation analysis, a six-gene RiskScore model was constructed via LASSO-Cox and multivariate Cox regression. Immune microenvironment was analyzed by ESTIMATE and MCPcounter; ICI responsiveness by TIDE; drug sensitivity by pRRophetic. Wet-lab validation included qPCR, CCK-8, and siRNA-mediated GNPNAT1 knockdown assays. RESULTS: A total of 2,290 upregulated and 1,959 downregulated genes were identified, with 266 overlapping MCRGs. The turquoise module showed the highest correlation with MCRG scores, and 940 overlapping genes were enriched in pathways like p53 signaling. The six-gene model (GNPNAT1, etc.) effectively stratified OS, PFI, and DSS in TCGA and was validated in GSE31210. High-risk tumors had lower immune scores, depleted key immune lineages, poor ICI response, and correlated with various drug IC50 values. Wet-lab assays confirmed abnormal expression of target genes in LUAD cells, and GNPNAT1 silencing inhibited proliferation, migration, and invasion. DISCUSSION: The MC-related molecular axis integrates tumor proliferation-metabolism-immunity networks, providing actionable guidance for perioperative and translational therapeutic stratification. CONCLUSION: We proposed an MC-anchored six-gene signature integrating prognostic, immune, and therapeutic dimensions in LUAD. This exploratory study has biological plausibility, but prospective multi-center studies are required before clinical application.
Disparities in deafness gene mutations between Han and Li ethnic newborns in Hainan, China: insights from a combined screening program.
Qi X, Wang D, Liu S … +4 more , Jiao B, Tian X, Dai P, Su Y
BMC Med Genomics · 2026 May · PMID 42152029 · Full text
OBJECTIVE: This study aimed to investigate the spectrum of deafness gene variants among newborns in Hainan Province, China. We also evaluated the effectiveness of a combined hearing and genetic screening approach in this...
OBJECTIVE: This study aimed to investigate the spectrum of deafness gene variants among newborns in Hainan Province, China. We also evaluated the effectiveness of a combined hearing and genetic screening approach in this region. Special attention was given to differences between the Han and Li populations, as well as the relationship between genetic variants and hearing follow-up outcomes. METHODS: From October 2020 to June 2022, 2128 newborns in Hainan (1502 Han, 626 Li) received combined hearing and genetic screening. Hearing screening followed national standards. Genetic screening was carried out using targeted next-generation sequencing of GJB2, SLC26A4, GJB3, and MT-RNR1. Infants with detected variants or those referred from hearing screening received diagnostic audiological follow-up. RESULTS: Among the 2128 newborns (1502 Han, 626 Li), 514 (24.15%) carried deafness gene variants. Variants in GJB2 were the most common, with a carrier rate of 22.51% (479/2128). The GJB2 c.109G > A (p.V37I) variant was the hotspot variant, with an overall carrier rate of 20.91% (445/2128). This rate was significantly higher in the Li ethnic group (28.6%, 179/626) than in the Han group (17.7%, 266/1502; P < 0.01). Thirty-seven newborns carried biallelic pathogenic variants in GJB2. Nine newborns (0.42%) were diagnosed with hearing loss at three months, and all 9 had biallelic GJB2 variants (7 homozygous c.109G > A, 1 compound heterozygote c.109G > A/299_300del, and 1 homozygous c.235del). Longitudinal follow-up of children with biallelic c.109G > A variants showed delayed-onset and progressive hearing loss, with confirmed cases increasing at ages 2 and 4. There are no significant differences in mean ABR thresholds or their standard deviations between Han and Li individuals with homozygous GJB2 c.109G > A mutations at 4 years of age. For patients with biallelic c.109G > A variants, the current setting of ABR thresholds may lead to missed diagnosis. CONCLUSION: This study showed a high prevalence of deafness gene variants, especially GJB2 c.109G > A, among newborns in Hainan, with clear ethnic differences. Combined screening was effective in identifying genetic hearing loss, including delayed-onset and progressive cases that could be missed by hearing screening alone. These findings support adding genetic screening to regional newborn screening programs and highlight the need for long-term monitoring of at-risk children.
