scholarly journals PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Catia Cavicchi ◽  
Abderrahim Oussalah ◽  
Silvia Falliano ◽  
Lorenzo Ferri ◽  
Alessia Gozzini ◽  
...  
Keyword(s):  
Genetic Variant ◽  
Clinical Phenotype ◽  
Antisense Transcription ◽  
Methylmalonic Aciduria ◽  
Metabolic Phenotype ◽  
Inborn Errors ◽  
Gene Testing ◽  
Genome Wide ◽  
Determining Factors ◽  
Cobalamin Metabolism

Abstract Background The role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported. Methods We report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients. Results All patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient’s fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients. Conclusions We provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.

scholarly journals Brain Circuit Alterations and Cognitive Disability in Late-Onset Cobalamin D Disorder

2020 ◽  
Vol 9 (4) ◽  
pp. 990
Author(s):  
Javier De Las Heras ◽  
Ibai Diez ◽  
Antonio Jimenez-Marin ◽  
Alberto Cabrera ◽  
Daniela Ramos-Usuga ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Late Onset ◽  
Ventricular Volume ◽  
Methylmalonic Aciduria ◽  
Cognitive Disability ◽  
Clinical Genetic ◽  
Inborn Errors ◽  
Motor Tracts ◽  
Brain Circuit ◽  
Cobalamin Metabolism

Neuroimaging studies describing brain circuits’ alterations in cobalamin (vitamin B12)-deficient patients are limited and have not been carried out in patients with inborn errors of cobalamin metabolism. The objective of this study was to assess brain functionality and brain circuit alterations in a patient with an ultra-rare inborn error of cobalamin metabolism, methylmalonic aciduria, and homocystinuria due to cobalamin D disease, as compared with his twin sister as a healthy control (HC). We acquired magnetic resonance imaging (including structural, functional, and diffusion images) to calculate brain circuit abnormalities and combined these results with the scores after a comprehensive neuropsychological evaluation. As compared with HC, the patient had severe patterns of damage, such as a 254% increment of ventricular volume, pronounced subcortical and cortical atrophies (mainly at striatum, cingulate cortex, and precuneus), and connectivity alterations at fronto-striato-thalamic circuit, cerebellum, and corpus callosum. In agreement with brain circuit alterations, cognitive deficits existed in attention, executive function, inhibitory control, and mental flexibility. This is the first study that provides the clinical, genetic, neuroanatomical, neuropsychological, and psychosocial characterization of a patient with the cobalamin D disorder, showing functional alterations in central nervous system motor tracts, thalamus, cerebellum, and basal ganglia, that, as far as we know, have not been reported yet in vitamin B12-related disorders.

scholarly journals Variation in VKORC1 Is Associated with Vascular Dementia

2021 ◽  
Vol 80 (3) ◽  
pp. 1329-1337
Author(s):  
Jure Mur ◽  
Daniel L. McCartney ◽  
Daniel I. Chasman ◽  
Peter M. Visscher ◽  
Graciela Muniz-Terrera ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Vascular Dementia ◽  
Genetic Variant ◽  
Warfarin Dose ◽  
Uk Biobank ◽  
Parental History ◽  
Genome Wide ◽  
History Of ◽  
First Time ◽  
The Relationship

Background: The genetic variant rs9923231 (VKORC1) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer’s disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p = 1.8×10–7), which was included in the genome-wide significant KAT8 locus. Objective: Our study aimed to investigate whether the relationship between rs9923231 and dementia persists only for certain dementia sub-types, and if those taking warfarin are at greater risk. Methods: We used logistic regression and data from 238,195 participants from UK Biobank to examine the relationship between VKORC1, risk of dementia, and the interplay with warfarin use. Results: Parental history of dementia, APOE variant, atrial fibrillation, diabetes, hypertension, and hypercholesterolemia all had strong associations with vascular dementia (p < 4.6×10–6). The T-allele in rs9923231 was linked to a lower warfarin dose (βperT - allele = –0.29, p < 2×10–16) and risk of vascular dementia (OR = 1.17, p = 0.010), but not other dementia sub-types. However, the risk of vascular dementia was not affected by warfarin use in carriers of the T-allele. Conclusion: Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia.

Rapid prenatal and postnatal detection of inborn errors of propionate, methylmalonate, and cobalamin metabolism: A sensitive assay using cultured cells

1976 ◽  
Vol 34 (3) ◽  
pp. 277-283 ◽  
Author(s):  
Huntington F. Willard ◽  
Lalit M. Ambani ◽  
Anita C. Hart ◽  
Maurice J. Mahoney ◽  
Leon E. Rosenberg
Keyword(s):  
Cultured Cells ◽  
Sensitive Assay ◽  
Inborn Errors ◽  
Cobalamin Metabolism

scholarly journals SNP-level FST outperforms window statistics for detecting soft sweeps in local adaptation

2022 ◽  
Author(s):  
Tiago da Silva Ribeiro ◽  
José A Galván ◽  
John E Pool
Keyword(s):  
Genetic Differentiation ◽  
Local Adaptation ◽  
Genetic Variant ◽  
Real Data ◽  
Selective Sweeps ◽  
Functional Categories ◽  
Genome Scans ◽  
Genome Wide ◽  
A Genome ◽  
Local Selection

