BMC Medical Genomics[JOURNAL]
Sun
200 papers
Levers and constraints on general practitioners offering and managing reproductive genetic carrier screening in Australian primary care: a rich graphic of the complex context.
Vizheh M, Lamprell K, Cormack M … +6 more , Patel R, Sheriff S, Churruca K, Ellis LA, Braithwaite J, Long JC
BMC Med Genomics · 2026 Apr · PMID 42050642 · Full text
Reproductive genetic carrier screening (RGCS) identifies people who have an increased chance of having a child with a serious genetic condition. In Australia, since November 2022, RGCS for three conditions, cystic fibros...
Reproductive genetic carrier screening (RGCS) identifies people who have an increased chance of having a child with a serious genetic condition. In Australia, since November 2022, RGCS for three conditions, cystic fibrosis, spinal muscular atrophy, and fragile X syndrome, has been publicly funded via Medicare (Australia's universal health insurance scheme). Therefore, tests are offered at no cost to eligible people and are accessible through general practitioners (GPs), making primary care a key point of access. This study aimed to develop a rich graphic illustrating the ecosystem of offering RGCS in Australian primary care. The three-stage, exploratory, qualitative approach involved: (1) constructing the first draft of the rich graphic using literature, policy documents, and team expertise; (2) conducting semi-structured interviews with eleven key informants representing diverse stakeholders; and (3) conducting a survey with key informants to review the penultimate version and produce the final version. The final rich graphic positioned GPs at the centre of a network of six stakeholder groups: consumers, government, laboratories, professional bodies, healthcare organisations, and consumer support groups. Inductive thematic analysis identified three overarching themes: (1) reinforcing patterns and feedback cycles; (2) structural misalignments and systemic tensions; and (3) emergent adaptations and system responses. Our analysis revealed that several factors influencing GPs' ability to offer RGCS are not isolated but parts of dynamic patterns of linkages, relationships, interactions, interdependencies, feedback loops, and behaviours that generate complex, sometimes unintended and contradictory, system-level effects, collectively shaping the complex system. Using rich graphic methodology revealed chains of interdependencies that would have remained obscured by using traditional linear implementation frameworks.
Shared genetic architecture between Alzheimer's disease and psychiatric disorders revealed by multi-trait genome-wide analyses.
Zhang H, Xie L, Meng F … +5 more , Cui J, Ma B, Wang Y, Zhang K, Miao X
BMC Med Genomics · 2026 Apr · PMID 42050540 · Full text
OBJECTIVE: Clarify the shared genetic architecture between Alzheimer’s disease (AD) and major psychiatric disorders. METHODS: We integrated large GWAS summary datasets derived predominantly from individuals of European a...
OBJECTIVE: Clarify the shared genetic architecture between Alzheimer’s disease (AD) and major psychiatric disorders. METHODS: We integrated large GWAS summary datasets derived predominantly from individuals of European ancestry for AD and eight psychiatric disorders; estimated genome-wide genetic correlations with LDSC/HDL; mapped local genetic correlations with SUPERGNOVA; ran pairwise Multi-trait analysis of GWAS (MTAG (AD with ADHD, BIP, MDD, PTSD, SCZ)) followed by FUMA; performed cross-trait colocalization with HyPrColoc and trait–eQTL colocalization using GTEx v8 (49 tissues). RESULTS: HDL identified significant genome-wide correlations for five AD–psychiatric pairs, led by AD–MDD; LDSC was significant for AD–MDD. We mapped 18 locally correlated regions. MTAG yielded 33 AD-associated loci (118 SNPs), including 12 novel (e.g., RAB27B/rs12968702, PTCH1/rs3824488, EP300/rs12157997), and 336 psychiatric-trait signals across 265 loci. HyPrColoc detected 74 AD–psychiatric colocalized regions (40 with PP ≥ 0.8), with 13 driven by a single candidate causal variant. Trait–eQTL colocalization prioritized 25 genes in 122 associations; brain-tissue signals implicated P4HTM, GPX1, CCDC71, and—at an AD–SCZ locus—ADAM10. CONCLUSION: AD shares substantial pleiotropic architecture with psychiatric disorders, particularly MDD. Integrative multi-trait association, colocalization, and tissue-specific eQTL evidence highlights convergent mechanisms—exosome biology (RAB27B), astrocytic Ca²⁺ signaling (P4HTM), and non-amyloidogenic APP processing (ADAM10)—and nominates testable therapeutic targets.
Multi-omics single-cell dissection of malignant epithelial heterogeneity identifies GJB2 as an EMT-driving biomarker in triple-negative breast cancer.
Xu H, Zhang C, Zhang X … +2 more , Zhang S, Zhou G
BMC Med Genomics · 2026 Apr · PMID 42045912 · Full text
BACKGROUND: Tumor heterogeneity poses a major challenge to elucidating the mechanisms underlying tumor progression and metastasis. However, the cellular heterogeneity of triple-negative breast cancer (TNBC) remains incom...