Long-term safety and efficacy of triheptanoin in Korean patients with long-chain fatty acid oxidation disorders: a prospective, open-label, single-center, phase II clinical study.
Yoon JH, Park JH, Kim D … +8 more , Hwang S, Park J, Kim JH, Choi S, Ko E, Lee BJ, Moon Y, Lee BH
BMC Med Genomics · 2026 May · PMID 42143327 · Full text
BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) are inherited metabolic conditions caused by impaired mitochondrial β-oxidation of long-chain fatty acids, leading to rhabdomyolysis, cardiomyopathy, and hy...
BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) are inherited metabolic conditions caused by impaired mitochondrial β-oxidation of long-chain fatty acids, leading to rhabdomyolysis, cardiomyopathy, and hypoglycemia. Triheptanoin, a medium odd-chain triglyceride, provides anaplerotic substrates that replenish tricarboxylic acid cycle intermediates, offering alternative energy sources and potential therapeutic benefit. METHODS: This open-label, single-center phase II study evaluated the safety and efficacy of triheptanoin in 10 Korean patients with genetically confirmed LC-FAOD who experienced recurrent rhabdomyolysis despite conventional treatment. Triheptanoin was titrated to 35% of total daily caloric intake, and all patients completed 3 years of treatment. The primary outcome was safety, assessed by adverse events. Secondary outcomes included changes in the major clinical event (MCE) rate and duration, functional capacity, health-related quality of life (HRQoL), and organ function. RESULTS: The mean study duration was 3.5 ± 0.3 years. Serious adverse events occurred in nine patients (90%), most commonly rhabdomyolysis (100%), and were considered unrelated to triheptanoin. Mild gastrointestinal symptoms during titration were the most frequent treatment-related adverse events (80%). The median annualized MCE rate and duration decreased by 42.4% and 43.6%, respectively (P = 0.114 and P = 0.059). The duration per MCE was significantly reduced by 3.5 days, as assessed by a linear mixed-effects model (P = 0.022), with a significant reduction observed in the child subgroup (P < 0.001). In eight patients, the 12-minute walk test distance increased by 12.4% at 6 months and was maintained over 3 years (P = 0.385). HRQoL improved to within the normative range in adults, whereas child self-reported and parent proxy-reported scores showed an initial increase but remained suboptimal at 3 years. Progressive neuropathy and newly developed retinopathy and attention-deficit/hyperactivity disorder were observed during treatment. CONCLUSION: Triheptanoin significantly reduced hospitalization burden in Korean patients with LC-FAOD and was well-tolerated, with potential benefits in physical function. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), Republic of Korea, KCT0006756, 15 November 2021.
Distinct genetic architecture of coronary heart disease in dyslipidemia patients.
Huang M, Song X, Zhou S … +10 more , Zhang H, He L, Chen Y, Chen G, Ding H, Jiang J, Wang Y, Wang DW, Sun Y, Wang H
BMC Med Genomics · 2026 May · PMID 42121140 · Full text
BACKGROUND: Mutations of LDLR, APOB and PCSK9 have been well-established to cause hypercholesterolemia while the pathogenic effects of LPL has been confirmed by cohorts and functional studies in hypertriglyceridemia. How...