Local adaptation can lead to elevated genetic differentiation at the targeted genetic variant and nearby sites. Selective sweeps come in different forms, and depending on the initial and final frequencies of a favored variant, very different patterns of genetic variation may be produced. If local selection favors an existing variant that had already recombined onto multiple genetic backgrounds, then the width of elevated genetic differentiation (high FST) may be too narrow to detect using a typical windowed genome scan, even if the targeted variant becomes highly differentiated. We therefore used a simulation approach to investigate the power of SNP-level FST (specifically, the maximum SNP FST value within a window) to detect diverse scenarios of local adaptation, and compared it against whole-window FST and the Comparative Haplotype Identity statistic. We found that SNP FST had superior power to detect complete or mostly complete soft sweeps, but lesser power than window-wide statistics to detect partial hard sweeps. To investigate the relative enrichment and nature of SNP FST outliers from real data, we applied the two FST statistics to a panel of Drosophila melanogaster populations. We found that SNP FST had a genome-wide enrichment of outliers compared to demographic expectations, and though it yielded a lesser enrichment than window FST, it detected mostly unique outlier genes and functional categories. Our results suggest that SNP FST is highly complementary to typical window-based approaches for detecting local adaptation, and merits inclusion in future genome scans and methodologies.

scholarly journals BisMapR: a strand-specific, nuclease-based method for genome-wide R-loop detection

2021 ◽  
Author(s):  
Phillip Wulfridge ◽  
Kavitha Sarma
Keyword(s):  
Genome Stability ◽  
Antisense Transcription ◽  
Gene Promoters ◽  
Normal Cells ◽  
Disease States ◽  
Detection Strategy ◽  
Genome Wide ◽  
Loop Detection ◽  
Nucleic Acid Structures ◽  
Nuclear Processes

AbstractR-loops are three stranded nucleic acid structures with essential roles in many nuclear processes. However, their unchecked accumulation as seen in some neurodevelopmental diseases and cancers and is associated with compromised genome stability. Genome-wide profiling of R-loops in normal cells and their comparison in disease states can help identify precise locations of pathogenic R-loops and advance efforts to attenuate deviant R-loops while preserving biologically important ones. Toward this, we have developed an antibody-independent R-loop detection strategy, BisMapR, that combines nuclease-based R-loop isolation with non-denaturing bisulfite chemistry to produce high-resolution, genome-wide R-loop profiles that retain strand information. Furthermore, BisMapR achieves greater resolution and is faster than existing strand-specific R-loop profiling strategies. We applied BisMapR to reveal discrete R-loop behavior at gene promoters and enhancers. We show that gene promoters exhibiting antisense transcription form R-loops in both directions. and uncover a subset of active enhancers that, despite being bidirectionally transcribed, form R-loops exclusively on one strand. Thus, BisMapR reveals a previously unnoticed feature of active enhancers and provides a tool to systematically examine their mechanisms in gene expression.

Prenatal Diagnosis of Methylmalonic Aciduria

PEDIATRICS ◽  
1974 ◽  
Vol 54 (4) ◽  
pp. 511-513
Author(s):  
D. Gompertz ◽  
Patricia A. Goodey ◽  
J. M. Saudubray ◽  
Christiane Charpentier ◽  
Agnes Chignolle ◽  
...  
Keyword(s):  
At Risk ◽  
Prenatal Diagnosis ◽  
Amniotic Fluid ◽  
Methylmalonic Acid ◽  
Methylmalonic Aciduria ◽  
Postnatal Period ◽  
Small Molecular Weight ◽  
Inborn Errors ◽  
Abnormal Accumulation ◽  
Amniotic Cell

The abnormal accumulation of small molecular weight metabolites in amniotic fluid in inborn errors of metabolism is unusual and prenatal diagnosis usually requires amniotic cell culture and specific enzyme assay. However, Morrow et al.1 reported raised concentrations of methylmalonic acid in the amniotic fluid of a pregnancy at risk from methylmalonic aciduria and confirmed the diagnosis in the postnatal period. More recently Mahoney et al.2 have reported an abnormal methylmalonic acid concentration in the amniotic fluid of one of two pregnancies at risk. They confirmed that the fetus in this case was affected by showing an impaired oxidation of methylmalonic acid in cultured amniotic cells.

scholarly journals Genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs

2016 ◽  
Vol 22 (5) ◽  
pp. 774-783 ◽  
Author(s):  
A P Wingo ◽  
L M Almli ◽  
J S Stevens ◽  
T Jovanovic ◽  
T S Wingo ◽  
...  
Keyword(s):  
Association Study ◽  
Positive Emotion ◽  
Genetic Variant ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide

Gene–environment interactions

2018 ◽  
Author(s):  
Barbara Franke ◽  
Jan K. Buitelaar
Keyword(s):  
Environmental Factors ◽  
Genetic Variant ◽  
Differential Susceptibility ◽  
Gene Environment ◽  
Genome Wide ◽  
Single Genome ◽  
Disease Aetiology ◽  
Different Types ◽  
Postnatal Risk Factors ◽  
Genome Wide Study

ADHD is highly heritable, but environmental factors also play significant roles in disease aetiology and outcome. Genetic and environmental influences are likely to show different types of interplay, with gene–environment interactions (G×E) playing a part. Different models of G×E exist, with the most frequently investigated in ADHD up to the present being the diathesis–stress and differential susceptibility models. The most frequently studied have been monoaminergic genes, often based on a single genetic variant. Only a single genome-wide study has been reported thus far. Environmental factors investigated include prenatal and postnatal risk factors for ADHD, in particular prenatal exposure to smoking or alcohol and aspects of parenting.

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