BACKGROUND: Tumor heterogeneity poses a major challenge to elucidating the mechanisms underlying tumor progression and metastasis. However, the cellular heterogeneity of triple-negative breast cancer (TNBC) remains incompletely understood. METHODS: We performed an integrated analysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets from TNBC to identify distinct malignant cell subtypes. Multiple analytical approaches were then applied to comprehensively characterize the metastasis-related subtype. Subsequently, we validated GJB2 as a biomarker of this subtype and confirmed its association with epithelial–mesenchymal transition (EMT) in TNBC cell lines. RESULTS: Based on six scRNA-seq datasets from GSE180286 and GSE161529, we constructed a comprehensive landscape of malignant-cell heterogeneity in TNBC and identified three malignant cell subtypes: an EMT-Subtype, a secretory-like subtype (Sec-like Subtype), and a metabolic subtype (Metab-Subtype). We further identified GJB2 as a marker of the EMT-Subtype. Enrichment analyses indicated that GJB2 was closely associated with the TGF-β signaling pathway, and this finding was further supported by in vitro functional assays. CONCLUSION: By classifying malignant TNBC cells into three subtypes, we identified GJB2 as a marker of the EMT-Subtype. Mechanistically, GJB2 may promote EMT through the TGF-β signaling pathway and therefore represent a potential therapeutic target in TNBC. Targeting the GJB2–TGF-β axis may provide a promising strategy for suppressing the highly metastatic behavior of TNBC.
A novel androgen receptor gene splice site mutation induces aberrant mRNA splicing and internal in-frame deletion in androgen insensitivity syndrome.
Liao B, Shuai M, Xiao L … +5 more , Huang G, He Y, Wang YL, Wang H, He S
BMC Med Genomics · 2026 Apr · PMID 42021352 · Full text
Androgen insensitivity syndrome (AIS) is a disorder caused by pathogenic mutations in the androgen receptor (AR) gene, leading to androgen resistance and impaired sex differentiation in 46,XY individuals. Despite increas...
Androgen insensitivity syndrome (AIS) is a disorder caused by pathogenic mutations in the androgen receptor (AR) gene, leading to androgen resistance and impaired sex differentiation in 46,XY individuals. Despite increasing recognition of AR mutations, the pathogenic mechanisms and genotype–phenotype correlations of many variants remain incompletely characterized. In this study, we identified a novel splice site mutation in the AR gene, c.2450-1G > A, in a 46,XY patient presenting with a female phenotype, including primary amenorrhea and classical features of AIS, confirmed by chromosomal analysis and ultrasonography. Functional validation using minigene splicing assays demonstrated that this variant disrupts normal splicing, leading to an aberrant transcript lacking 6 bp at the 5′ end of exon 7. This results in an aberrant in-frame transcript, c.2450_2455del, encoding a mutant protein with a three-amino acid deletion and a methionine insertion (p.Ile817_Val819delinsMet), while preserving the reading frame. In silico structural modeling suggested that this alteration may disturb the ligand-binding domain (LBD) conformation and receptor functionality. These findings highlight the pathogenic significance of splice-site variants in AR and provide mechanistic insight into AIS diagnosis and management.
Bioinformatics analyses of a potential miRNA‒mRNA regulatory axis in lumbar degenerative disc disease.
Wang J, Zhu L, Weng F … +4 more , Zeng J, Xu L, Chen Y, Shi Y
BMC Med Genomics · 2026 Apr · PMID 42015228 · Full text
BACKGROUND: Intervertebral disc degeneration (IDD), normally characterized by a loss of nucleus pulposus cells (NPCs), is one of the leading causes of lower back pain and various degenerative spinal disorders and has bee...
BACKGROUND: Intervertebral disc degeneration (IDD), normally characterized by a loss of nucleus pulposus cells (NPCs), is one of the leading causes of lower back pain and various degenerative spinal disorders and has been regarded as a public health issue because of its heavy social and economic consequences. However, the molecular mechanisms underlying IDD formation and progression are unclear so far, which results in the lack of existing biomarkers or treatments in targeting early degeneration effectively. Novel potential biomarkers for the early diagnosis, prevention and treatment of IDD are urgently needed. METHODS: In this study, miRNA sequencing and qRT-PCR validation were performed on original clinical nucleus pulposus (NP) tissues from our own IDD patient cohort. Furthermore, we applied bioinformatics analysis to the mRNA expression profiles in NP tissues (GSE186542) and whole blood (GSE124272) from IDD patients. We screened key genes and miRNA regulators by conducting overlap analysis. RESULTS: The results showed that 466 differentially expressed miRNAs, 187 downregulated and 279 upregulated significantly, were identified from miRNA sequencing analysis in NP tissues. Overlap analysis with the predicted miRNA targets and the differentially expressed genes (DEGs) in the GSE186542 database exhibited 27 overlapping genes, among which copine-6 (CPNE6) and beta-1,3-glucuronyltransferase (B3GAT1) overlapped with the DEGs from the whole blood of IDD patients in the GSE124272 database. Further qRT‒PCR results revealed that CPNE6 and B3GAT1 expression was significantly upregulated, but their corresponding miRNA regulators miR-3620-5p and miR-6511b-3p were significantly downregulated in IDD patients. Moreover, cells proliferation was inhibited, but the IL-1β, IL-18 and TNF-α contents were significantly increased, in ATDC5 cells after miR-3620-5p and miR-6511b-3p inhibition. CONCLUSION: Thus, miR-3620-5p and miR-6511b-3p might be the key effectors in IDD progression by mediating the expression of CPNE6 and B3GAT1 in NP tissues. This newly discovered specific miRNA‑mRNA interactions were identified and validated using our original patient samples, with public datasets used for bioinformatic cross‑validation. It holds huge potential applications for miRNA-based therapies in early diagnosis and treatment of IDD.