BACKGROUND: Mutations of LDLR, APOB and PCSK9 have been well-established to cause hypercholesterolemia while the pathogenic effects of LPL has been confirmed by cohorts and functional studies in hypertriglyceridemia. However, these mutations do not fully account for all dyslipidemia, and it remains unexplained why some patients with dyslipidemia develop coronary heart disease (CHD) while others do not. METHODS: We enrolled 108 patients with lipid disturbances (67 with hypercholesterolemia and 41 with hypertriglyceridemia) and 414 controls from Tongji Hospital, Wuhan, China. Whole exome sequencing (WES) was performed, and candidate genes were assessed using the optimal sequence kernel association test (SKAT-O). Subgroup analysis compared genetic profiles between CHD and non-CHD patients. RESULTS: We identified 13 pathogenic or likely pathogenic (PP/LPP) variants in LDLR in hypercholesterolemia patients and four in LPL as well as two in APOA5 in hypertriglyceridemia patients. With exclusion of patients with PP/LPP variants, SKAT-O identified 192 and 184 additional genes associated with hypercholesterolemia and hypertriglyceridemia, respectively. In subgroup analysis, 119 genes showed relevance to CHD by comparison of patients with and without CHD in hypercholesterolemia cohort. Further enrichment analysis identified COL5A1, COL24A1, COL6A6, COL6A2, SLC3A1, ATP1A4 and SLC7A9 as candidate causal genes of CHD. CONCLUSIONS: This study described the genetic landscape of dyslipidemia in Chinese Han population, and revealed novel susceptibility genes beyond canonical lipid pathways. Genes implicated in CHD suggests extracellular matrix remodeling may mediate atherosclerotic progression in hypercholesterolemia. These findings provide novel mechanistic insights into CHD development and highlight promising targets for functional validation.
Quantifying the utility of type 2 diabetes polygenic risk score for predicting incident diabetes: an analysis of large US-based cohort studies.
Hanson RL, Kobes S, Wedekind LE … +3 more , Arreola EV, Ramirez-Luzuriaga MJ, Hsueh WC
BMC Med Genomics · 2026 May · PMID 42120982 · Full text
BACKGROUND: Genome-wide association analyses (GWASs) have identified numerous genetic variants associated with type 2 diabetes, but the utility of polygenic risk scores (PRSs) derived from these associations for predicti...
BACKGROUND: Genome-wide association analyses (GWASs) have identified numerous genetic variants associated with type 2 diabetes, but the utility of polygenic risk scores (PRSs) derived from these associations for predicting future incident diabetes remains uncertain. We analyzed utility of PRSs to predict incident diabetes in longitudinal studies, consisting of African Americans (AfrAm) and European Americans (EurAm) from the publicly available dbGAP resource. METHODS: Data consisted of 3,886 AfrAm and 17,345 EurAm with GWAS data, who were initially without diabetes; there were 688 incident diabetes cases in AfrAm and 2,304 in EurAm. Strength of association was assesed by the hazard ratio (HR), while ability to discriminate between those who did and did not develop diabetes was assessed by change in the C statistic (ΔC), and ability to correctly reclassify diabetes risk was assessed by the net reclassficiation information (NRI). Decision curve analysis was used to model potential benefits of using the PRS to select individuals for a preventive intevention across a range of thresholds for implementation. RESULTS: Among the 8 PRSs evaluated, PGS002308 (1.2 M variants, from a multi-ancestry GWAS) provided the best performance. With adjustment for age, sex, parental history of diabetes, body mass index (BMI) and fasting glucose levels, the HR was 1.50 per 5000 risk alleles (95% confidence interval, 1.41-1.60). The NRI was 0.313 (0.229-0.397) and ΔC was 0.010 (0.007-0.014). In comparison, NRI was 0.401 (0.338-0.464) for BMI and 0.257 (0.188-0.327) for serum lipid levels. The PRS provided a 5.9% (1.6-10.4) improvement in area under the decision curve. For most measures of predictive utility there was little heterogeneity between AfrAm and EurAm. In contrast, measures of predictive utility were stronger in younger, than in older, individuals. CONCLUSIONS: PRSs for type 2 diabetes, as currently constructed, provide utility for clinical prevention purposes that is similar to that provided by commonly used clinical predictors; utility is likely greater in younger than in older individuals. Further studies of diabetes risk assessment and those that aim to determine optimal target populations for diabetes prevention efforts would be strengthened by incorporating PRSs.
