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Metabolites Mar 2024Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We...
Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting female twins from a consanguineous family. The sisters presented with polymicrogyria, a Dandy-Walker malformation, respiratory distress, and multiorgan dysfunctions. Through WGS, we identified two rare homozygous variants in both subjects, a pathogenic variant in (p.Arg565Trp) and a novel variant in (p.Glu910Val). These genes have been previously associated with autosomal recessive polymicrogyria and hypomyelinating neuropathy with/without contractures, respectively. The twins exhibited symptoms that overlapped with both of these conditions. The results of the untargeted metabolomics analysis revealed significant metabolic perturbations relating to neurodevelopmental abnormalities, kidney dysfunction, and microbiome. The significant metabolites belong to essential pathways such as lipids and amino acid metabolism. The identification of variants in two genes, combined with the support of metabolic perturbation, demonstrates the rarity and complexity of this phenotype and provides valuable insights into its underlying mechanisms.
PubMed: 38535312
DOI: 10.3390/metabo14030152 -
Med (New York, N.Y.) Apr 2024In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk...
BACKGROUND
In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets.
METHODS
In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals.
FINDINGS
The frequencies of CXCR3 memory B cells were reduced in the blood of genetically identical twins with MS compared to their unaffected twin siblings. Natalizumab (anti-VLA-4 antibody) was the only treatment regimen under which these frequencies were reversed. The CNS-homing features of CXCR3 memory B cells were supported by elevated CXCL10 levels in MS cerebrospinal fluid and their in vitro propensity to develop into antibody-secreting cells.
CONCLUSIONS
Circulating CXCR3 memory B cells are affected by non-heritable cues in people who develop MS. This underlines the requirement of environmental risk factors such as Epstein-Barr virus in triggering these B cells. We propose that after CXCL10-mediated entry into the CNS, CXCR3 memory B cells mature into antibody-secreting cells to drive MS.
FUNDING
This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement no. 882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478).
Topics: Humans; Multiple Sclerosis; Memory B Cells; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Natalizumab; Receptors, CXCR3
PubMed: 38531361
DOI: 10.1016/j.medj.2024.02.013 -
Acta Ophthalmologica Mar 2024To examine age-related macular degeneration (AMD) and retinal pigment epithelium (RPE)-Bruch's membrane (BrM) complex volume associations in monozygotic twin pairs.
PURPOSE
To examine age-related macular degeneration (AMD) and retinal pigment epithelium (RPE)-Bruch's membrane (BrM) complex volume associations in monozygotic twin pairs.
METHODS
In this study, 106 elderly twins (53 twin pairs) from the Finnish Twin Cohort study were recruited. Each participant underwent dilated 35-degree digital colour fundus photography (CFP), and spectral domain optical coherence tomography (OCT) and replied to a structured study questionnaire. The CFPs were graded according to the Age-Related Eye Disease Study (AREDS) classification. The OCT images were segmented and volumetric data of the RPE-BrM complex volume was calculated with the Orion™ software. The worse eye according to AREDS classification was used for the analysis.
RESULTS
Twenty-nine (55%) of the twin pairs were discordant with regard to AREDS classification. Fourteen (26%) pairs were discordant with one twin participant having AMD (AREDS 2-4) and the other being unaffected (AREDS 1). Four (8%) pairs had one twin participant with intermediate or late AMD (AREDS 3-4) versus the other being unaffected (AREDS 1). The within-pair polychoric correlation for AREDS was 0.605 (95% confidence interval 0.418-0.792). In multivariate analysis intermediate and late AMD as well as age associated with RPE-BrM complex volume. RPE-BrM complex volume showed a within twin pair correlation, r = 0.430 (95% confidence interval 0.172-0.688, p < 0.01).
CONCLUSION
A substantial proportion of monozygotic twin pairs are discordant with regard to age-related macular degeneration phenotype. RPE-BrM complex volume associated with age and intermediate and late AMD.
PubMed: 38528623
DOI: 10.1111/aos.16671 -
NeuroImage. Clinical 2024Intracranial volume (ICV) represents the maximal brain volume for an individual, attained prior to late adolescence and remaining constant throughout life after. Thus,...
OBJECTIVE
Intracranial volume (ICV) represents the maximal brain volume for an individual, attained prior to late adolescence and remaining constant throughout life after. Thus, ICV serves as a surrogate marker for brain growth integrity. To assess the potential impact of adult-onset multiple sclerosis (MS) and its preceding prodromal subclinical changes on ICV in a large cohort of monozygotic twins clinically discordant for MS.
METHODS
FSL software was used to derive ICV estimates from 3D-T1-weighted-3 T-MRI images by using an atlas scaling factor method. ICV were compared between clinically affected and healthy co-twins. All twins were compared to a large healthy reference cohort using standardized ICV z-scores. Mixed models assessed the impact of age at MS diagnosis on ICV.