Whole-exome sequencing identifies PRSS56 variants in Chinese patients with microphthalmia.
Luo J, Li K, Yang R … +2 more , Tang M, Ge J
BMC Med Genomics · 2026 Apr · PMID 42015194 · Full text
PURPOSE: This study aimed to elucidate the genetic and clinical profiles of Chinese patients with microphthalmia harbouring PRSS56 variants and investigate the genotype‒phenotype correlation. METHODS: Whole-exome sequenc...
PURPOSE: This study aimed to elucidate the genetic and clinical profiles of Chinese patients with microphthalmia harbouring PRSS56 variants and investigate the genotype‒phenotype correlation. METHODS: Whole-exome sequencing (WES) was performed in patients with microphthalmia and available family members to assess coding regions and adjacent intronic splice boundaries for variant detection and downstream interpretation. The axial lengths (ALs) of all the probands and available family members were measured. The genotype‒phenotype correlation was explored by statistical analysis, and protein structure prediction was analysed in silico. RESULTS: Seven PRSS56 variants were detected across four of the seven families, including two novel candidate variants (c.175G > A:p.E59K and c.1030 C > A:p.P344T) and five previously reported variants. Variant p.Q356Pfs152 was found in two unrelated families and was the most frequent. The mutational spectrum frequency in the Chinese population differed from that in other ethnic groups worldwide. The average AL was 17.82 ± 1.51 mm. In an exploratory pooled analysis combining the current cohort with previously published cases, eyes with biallelic LoF variants showed shorter ALs than eyes with missense variants. Variants p.G107V and p.E396K, which were reported exclusively in Chinese microphthalmia cases, were predicted to destabilize the PRSS56 protein. CONCLUSIONS: Among nine individuals from seven families, seven PRSS56 variants were identified in four families, underscoring the significant genetic diversity within the Chinese population. The reported variant p.Q356Pfs*152 had the highest frequency in our cohort. Our findings expand current understanding of PRSS56-associated microphthalmia and provide valuable information for prenatal diagnosis and future therapeutic strategies.
Genetic polymorphisms and expression of SARS-CoV-2 host entry genes associate with COVID-19 severity in an unvaccinated Moroccan cohort.
Aqillouch S, Laazaazia O, Ouladlahsen A … +6 more , Noureddine R, Baba H, Akarid K, Benjelloun S, Pineau P, Ezzikouri S
BMC Med Genomics · 2026 Apr · PMID 41998646 · Full text
BACKGROUND: Host molecular and genetic factors regulating SARS-CoV-2 entry are increasingly recognized as key determinants of infection susceptibility and disease severity. However, the combined impact of transcriptional...
BACKGROUND: Host molecular and genetic factors regulating SARS-CoV-2 entry are increasingly recognized as key determinants of infection susceptibility and disease severity. However, the combined impact of transcriptional and genetic variation in these pathways remains incompletely defined. This study aimed to identify clinically relevant biomarkers associated with COVID-19 outcomes by integrating gene expression and genetic variability analyses of major viral entry factors. METHODS: We analyzed the expression and genetic variability of key SARS-CoV-2 entry-related genes (ACE2, TMPRSS2, FURIN, and NRP1) in 184 severe patients, 182 benign cases, and 180 healthy controls. Gene expression was quantified by qRT-PCR, and six SNPs (rs2285666, rs2070788, rs1475908, rs4702, rs4932178, rs1412115) were genotyped using TaqMan assays. RESULTS: TMPRSS2 and FURIN were significantly overexpressed in severe COVID-19 patients (p < 0.05) and positively correlated with platelet count (r = 0.34–0.36, p < 0.05). FURIN expression also correlated with viral load (r = 0.40, p = 0.007). Genetically, the TMPRSS2 rs1475908 GG genotype was associated with higher gene expression (p = 0.009), while the A allele conferred protection against disease severity (OR = 0.53, 95% CI: 0.33–0.84, p = 0.006). Conversely, the rs2070788 GA genotype increased infection susceptibility (OR = 1.69, 95% CI: 1.10–2.60, p = 0.048). FURIN rs4702 was significantly associated with both infection risk and severe disease (OR = 1.53, p = 0.002; OR = 1.60, p = 0.012). After FDR correction, the association of rs4702 with infection susceptibility remained statistically significant. Haplotype analyses further supported these findings, highlighting the role of TMPRSS2 in disease severity and FURIN in susceptibility. CONCLUSION: Our findings identify TMPRSS2 and FURIN as biomarkers that integrate transcriptional and genetic signatures. These variants, particularly FURIN rs4702 and TMPRSS2 rs1475908, may hold potential utility for early risk stratification and personalized management of COVID-19.