New insights into HPDL protein: identification of a novel Bi-allelic variant, docking simulation study, and literature review.
Vaghefi F, Khosravi T, Motallebi F … +7 more , Zarghami S, Al Sudani ZM, Rahimzadeh A, Kowsari A, Sefidbakht Y, Dolatabadi AK, Oladnabi M
BMC Med Genomics · 2026 May · PMID 42116150 · Full text
BACKGROUND: Hereditary Spastic Paraplegia (HSP) is a rare neurodegenerative disorder causing progressive weakness and spasticity in the lower limbs. variants in the HPDL gene are linked to Spastic Paraplegia 83 (SPG83),...
BACKGROUND: Hereditary Spastic Paraplegia (HSP) is a rare neurodegenerative disorder causing progressive weakness and spasticity in the lower limbs. variants in the HPDL gene are linked to Spastic Paraplegia 83 (SPG83), an autosomal recessive form of HSP. While HPDL variants are known to cause SPG83, the molecular mechanisms behind its role remains unclear, mostly due to rare nature of the condition. METHODS: The primary objective was to identify the genetic cause of HSP in two Iranian consanguineous families. Whole-exome sequencing (WES) was employed to identify genetic variants in the probands. Molegro Virtual Docker (MVD), a cutting-edge integrated platform, was utilized to perform protein-ligand docking simulations. This approach aimed to characterize the structural and functional consequences of the identified variants associated with SPG83 pathogenicity. RESULTS: WES identified two biallelic variants in HPDL: c.3G > C, a start-loss variant abolishing the canonical initiation codon, and c.128G > C, a missense variant. The c.128G > C variant is novel and is documented here for the first time in an SPG83 patient. Trio-based co-segregation analysis confirmed inheritance of variants. Furthermore, a comprehensive literature review revealed a significant consanguinity rate (49.55%) within families harboring HPDL variants. CONCLUSION: This study expands the genetic and clinical spectrum of HPDL variants. The identification of the genetic variants in the probands underscores the clinical value of genetic testing methods like WES as a valuable diagnostic tool.
Transcriptomic and proteomic analysis of osteogenesis imperfecta disease-specific induced pluripotent stem cells.
Guo R, Huang L, Sha Y … +5 more , Mo C, Li C, Gong W, Hou X, Ou M
BMC Med Genomics · 2026 May · PMID 42116115 · Full text
BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic bone disorder for which treatment options remain limited. Disease-specific induced pluripotent stem cells (iPSCs) offer a valuable model to investigate its under...
BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic bone disorder for which treatment options remain limited. Disease-specific induced pluripotent stem cells (iPSCs) offer a valuable model to investigate its underlying pathological mechanisms. METHODS: Peripheral blood cells from two OI patients were reprogrammed into iPSCs. Transcriptomic sequencing and proteomic analysis were employed to systematically identify differentially expressed genes (DEGs) and proteins (DEPs) between OI-iPSCs and normal iPSCs. Bioinformatics approaches were subsequently applied for enrichment analysis and protein-protein interaction network investigation. RESULTS: OI-iPSCs were successfully established. Integrated multi-omics analysis identified 671 common DEGs and 636 common DEPs. These molecules were significantly enriched in metabolic pathways, with the oxidative phosphorylation pathway being particularly prominent. Further cross-omics screening revealed 22 genes that were differentially expressed at both the mRNA and protein levels. Among these, the focal adhesion protein VCL emerged as a central hub within the protein-protein interaction network. CONCLUSION: Through multi-omics analysis, this study revealed widespread dysregulation of metabolic pathways in OI-iPSCs, suggesting that targeted interventions on specific metabolic pathways may represent a novel therapeutic strategy for OI. VCL emerged as a key candidate molecule, warranting further functional validation in subsequent studies. These findings provide new insights into the mechanisms of OI and potential avenues for therapeutic development.
Functional analysis of a novel splice site variant of RAB3GAP2 in a fetus with congenital cataracts.