RESULTS
54 twin-pairs (108 individuals/80female/42.45 ± 11.98 years), 731 individuals (375 non-twins, 109/69 monozygotic/dizygotic twin-pairs; 398female/29.18 ± 0.13 years) and 35 healthy local individuals (20male/31.34 ± 1.53 years). In 45/54 (83 %) twin-pairs, both clinically affected and healthy co-twins showed negative ICV z-scores, i.e., ICVs lower than the average of the healthy reference cohort (M = -1.53 ± 0.11, P<10). Younger age at MS diagnosis was strongly associated with lower ICVs (t = 3.76, P = 0.0003). Stratification of twin-pairs by age at MS diagnosis of the affected co-twin (≤30 versus > 30 years) yielded lower ICVs in those twin pairs with younger age at diagnosis (P = 0.01). Comparison within individual twin-pairs identified lower ICVs in the MS-affected co-twins with younger age at diagnosis compared to their corresponding healthy co-twins (P = 0.003).
CONCLUSION
We offer for the first-time evidence for strong associations between adult-onset MS and lower ICV, which is more pronounced with younger age at diagnosis. This suggests pre-clinical alterations in early neurodevelopment associated with susceptibility to MS both in individuals with and without clinical manifestation of the disease.
Topics: Humans; Adult; Female; Male; Twins, Monozygotic; Magnetic Resonance Imaging; Multiple Sclerosis; Middle Aged; Brain; Young Adult; Age of Onset; Organ Size
PubMed: 38522363
DOI: 10.1016/j.nicl.2024.103597 -
Medecine Sciences : M/S Mar 2024Rare unrelated individuals show striking resemblance, almost as high as monozygotic twins. Extensive genetic analysis of a set of such individuals shows that every...
Rare unrelated individuals show striking resemblance, almost as high as monozygotic twins. Extensive genetic analysis of a set of such individuals shows that every couple shares a given allele at a large set of loci, enriched for "face genes". The similarity is limited to this set of loci, and the rest of the genome is quite diverse in these "look alike" individuals.
Topics: Humans; Twins, Monozygotic; Genome, Human
PubMed: 38520107
DOI: 10.1051/medsci/2024016 -
Molecular Psychiatry Mar 2024Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune...
Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes compared to healthy individuals. Microglia from affected twins had also reduced response to interleukin 1 beta (IL1β) treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of major histocompatibility complex (MHC) class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation.
PubMed: 38519640
DOI: 10.1038/s41380-024-02529-1 -
Cureus Feb 2024We analyzed multimodal retinal and choroidal imaging, including optical coherence tomography (OCT) and OCT angiography (OCTA), to assess differences and characterize...
We analyzed multimodal retinal and choroidal imaging, including optical coherence tomography (OCT) and OCT angiography (OCTA), to assess differences and characterize variations in the retinal and choroidal structure and microvasculature between healthy monozygotic twins without ocular or systemic pathology over a five-year period. Retinal imaging of both subjects revealed normal age-related changes. There was up to an 11% difference in OCT and OCTA variables within the subjects, both at baseline and at five years, and there was up to an 18% difference in OCT and OCTA parameters between the subjects for both time points. Larger changes in subfoveal choroidal thickness and foveal avascular zone area were observed. Our observations suggest that the parafoveal superficial capillary plexus, choroidal vascularity index, central subfield thickness, retinal nerve fiber layer thickness, and ganglion cell-inner plexiform layer thickness may be more heavily influenced by genetic, rather than environmental, factors. In contrast, subfoveal choroidal thickness and the foveal avascular zone area may be more heavily influenced by environmental factors. The environmental impact on retinal and choroidal structure and microvasculature is increasingly important to characterize, as such imaging parameters are being explored as potential biomarkers of systemic disease. These differences, as seen in these identical twin subjects, may be important considerations in supporting the security of biometric identifiers.
PubMed: 38516463
DOI: 10.7759/cureus.54557 -
Fa Yi Xue Za Zhi Feb 2024
Topics: Humans; Male; Genetic Markers; Twins, Monozygotic; Fathers
PubMed: 38500475
DOI: 10.12116/j.issn.1004-5619.2023.530702 -
BioRxiv : the Preprint Server For... Mar 2024Clonal hematopoiesis becomes increasingly common with age, but its cause is enigmatic because driver mutations are often absent. Serial observations infer weak selection...
Clonal hematopoiesis becomes increasingly common with age, but its cause is enigmatic because driver mutations are often absent. Serial observations infer weak selection indicating variants are acquired much earlier in life with unexplained initial growth spurts. Here we use fluctuating CpG methylation as a lineage marker to track stem cell clonal dynamics of hematopoiesis. We show, via the shared prenatal circulation of monozygotic twins, that weak selection conferred by stem cell variation created before birth can reliably yield clonal hematopoiesis later in life. Theory indicates weak selection will lead to dominance given enough time and large enough population sizes. Human hematopoiesis satisfies both these conditions. Stochastic loss of weakly selected variants is naturally prevented by the expansion of stem cell lineages during development. The dominance of stem cell clones created before birth is supported by blood fluctuating CpG methylation patterns that exhibit low correlation between unrelated individuals but are highly correlated between many elderly monozygotic twins. Therefore, clonal hematopoiesis driven by weak selection in later life appears to reflect variation created before birth.
PubMed: 38496542
DOI: 10.1101/2024.03.02.583106