Association of TP53 polymorphic variants rs1042522 and rs1642785 with susceptibility and prognosis of acute lymphoblastic leukemia in a Brazilian Amazon population.
Nogueira GM, Gonçalves LGM, Pereira-Ribeiro TL … +7 more , Santos LS, Magalhães-Gama F, Araújo ND, Malheiro A, Tarragô AM, Alves-Hanna FS, Costa AG
BMC Med Genomics · 2026 Apr · PMID 41981649 · Full text
BACKGROUND: Tumor suppressor genes play a central role in cancer development, and inherited genetic variation may influence both disease susceptibility and clinical outcomes. This study aimed to investigate the frequency...
BACKGROUND: Tumor suppressor genes play a central role in cancer development, and inherited genetic variation may influence both disease susceptibility and clinical outcomes. This study aimed to investigate the frequency and prognostic relevance of TP53 polymorphic variants in patients with acute lymphoblastic leukemia (ALL) from an admixed population in the Brazilian Amazon. METHODS: A population-based case–control study was conducted including 193 patients diagnosed with ALL and 215 healthy controls. Germline TP53 polymorphisms rs1042522 and rs1642785 were genotyped, and allele and genotype frequencies were compared between groups. Associations with ALL susceptibility, relapse, and mortality were evaluated using multiple genetic models adjusted for age and sex. Combined genotype and haplotype analyses were performed, and overall survival was estimated using Kaplan-Meier curves and log-rank tests. RESULTS: The CC genotype and the allele C were more frequent among ALL cases than controls. The allele C of rs1042522 (p = 0.021) and rs1642785 (p = 0.022) was associated with increased susceptibility to ALL. In addition, the allele C of rs1042522 was associated with a higher risk of relapse (p = 0.016) and death (p = 0.009). Protective effects against ALL were observed under the recessive model for rs1042522 (p = 0.019) and the codominant model for rs1642785 (p = 0.013). Both variants showed protective associations with mortality under the log-additive model. Combined genotype analysis revealed that the CG and GG genotypes of rs1042522 were associated with a reduced risk of relapse (p < 0.001). Overall survival analysis showed reduced survival associated with the CC genotype, whereas improved survival was observed for the heterozygous CG genotype. Haplotype analysis indicated that the GG haplotype was associated with a reduced risk of ALL (p = 0.007) and death (p = 0.013). CONCLUSIONS: Our findings suggest that germline TP53 variants rs1042522 and rs1642785 modulate susceptibility and clinical outcomes in ALL, supporting their potential role as prognostic biomarkers. This study highlights the importance of population-based genomic investigations in underrepresented populations.
Advances in research on circadian rhythms and colorectal cancer.
Jia L, Zhu M, Wu X … +3 more , Zheng W, Zhang Y, Xiao J
BMC Med Genomics · 2026 Apr · PMID 41981628 · Full text
With the change of people's dietary habits and irregular lifestyle, such as frequent high-fat diets and overtime work, the prevalence of colorectal cancer nowadays is increasing year by year. Due to the long latency peri...
With the change of people's dietary habits and irregular lifestyle, such as frequent high-fat diets and overtime work, the prevalence of colorectal cancer nowadays is increasing year by year. Due to the long latency period of colorectal cancer, how to prevent the high-risk factors associated with the development of colorectal cancer is one of the hotspots of research. Studies have shown that there is a significant correlation between circadian rhythms and colorectal cancer, and it is possible to prevent and treat colorectal cancer from the perspective of circadian rhythms to reduce its incidence, recurrence and prolong the survival cycle of patients. In this paper, we review the studies related to circadian rhythms and colorectal cancer.
CRABP2 upregulation in perichondral stem cells is associated with microtia.
Zhang J, Chu F, Hu X … +6 more , Yang X, Lei S, He L, Wu D, Lin L, Jiang H
BMC Med Genomics · 2026 Apr · PMID 41975397 · Full text
Microtia is a common congenital craniofacial malformation characterized by the partial or complete absence of the external ear structure. Despite its relatively high incidence, the pathogenesis of microtia remain poorly...
Microtia is a common congenital craniofacial malformation characterized by the partial or complete absence of the external ear structure. Despite its relatively high incidence, the pathogenesis of microtia remain poorly understood. In this study, we analyzed both single-cell and bulk RNA sequencing data from microtia cases and identified a population of COL1 + HES1+mesenchymal stem cell in perichondrium with significantly higher expression of the CRABP2 gene, a gene that encodes a nuclear transporter of retinoic acid. Gene expression analysis further confirmed that the RA signaling intensity and stemness are both higher in COL1 + HES1+ perichondral stem cells from microtia patients, possibly due to elevated CRABP2 levels. Through histological verification we further confirmed the presence of this cell population with high CRABP2 expression in the perichondrium. Mechanistically, the elevated CRABP2 expression in perichondral stem cells seen in microtia patients may cause dysregulated RA signaling and disrupt the regulation of stem cell differentiation during auricular development. Histological analysis further revealed higher KLF2 expression as well as cartilage hypoplasia in microtia samples. Our study identified that the CRABP2-induced RA dysregulation in COL1 + HES1+ perichondral stem cells may contribute to microtia. These findings offer new insights into the etiology of microtia and provide potential directions for prenatal prevention and tissue engineering treatments.