Tan X, Huang Y, Wei X … +8 more , Lai Q, Pang L, Lan J, Liu Q, Qin J, Zeng F, Chen L, Yuan D
BMC Med Genomics · 2026 May · PMID 42106822 · Full text
BACKGROUND: Mutations in RAB3GAP2 are associated with Martsolf syndrome 1, characterized by postnatal microcephaly, congenital cataracts, and developmental delay. Two compound heterozygous variants of RAB3GAP2 were ident...
BACKGROUND: Mutations in RAB3GAP2 are associated with Martsolf syndrome 1, characterized by postnatal microcephaly, congenital cataracts, and developmental delay. Two compound heterozygous variants of RAB3GAP2 were identified in a fetus with congenital cataract. This study aimed to assess the pathogenicity of the RAB3GAP2 variant c.304 + 5G > T. METHODS: Fetal lenses were evaluated using ultrasound. Whole exome sequencing (WES) was employed to identify splicing variants in RAB3GAP2, and Sanger sequencing confirmed the results. Pathogenicity was predicted using bioinformatics tools, including Mutation Taster, Combined Annotation Dependent Depletion, Splice AI, NetGene2, SpliceRover, and Alternative Splice Site Predictor. Reverse transcription PCR (RT-PCR) was conducted to detect RAB3GAP2 transcripts in peripheral blood leukocytes. A minigene assay was used to examine the variant's impact on splicing. RESULTS: Ultrasound examination revealed increased echogenicity in both fetal lenses, consistent with congenital cataracts. WES identified two compound heterozygous variants in RAB3GAP2: c.812-2 A > G (rs556159021) and c.304 + 5G > T. This study focused on the RAB3GAP2 variant c.304 + 5G > T. In silico analysis predicted that this variant disrupts the donor splice site in intron 3. RT-PCR analysis revealed an abnormal transcript with skipping of exon 3. The minigene assay showed that the RAB3GAP2 c.304 + 5G > T variant impaired mRNA splicing in HEK293T and HeLa cells. CONCLUSIONS: The RAB3GAP2 splicing variant (NM_012414.4:c.304 + 5G > T) is predicted to cause aberrant splicing and truncated proteins. These findings contribute valuable information for genetic counseling regarding congenital cataracts in future pregnancies within affected families.
Characterizing core outcomes of responsible stewardship for human genomic data in the cloud.
Rahimzadeh V, Walsh B, Rehm HL … +2 more , Cho M, McGuire AL
BMC Med Genomics · 2026 May · PMID 42092915 · Full text
We present findings from a scoping review of the genomic data sharing literature used to inform a core outcomes set for responsible data stewardship in the cloud. Genomic and related health data stemming from government...
We present findings from a scoping review of the genomic data sharing literature used to inform a core outcomes set for responsible data stewardship in the cloud. Genomic and related health data stemming from government funded research have undergone mass migration to the cloud where they can be more securely stored, accessed, and analyzed within shared computing environments. While this migration reflects a shift in privacy and security infrastructure for cloud-based repositories as oversight becomes more globalized, it also necessitates new data stewardship responsibilities to align authorized data access with ethical data use. Responsible data stewardship refers to the ethical and secure management, use, and protection of data to ensure its accuracy, privacy, integrity, and appropriate access throughout its lifecycle. Practicing responsible data stewardship is therefore one axis by which repositories can demonstrate trustworthiness in their data access and management practices. We searched the cloud governance and data sharing literature indexed in Web of Science as well as Elicit using the scoping review approach by Arksey and O'Mally. A total of 46 articles met our inclusion criteria, to which we applied a deductive, thematic content analysis to generate relevant outcome domains as well as individual core outcomes of cloud-based data. Our qualitative synthesis resulted in 35 individual core outcomes organized under 9 core domains: transparency, authentication, auditing, accountability, security, sustainability, standardization, consent and compliance, and community engagement.
A novel pathogenic variant in folliculin identified in a Chinese family with BHD syndrome.
Xing N, Li YS, Wei W … +1 more , Feng Y
BMC Med Genomics · 2026 May · PMID 42092894 · Full text
BACKGROUND: This study aimed to investigate FLCN gene variants in Chinese patients presenting with familial spontaneous pneumothorax associated with Birt-Hogg-Dubé syndrome (BHDS). METHODS: A Chinese family with a histor...
BACKGROUND: This study aimed to investigate FLCN gene variants in Chinese patients presenting with familial spontaneous pneumothorax associated with Birt-Hogg-Dubé syndrome (BHDS). METHODS: A Chinese family with a history of familial spontaneous pneumothorax linked to BHD was analyzed. Genetic screening of the folliculin (FLCN) gene was conducted using next-generation sequencing (NGS) technology. RESULTS: A nonsense variant (c.439 C > T) in the FLCN gene was identified in six individuals within the family. This variant, previously unreported in the Chinese population, results in the substitution of glutamine at the 147th amino acid position in exon 6 with a premature stop codon. The variant is hypothesized to induce nonsense-mediated mRNA decay, potentially leading to the absence of functional protein expression, which may underlie the pathogenesis of pneumothorax in this family. CONCLUSIONS: The findings elucidate the FLCN variant associated with familial spontaneous pneumothorax in BHD, thereby expanding the variantion spectrum of the FLCN gene and providing insights into the molecular mechanisms of this condition.
Global distribution of mcr-carrying bacteria: an analysis of genomic data.
Dossouvi KM, Sellera FP, Ibadin EE … +6 more , Bouyo T, Kanzin D, Ba BS, Dossim S, El Kelish A, Camara M
BMC Med Genomics · 2026 May · PMID 42067937 · Full text
BACKGROUND: Mobilized colistin resistance (mcr) gene has emerged as a major driver of colistin resistance. Therefore, this study aimed to determine the distribution of mcr-variants and mcr-carrying genomes deposited in t...
BACKGROUND: Mobilized colistin resistance (mcr) gene has emerged as a major driver of colistin resistance. Therefore, this study aimed to determine the distribution of mcr-variants and mcr-carrying genomes deposited in the NCBI database by sample collection periods and across continents, countries, genera, species, and ecosystems. METHODS: In this database mining study, the keyword "mcr" was used to identify all mcr-carrying genomes deposited in the NCBI Pathogen Detection database until June 07, 2025, 12h15 GMT. A purely descriptive approach was used in this study, and percentages were calculated by dividing the number of an event by the total number of events (percentage = n/Nx100). RESULTS: Of the 2422739 whole genomes registered in the NCBI database, 18785 (0.78%) carried complete mcr variant sequences. Seventy-seven mcr subvariants were detected, including mostly mcr-1.1 (9431/18785; 50%), and mcr-9.1 (5971/18785; 32%). Mcr-9.1 was the most frequently detected subvariant in several genera, including Serratia spp. (17/17; 100%), Cronobacter spp. (155/160; 97%), and Pluralibacter spp. (19/20; 95%), whereas mcr-1.1 was the most commonly detected subvariant in Escherichia and Shigella spp. (8235/9678; 85%). Regarding geographical distribution, mcr-1.1 was the most observed subvariant in Asia (6759/9033; 75%) and Europe (1886/4680; 40%), whereas mcr-9.1 was the most identified in America (2982/4017; 74%) and Oceania (546/771; 71%). In Africa, mcr-10.1 (52/160; 33%), and mcr-1.1 (50/160; 31%) were the most frequent subvariants. Mcr-carrying genomes deposited in the NCBI database were distributed across ecosystems, including humans (n = 8185), animals (n = 4521), the environment (n = 468), and food (n = 48). The sample collection years for mcr-carrying bacteria ranged from 1953 to 2025, and the distribution of mcr-carrying genomes was as follows: 1953-1990 (n = 49), 1991-1999 (n = 47), 2000-2009 (n = 704), 2010-2019 (n = 12810), and 2020-2025 (n = 4297). Another key finding was that 705 of the 18785 mcr-carrying genomes deposited in the NCBI database (3.8%) harbored multiple mcr genes, including 693 and 12 genomes co-carrying two and three mcr genes, respectively. CONCLUSION: Mcr-carrying bacteria represent a significant One Health concern because of their major role in colistin resistance and potential for global dissemination. Key actions, such as global surveillance, One Health monitoring, and appropriate stewardship, should be taken to preserve the efficacy of colistin for decades.