Downward bias in the association between APOE and Alzheimer's disease using prevalent and by-proxy disease sampling in the All of Us research program.
Mansel CO, Ghisays V, Mahnken JD … +5 more , Swerdlow RH, Reiman EM, Karnes JH, Denny JC, Veatch OJ
BMC Med Genomics · 2026 Apr · PMID 41965633 · Full text
BACKGROUND: Recent genome-wide association studies for Alzheimer’s Disease and related dementias (ADRD) have increased statistical power via larger analysis datasets from biobanks by (1) including non-age-matched control...
BACKGROUND: Recent genome-wide association studies for Alzheimer’s Disease and related dementias (ADRD) have increased statistical power via larger analysis datasets from biobanks by (1) including non-age-matched controls and prevalent cases, and/or (2) including individuals who report a family history of ADRD as proxy cases. However, these methods have the potential to increase noise and distort genetic associations which are important for genomic-informed prevention and treatment of ADRD. Here, we sought to understand how the effect sizes of genetic associations in ADRD could be sensitive to these methodological choices, using APOE genotypes as an example. METHODS: Participants in the All of Us Research Program over the age of 49 at enrollment (n = 229,722) were assigned one of four categories: incident ADRD (developed after enrollment in All of Us), prevalent ADRD (present on enrollment), proxy ADRD (participant noted a family history of ADRD), and control (no history or diagnosis of ADRD). ADRD diagnoses were determined using available electronic health records and APOE genotype was determined using whole-genome sequencing. Effect sizes for the associations between APOE risk alleles and ADRD diagnoses were compared using polychotomous logistic regression and presented as adjusted generalized ratios (AGR). RESULTS: The mean age of the cohort was 64 ± 9 years, and it was 57% female; 65% clustered predominantly with European genetic reference populations. Among the participants, 733 (0.3%) had prevalent ADRD, 684 (0.3%) had incident ADRD, and 19,186 (8.4%) reported a family history of ADRD (proxy ADRD). The effect size for APOE ε4 heterozygote was similar for proxy ADRD (AGR [95% CI]: 2.10 [1.96–2.24]) but attenuated for prevalent ADRD (1.38 [1.17–1.63]) compared to incident ADRD (2.13 [1.81–2.50]). For APOE ε4 homozygotes, the effect sizes were significantly attenuated in both proxy (3.53 [2.93–4.26]) and prevalent (3.12 [2.20–4.45]) ADRD. Furthermore, APOE and ADRD association effect sizes increased when restricting the control (no ADRD) group to older age brackets. CONCLUSIONS: Our study highlights how genetic associations with ADRD can be sensitive to how cases are defined in biobanks like All of Us, with effect sizes downwardly biased when using prevalent or by-proxy cases compared to incident cases.
Prenatal phenotypic delineation of a de novo EYA1 likely pathogenic variant in branchio-oto-renal syndrome.
Sun L, Shu D, He W … +7 more , Ma R, Tao H, Yang Z, Li Y, Liu Z, Zhang Y, Zhao Y
BMC Med Genomics · 2026 Apr · PMID 41965611 · Full text
BACKGROUND: Branchio-oto-renal (BOR; MIM 113650) syndrome is primarily linked to pathogenic variants in the EYA1 gene. Although over 200 pathogenic variants of the EYA1 gene have been reported, validation of the pathogen...
BACKGROUND: Branchio-oto-renal (BOR; MIM 113650) syndrome is primarily linked to pathogenic variants in the EYA1 gene. Although over 200 pathogenic variants of the EYA1 gene have been reported, validation of the pathogenicity of novel variants and the aggregation of prenatal phenotypes are crucial to guide prenatal diagnosis. METHODS: This study analyzed the clinical and genetic data of a fetus presenting with BOR syndrome. A de novo EYA1 gene variant was identified and the functional impact of this variant was validated using minigene splicing assays in vitro. Additionally, a systematic review of prenatal cases with EYA1 variants was conducted to summarize phenotypic frequencies. RESULTS: Prenatal ultrasound detected left ear anomaly, facial cyst and a persistent right umbilical vein. Genetic testing revealed a novel variant c.640-15G > A in the EYA1 gene. In vitro minigene assays demonstrated an aberrant effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was reclassified as likely pathogenic. Systematic literature review indicated that urinary system abnormalities and amniotic fluid anomalies were more prevalent in prenatal cases. CONCLUSIONS: This study adds a novel likely pathogenic variant to the EYA1 variant spectrum in BOR syndrome and suggests that certain prenatal ultrasound phenotypic markers might be strongly associated with EYA1-related diseases.
Genetic analysis reveals phenotypic variability in three Colombian families with dopa-responsive dystonia: novel genotype-phenotype correlations.