Genotypic and phenotypic spectrum of PRRT2-related variations: clinical analysis and treatment response in fourteen unrelated Chinese patients.
Liu F, Huang J, Xiao Q … +5 more , Huang S, Lin S, Fang D, Li J, Luo Q
BMC Med Genomics · 2026 Apr · PMID 42063051 · Full text
BACKGROUND: PRRT2 gene mutations are one of the most common genetic factors leading to neurodevelopmental disorders, such as autism spectrum disorder, intellectual disability, and epilepsy. This gene encodes a proline-ri...
BACKGROUND: PRRT2 gene mutations are one of the most common genetic factors leading to neurodevelopmental disorders, such as autism spectrum disorder, intellectual disability, and epilepsy. This gene encodes a proline-rich transmembrane protein 2, which plays a crucial role in neuronal development and synaptic transmission. Mutations in this gene can result in a variety of clinical phenotypes. METHODS: We retrospectively analyzed 14 pediatric patients from unrelated families with epilepsy or paroxysmal motor disorders, all genetically confirmed to harbor PRRT2 mutations. Comprehensive clinical data were collected, including seizure semiology, EEG, MRI, treatment response, and developmental outcomes. Genetic analysis involved whole-genome sequencing or a customized epilepsy gene panel, with single nucleotide variants validated by Sanger sequencing. The pathogenesis of both mutations((c.189delC p.Lys64Argfs*26) and c.971G > C p.Gly324Ala)) was studied by in vitro experiments. RESULTS: The cohort comprised 6 females and 8 males with onset ages ranging from 3 to 7 months. We identified 13 patients with point mutations and one with an exon 2–4 deletion.The hotspot mutation c.649dupC p.Arg217Profs*8 was most prevalent (11/14). Eleven patients exhibited the Self-limited Infantile Epilepsy (SeLIE) phenotype, one had PKD, and two were unclassifiable. Most patients (12/14, 85.7%) achieved seizure freedom, showing favorable responses to oxcarbazepine or levetiracetam. Developmental delays were observed in 5 patients, of which only 2 carried non-c.649dupC classical variants (c.189delC p.Lys64Argfs*26 and exon 2–4 deletion). Functional studies confirmed that the c.189delC p.Lys64Argfs*26 mutation significantly reduced mRNA and protein expression, while the c.971G > C p.Gly324Ala variant did not affect splicing but was predicted pathogenic.
Variant-to-function dissection of the 17q21.31 locus resolves ANKRD1 as a convergent regulatory target.
Olaoye OJ, Farrow SL, Cooper AA … +2 more , Nyaga DM, O'Sullivan JM
BMC Med Genomics · 2026 Apr · PMID 42057133 · Full text
BACKGROUND: The 17q21.31 locus is structurally complex, harbouring a common H1/H2 inversion and dense regulatory variation; one of the two SNPs studied lies within the inversion and the other outside it. Disentangling th...