Lince-Rivera I, Martinez-Córdoba N, Ramón-Gómez JL … +2 more , Cabarcas L, Zarante-Bahamón AM
BMC Med Genomics · 2026 Apr · PMID 41965601 · Full text
BACKGROUND: Dopa-responsive Dystonia (DRD) due to GTP cyclohydrolase 1 (GTPCH1) deficiency is a neurogenetic disorder caused by pathogenic GCH1 variants. Tetrahydrobiopterin (BH4) deficiency impairs dopamine synthesis in...
BACKGROUND: Dopa-responsive Dystonia (DRD) due to GTP cyclohydrolase 1 (GTPCH1) deficiency is a neurogenetic disorder caused by pathogenic GCH1 variants. Tetrahydrobiopterin (BH4) deficiency impairs dopamine synthesis in the basal ganglia, leading to childhood-onset dystonia with excellent response to levodopa. CASE PRESENTATION: We report eight patients from three unrelated families with GCH1 (NM_000161.3) variants: c.142 C > T; p.(Gln48*), c.241T > C; p.(Ser81Pro), and c.607G > A; p.(Gly203Arg). Two individuals homozygous for c.142 C > T showed phenotypic discordance. Mean age at onset was 7.3 years (range: 6–12), with an average diagnostic delay of 13.4 years. All symptomatic individuals responded well to low-dose levodopa. DISCUSSION: This is the first report to describe variable expressivity among individuals homozygous for p.(Gln48*). Previous literature has focused on heterozygous carriers with incomplete penetrance, and homozygous variability remains scarcely documented. CONCLUSIONS: Our findings expand the clinical and molecular spectrum of DRD and challenge the assumption that autosomal recessive GCH1 variants invariably cause a severe phenotype. This report underscores the importance of family-based genetic studies, detailed pedigrees, and careful clinical surveillance of asymptomatic carriers. A low threshold for levodopa trials is warranted, even when inheritance patterns or symptom severity deviate from classical expectations. These insights are critical to improving early recognition and timely treatment.
Alkaptonuria in two Colombian patients: identification of HGD variants including a novel finding.
León-Sanabria MC, Zarante-Bahamón AM
BMC Med Genomics · 2026 Apr · PMID 41963999 · Full text
BACKGROUND: Alkaptonuria (AKU) is a rare autosomal recessive inborn error of metabolism caused by deficiency of homogentisate 1,2-dioxygenase (HGD), its deficiency results in homogentisic acid (HGA) accumulation, which o...
BACKGROUND: Alkaptonuria (AKU) is a rare autosomal recessive inborn error of metabolism caused by deficiency of homogentisate 1,2-dioxygenase (HGD), its deficiency results in homogentisic acid (HGA) accumulation, which oxidizes to form melanin-like pigments that deposit in connective tissues, leading to ochronosis and progressive multisystem complications. We describe two unrelated Colombian female patients with AKU, emphasizing clinical variability and novel genetic findings. CASE REPORTS: Case 1: Female with onset of symptoms at age 16, including scleral pigmentation, glaucoma, retinal detachment, and joint pain. Arthroscopy revealed ochronotic pigmentation and cystic changes in the glenohumeral cartilage, pigmented deposits were observed in the ears and sclera during adulthood. Whole-exome sequencing (WES) identified two HGD variants: c.164_166del (p.Thr55del) and c.774+69C>T, both classified as variants of uncertain significance (VUS). Case 2: Female with reddish urine noted perinatally and recurrent darkened urine episodes during infections. At age 8, she developed intermittent bilateral bone pain in knees and wrists, worsened by physical activity. No evident ochronosis was observed. Whole genome sequencing (WGS) revealed compound heterozygosity for HGD variants: c.808G>A (p.Gly270Arg), likely pathogenic, and c.774+69C>T (VUS). CONCLUSIONS: Both patients shared the intronic HGD variant c.774 + 69 C > T in heterozygosity, a VUS located outside the canonical splice site. Its recurrence in two unrelated individuals with AKU-compatible features and an additional HGD variant suggests potential pathogenic relevance. This report highlights the value of molecular diagnosis for confirming AKU and genetic counseling, and describes a previously unreported HGD variant in a Latin American population, contributing to the understanding of the disorder’s genetic heterogeneity and the importance of genomic characterization in underrepresented groups.
Application of artificial intelligence in lung cancer diagnosis, therapy, and prognosis.
Wang J, Tian R, Liu J … +3 more , Duan S, Zhang Y, Guo S
BMC Med Genomics · 2026 Apr · PMID 41963934 · Full text
Lung cancer is the highest global incidence and mortality rates, imposing substantial burdens on patients’ lives. As the most transformative technology of the modern era, artificial intelligence (AI) has been deeply inte...
Lung cancer is the highest global incidence and mortality rates, imposing substantial burdens on patients’ lives. As the most transformative technology of the modern era, artificial intelligence (AI) has been deeply integrated into medical research and clinical practice. Currently, AI is widely applied in the diagnosis, treatment, and prognostic evaluation of lung cancer. This paper outlines the historical development of lung cancer and its current diagnostic and therapeutic approaches. Then examines the evolution of AI technologies and their learning methodologies, culminating in a focus on the latest advancements in AI applications for lung cancer diagnosis, treatment, and prognosis. This article summarizes the current state of AI integration in lung cancer care and proposes potential directions for future development.
Association between the IGFBP-3 rs2854744 polymorphism and cancer risk: a meta-analysis.
Sun D, Xu L, Chen Y … +3 more , Wang W, Wang N, Hu G
BMC Med Genomics · 2026 Apr · PMID 41963924 · Full text
BACKGROUND: Recently, the association of IGFBP-3 polymorphism and cancer risk has attracted many attentions. Previous studies have shown that IGFBP-3 rs2854744 was associated with cancer, but the results were conflicting...
BACKGROUND: Recently, the association of IGFBP-3 polymorphism and cancer risk has attracted many attentions. Previous studies have shown that IGFBP-3 rs2854744 was associated with cancer, but the results were conflicting. METHOD AND RESULTS: We performed a meta-analysis including 33 studies with 24,688 cases and 28,972 controls to seek the association among them. A significant increase of cancer risk was found between the IGFBP-3 rs2854744 Polymorphism and cancer risk in Recessive Model (CC vs. AC/AA: OR = 1.097, 95%CI: 1.020, 1.180, P < 0.05). While in subgroup analysis, A same increase of breast cancer risk also have been shown in our study in Recessive Model (CC vs. AC/AA: OR = 1.126, 95%CI: 1.007, 1.260, P < 0.05). CONCLUSIONS: The results of our meta-analysis concluded that the IGFBP-3 rs2854744 polymorphism was closely related with the increase of cancer risk while further large size case–control studies are required.
DIAPH1 regulates the Wnt/β-catenin pathway resulting in microcephaly and visual impairment.
Wang D, Lai P, Wang K … +2 more , Wu Z, Li X
BMC Med Genomics · 2026 Apr · PMID 41963888 · Full text
BACKGROUND: Biallelic DIAPH1 mutations are linked to hereditary microcephaly syndrome, yet the underlying pathogenic mechanism remains unelucidated. This study aimed to clarify how DIAPH1 biallelic mutations cause microc...
BACKGROUND: Biallelic DIAPH1 mutations are linked to hereditary microcephaly syndrome, yet the underlying pathogenic mechanism remains unelucidated. This study aimed to clarify how DIAPH1 biallelic mutations cause microcephaly and visual impairment, focusing on the gene’s regulatory role in the Wnt/β-catenin signaling pathway. METHODS: Whole exome sequencing was performed on a patient’s peripheral blood to identify DIAPH1 mutations. A zebrafish model was established by microinjecting mutant human DIAPH1 cDNA into one-cell embryos (no zebrafish DIAPH1 homolog exists). Phenotypic analyses (morphology, neuronal axon growth, behavior) and quantitative real-time PCR for Wnt/β-catenin pathway genes were conducted. Data were mean ± SEM; statistical tests (Student’s t-test, ANOVA, χ²) used GraphPad Prism 5.0 (P < 0.05, P < 0.0001 for significance). RESULTS: Compound heterozygous DIAPH1 mutations (c.1051 C > T, p.R351X; c.609delA, p.E203E fs*19) were found and associated with clinical symptoms. Mutant DIAPH1 zebrafish showed abnormal eye shape, shortened body length, axis defects, impaired motor axon growth, reduced locomotor activity, upregulated WNT8A, WNT9A, LRP5, LRP6, and downregulated AXIN1, AXIN2, β-CATENIN, indicating excessive Wnt/β-catenin pathway activation. CONCLUSIONS: DIAPH1 compound heterozygous mutations may trigger microcephaly and visual impairment by abnormally activating the Wnt/β-catenin pathway. The zebrafish model provides a reliable in vivo system for studying DIAPH1-related microcephaly, advancing understanding of hereditary primary microcephaly pathogenesis and potential therapeutic target exploration.
CSTA and DDX24: potential biomarkers regulating ferroptosis in sepsis and their diagnostic value.
Shen X, Jin Y, Yang K … +2 more , Qian X, Guo J
BMC Med Genomics · 2026 Apr · PMID 41952180 · Full text
BACKGROUND: Sepsis is a critical condition involving dysregulated immune and metabolic responses. Ferroptosis has been implicated in its pathogenesis. However, the precise molecular mechanisms governing ferroptosis in se...
BACKGROUND: Sepsis is a critical condition involving dysregulated immune and metabolic responses. Ferroptosis has been implicated in its pathogenesis. However, the precise molecular mechanisms governing ferroptosis in sepsis remain unclear. METHODS: Multiple transcriptomic datasets related to sepsis were comprehensively analyzed to screen potential hub genes. Differential expression profiling, weighted gene co-expression network construction, and three distinct machine learning approaches were applied in combination. To further elucidate the cellular distribution of these genes, single-cell RNA sequencing data were analyzed, and a corresponding miRNA–mRNA interaction network was established. The biological significance of the identified candidates was subsequently verified through in vitro functional experiments. RESULTS: Two core genes were identified. CSTA was significantly upregulated in sepsis and positively correlated with neutrophil infiltration and M1 macrophage polarization. DDX24 was markedly downregulated and positively associated with CD8⁺ T cell and NK cell function. Both genes demonstrated strong diagnostic performance (AUC > 0.87) in validation cohorts. In vitro modulation of these genes revealed that CSTA knockdown or DDX24 overexpression enhanced cell viability and reversed dysregulation of ferroptosis-related proteins, including upregulation of GPX4 and SLC7A11 and downregulation of ACSL4. CONCLUSIONS: CSTA and DDX24 are central regulators of ferroptosis in sepsis, exhibiting diagnostic and therapeutic potential.
The first report of primary hypotonia with abnormal electromyogram and CBS mutation in a Chinese child.
Zhang Z, Xu S, Wu T … +3 more , Xu W, Wu B, Yang C
BMC Med Genomics · 2026 Apr · PMID 41943097 · Full text
BACKGROUND: Classic Homocystinuria (HCU) is the second most treatable aminoacidopathy. It affects multiple organs in varying degrees, and early recognition and treatment is crucial to improve the prognosis. Mutations in...
BACKGROUND: Classic Homocystinuria (HCU) is the second most treatable aminoacidopathy. It affects multiple organs in varying degrees, and early recognition and treatment is crucial to improve the prognosis. Mutations in the CBS gene result in classic HCU, the most common form. Genetic testing is important for the accurate diagnosis of this severe disorder. METHOD: Case report. RESULT: A 6-year-old boy presented with high myopia, ectopia lentis, and hypotonia. A brain MRI showed no abnormality, and his electromyogram implicated myogenic damage. His serum homocysteine was 277.5 µmol/L (normal ≤ 15 µmol/L), and methionine was 352.56 µmol/L (normal 0–80 µmol/L); thus, he was diagnosed with classic HCU. Compound heterozygous mutations at two different sites on the cystathionine beta‑synthase (CBS) gene (c.767G > T, c.949 A > G) were identified; the former had not been reported previously. CONCLUSIONS: This study reported a novel mutation of CBS gene (c.767G > T). To our knowledge, this is the first report of this novel clinical manifestation of primary hypotonia in homocystinuria patients.
The inverse relationship between copy number variation burden and age of onset of metabolic syndrome in Korean middle-aged adults.
Ko SH, Kim M, Shin D
BMC Med Genomics · 2026 Apr · PMID 41928242 · Full text
BACKGROUND: Metabolic syndrome (MetS) shows wide inter-individual variation in age at onset, yet the contribution of structural genomic variation is underexplored. We posited that copy number variation (CNV) burden—an ag...
BACKGROUND: Metabolic syndrome (MetS) shows wide inter-individual variation in age at onset, yet the contribution of structural genomic variation is underexplored. We posited that copy number variation (CNV) burden—an aggregate of autosomal deletions and duplications—anticipates the timing of MetS. Our objective was to test whether higher CNV burden is associated with earlier onset of MetS and to nominate CNV regions enriched for metabolic biology, clarifying genetic architecture and guiding prevention. We leveraged a longitudinal Korean cohort to address this gap and provide evidence. METHODS: A total of 546 adults from the Korean Genome and Epidemiology Study (KoGES) cohort, with baseline genotyping and up to 20 years of follow-up, were analyzed. CNV burden was quantified as the total number of autosomal CNV segments identified after quality control. For each genomic segment, log2-transformed copy number ratios outside the diploid range were classified as CNV-present (value = 1) and those within the diploid interval were set to zero. Individual CNV burden was calculated by summing all non-zero segments and log-transformed to reduce skewness prior to analysis. MetS was defined according to NCEP ATP III and Korean waist circumference reference values. Onset age of MetS was calculated by adding the elapsed follow-up time (years) until the first diagnosis of MetS to each participant’s age at baseline. Participants who did not develop MetS were excluded from the onset-age calculation. We used multivariable logistic regression, multivariable linear regression, Kaplan–Meier with log-rank tests, and Cox proportional hazards models. RESULTS: A total of 403 CNVs showed nominal associations with MetS based on multivariable logistic regression adjusted for demographic, lifestyle, and clinical covariates (P < 0.05). The strongest signals were located in the amylase gene clusters (AMY1A/B/C, AMY2A/B) and KDM4C, although no CNV survived multiple-testing correction. Higher CNV burden was associated with earlier MetS onset in men (β = −21.42, P = 0.0249) and women (β = −14.09, P = 0.0451). In sex-stratified Cox proportional hazards models, CNV burden was consistently associated with an increased risk of incident MetS in men across all adjustment models, with hazard ratios ranging from 1.18 to 1.21. In women, the association showed a similar positive direction, with significance observed in partially adjusted models, although attenuated after full adjustment. CONCLUSIONS: Greater CNV burden consistently was associated with earlier MetS onset in a population-based Korean cohort, positioning structural variation as a contributor to cardiometabolic trajectories. The prominence of AMY1/AMY2 and KDM4C suggests convergent pathways linking starch metabolism and epigenetic regulation to disease timing. CNV burden may serve as a biomarker to prioritize early clinical surveillance and tailored prevention, warranting mechanistic and external validation studies.
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