BACKGROUND: The 17q21.31 locus is structurally complex, harbouring a common H1/H2 inversion and dense regulatory variation; one of the two SNPs studied lies within the inversion and the other outside it. Disentangling the effects of individual non-coding variants in this context remains challenging. We used reciprocal double-editing in isogenic human iPSCs as a cross-background validation strategy, together with multi-clone replication and a three-way intersection filter (WT-anchored edit and the two reciprocal edit configurations) to resolve variant-linked transcriptional effects for rs77692262 (A > G) and rs79724577 (A > C). RESULTS: rs77692262 affected two TGF-β/SMAD-responsive genes, with ANKRD1 replicating across reciprocal and independent contexts, while ACTA2 showed context-dependent effects. By contrast, rs79724577 yielded seven candidates (ANKRD1, CUZD1, GJA5, PRICKLE1, RAB17, RSPO4, SNPH). Independent validation refined these sets: four discovery-set genes, ANKRD1, CUZD1, PRICKLE1, RAB17, replicated for rs79724577 across edited clones/reciprocal contexts, defining a compact, reproducible signature; ANKRD1 also replicated for rs77692262 and was recovered as the sole consistent DEG when rs77692262 was retested in the reciprocal configuration, making it the most clone-invariant target across both variants. GJA5 appeared in discovery but did not replicate and is treated as hypothesis-generating. Motif analyses were consistent with disrupted T-box/SMAD input at rs77692262 and loss of RFX-family recognition at rs79724577. Long-read CpG methylation profiling detected no significant differences at promoters/gene bodies or at/near the SNP sites, supporting a methylation-independent mechanism involving altered transcription-factor occupancy. CONCLUSIONS: These data identify reproducible, variant-linked transcriptional effects at 17q21.31 within a fixed H1/H1 haplotypic background, centered on ANKRD1 and a validated four-gene signature for rs79724577, and outline a generalizable, replication-first strategy for variant-to-function dissection in structurally polymorphic regions.
Comprehensively identifying and validating the implications of NR5A1 and DHX37 variants for 46,XY disorders of sex development diagnosis.
Li C, Yang B, Li X … +6 more , Zhen S, Liu X, Li P, Chen W, Wang X, Xue M
BMC Med Genomics · 2026 Apr · PMID 42057034 · Full text
BACKGROUND: The clinical phenotype and pathogenic mechanism of 46,XY disorders of sex development (DSD) are complex, and several pathogenic variants are identified by next-generation sequencing. However, these variants c...
BACKGROUND: The clinical phenotype and pathogenic mechanism of 46,XY disorders of sex development (DSD) are complex, and several pathogenic variants are identified by next-generation sequencing. However, these variants currently require additional interpretation and validation prior to their application in 46,XY DSD diagnosis and clinical guidance. RESULTS: Here, we identified three genetic variants in two 46,XY DSD patients by whole exome sequencing screening and Sanger sequencing validation. The pathogenicity of three genetic variants was identified by in silico analysis and functional experiments. One patient carrying the reported pathogenic variant (c.319 C > T) of NR5A1 showed a phenotype of 46,XY complete gonadal dysgenesis, which was different from the reported 46,XY partial gonadal dysgenesis. These findings suggested that the variant (c.319 C > T) of NR5A1 contributes to the clinical phenotypic heterogeneity of 46,XY DSD. The other patient carried two genetic variants, among which the c.1252 C > T variant of NR5A1 produced truncated protein and lost the transcriptional activation of NR5A1 to the targeted genes. The other c.769G > A variant of DHX37 had no significant effect on the expression level and cellular localization of DHX37, and the downstream signaling pathway of DHX37. Moreover, the in silico and structural analysis identified the c.769G > A variant of DHX37 as a deleterious variant that may affect DHX37 function. According to the American College of Medical Genetics and Genomics guidelines and relevant literature reports, combined with the patient's clinical phenotype and pedigreed analysis, it is proposed that the likely pathogenic variant identified in this patient is the c.1252 C > T variant of NR5A1. Nonetheless, the potential pathogenicity of the DHX37 (c.769G > A) variant of this patient also merits further investigation and consideration. CONCLUSIONS: Our results have expanded the clinical phenotype spectrum and genetic diagnosis spectrum of 46,XY DSD, which will contribute to the accurate diagnosis and treatment guidance for 46,XY DSD patients and provide evidence-based genetic counseling for 46,XY DSD family fertility.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe