Human neuronal networks on micro-electrode arrays are a highly robust tool to study disease-specific genotype-phenotype correlations in vitro.
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ABSTRACT:
SUBMITTER: Mossink B
PROVIDER: S-EPMC8452490 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundFacial-scapular-humeral myodystrophy Landouzy-Dejerine (FSHD) is an autosomal dominant disease, the basis of its pathogenesis is ectopic expression of the transcription factor DUX4 in skeletal muscle. There are two types of the disease: FSHD1 (MIM:158900) and FSHD2 (MIM: 158901), which have different genetic causes but are phenotypically indistinguishable. In FSHD1, partial deletion of the D4Z4 repeats on the 4th chromosome affects the expression of DUX4, whereas FSHD2 is caused by the mutations in the protein regulating the methylation status of chromatin - SMCHD1. High variability of clinical picture, both intra - and inter-family indicates a large number of factors influencing clinical picture. There are key genetic, epigenetic and gender factors that influence the expressivity and penetrance of the disease. Using only one of these factors allows just a rough prediction of the course of the disease, which indicates the combined effect of all of the factors on the DUX4 expression and on the clinical picture.ResultsIn this paper, we analyzed the impact of genetic, epigenetic and gender differences on phenotype and the possibility of using them for disease prognosis and family counselling.ConclusionsKey pathogenesis factors have been identified for FSHD. However, the pronounced intra - and inter-family polymorphism of manifestations indicates a large number of modifiers of the pathological process, many of which remain unknown.
| S-EPMC6416831 | biostudies-literature
Project description:BackgroundThe PAX6 protein is a highly conserved transcriptional regulator that is important for normal ocular and neural development. In humans, heterozygous mutations of the PAX6 gene cause aniridia (absence of the iris) and related developmental eye diseases. PAX6 mutations are archived in the Human PAX6 Allelic Variant Database, which currently contains 309 records, 286 of which are mutations in patients with eye malformations.ResultsWe examined the records in the Human PAX6 Allelic Variant Database and documented the frequency of different mutation types, the phenotypes associated with different mutation types, the contribution of CpG transitions to the PAX6 mutation spectrum, and the distribution of chain-terminating mutations in the open reading frame. Mutations that introduce a premature termination codon into the open reading frame are predominantly associated with aniridia; in contrast, non-aniridia phenotypes are typically associated with missense mutations. Four CpG dinucleotides in exons 8, 9, 10 and 11 are major mutation hotspots, and transitions at these CpG's account for over half of all nonsense mutations in the database. Truncating mutations are distributed throughout the PAX6 coding region, except for the last half of exon 12 and the coding part of exon 13, where they are completely absent. The absence of truncating mutations in the 3' part of the coding region is statistically significant and is consistent with the idea that nonsense-mediated decay acts on PAX6 mutant alleles.ConclusionThe PAX6 Allelic Variant Database is a valuable resource for studying genotype-phenotype correlations. The consistent association of truncating mutations with the aniridia phenotype, and the distribution of truncating mutations in the PAX6 open reading frame, suggests that nonsense-mediated decay acts on PAX6 mutant alleles.
| S-EPMC1156885 | biostudies-literature
Project description:Once the genome sequence of an organism is obtained, attention turns from identifying genes to understanding their function, their organization and control of metabolic pathways and networks that determine its physiology. Recent technical advances in acquiring genome-wide data have led to substantial progress in identifying gene functions. However, we still do not know the function of a large number of genes and, even when a gene product has been assigned to a functional class, we cannot normally predict its contribution to the phenotypic behaviour of the cell or organism--the phenome. In this study, we assessed bacterial growth parameters of 4030 non-redundant PA14 transposon mutants in the pathogenic bacterium Pseudomonas aeruginosa. The genome-wide simultaneous analysis of 119 distinct growth-related phenotypes uncovered a comprehensive phenome and provided evidence that most genotypes are not phenotypically isolated but rather define specific complex phenotypic clusters of genotypes. Since phenotypic overlap was demonstrated to reflect the relatedness of genotypes on a global scale, knowledge of an organism's phenome might significantly contribute to the advancement of functional genomics.
| S-EPMC2928780 | biostudies-other
Project description:Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin-protein ligase E3A (UBE3A) on the chromosome 15q11-13 region. AS is characterized by global developmental delay, severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy, and distinct behavioral profile. There are four molecular mechanisms of etiology: maternal deletion of chromosome 15q11-q13, paternal uniparental disomy of chromosome 15q11-q13, imprinting defects, and maternally inherited UBE3A mutations. Different genetic types may show different phenotypes in performance, seizure, behavior, sleep, and other aspects. AS caused by maternal deletion of 15q11-13 appears to have worse development, cognitive skills, albinism, ataxia, and more autistic features than those of other genotypes. Children with a UBE3A mutation have less severe phenotypes and a nearly normal development quotient. In this review, we proposed to review genotype-phenotype correlations based on different genotypes. Understanding the pathophysiology of the different genotypes and the genotype-phenotype correlations will offer an opportunity for individualized treatment and genetic counseling. Genotype-phenotype correlations based on larger data should be carried out for identifying new treatment modalities.
| S-EPMC8304328 | biostudies-literature
Project description:Germ-line mutations of the tumor suppressor APC are implicated in attenuated adenomatous polyposis coli (AAPC), a variant of familial adenomatous polyposis (FAP). AAPC is recognized by the occurrence of <100 colonic adenomas and a later onset of colorectal cancer (age >40 years). The aim of this study was to assess genotype-phenotype correlations in AAPC families. By protein-truncation test (PTT) assay, the entire coding region of the APC gene was screened in affected individuals from 11 AAPC kindreds, and their phenotypic differences were examined. Five novel germ-line APC mutations were identified in seven kindreds. Mutations were located in three different regions of the APC gene: (1) at the 5' end spanning exons 4 and 5, (2) within exon 9, and (3) at the 3' distal end of the gene. Variability in the number of colorectal adenomas was most apparent in individuals with mutations in region 1, and upper-gastrointestinal manifestations were more severe in them. In individuals with mutations in either region 2 or region 3, the average number of adenomas tended to be lower than those in individuals with mutations in region 1, although age at diagnosis was similar. In all AAPC kindreds, a predominance of right-sided colorectal adenomas and rectal polyp sparing was observed. No desmoid tumors were found in these kindreds. Our data suggest that, in AAPC families, the location of the APC mutation may partially predict specific phenotypic expression. This should help in the design of tailored clinical-management protocols in this subset of FAP patients.
| S-EPMC1377162 | biostudies-other
Project description:Williams Syndrome (WS) is a rare neurodevelopmental disorder caused by heterozygous deletions in a chromosome 7q11.23 region typically encompassing 26-28 genes. WS patients exhibit a wide spectrum of symptoms, including cardiovascular disease, intellectual disability, visuospatial deficits and hypersociability a behavioral profile that contrasts with autism spectrum disorder (ASD). However, the relationship between neuropsychiatric phenotypes and dysregulated gene networks caused by the 7q11.23 deletion is unknown. We report results from a large-scale integrated transcriptome analysis of peripheral blood in clinically evaluated subjects with WS, ASD and matched controls. We identified significantly differential expressed genes in WS as compared with ASD or controls, even after removing genes spanning the 7q11.23 region. Using weighted gene co-expression network analysis (WGCNA), we found that three co-expression modules were upregulated in WS, and were significantly associated with the intermediate phenotypes such as anxiety and attention problems. Notably, these three co-expression modules were only composed of genes located outside of 7q11.23 critical region. One module was associated with immune systems and B cell proliferation. Its top hub gene, BCL11A, is implicated in ASD and chromatin modification. Another module was enriched with genes associated with astrocytes and oligodendrocytes, and the third module was associated with RNA processing and neurons. MicroRNA (miRNA) profiling revealed differentially expressed miRNAs whose targets were enriched in each co-expression module associated with WS. These results identify genes and potential driver miRNAs, located outside of 7q11.23 critical region, that are novel candidates for mediating the neuropsychiatric phenotypes in WS.
2018-11-06 | GSE89594 | GEO
Project description:Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes (ENG, ACVRL1, and SMAD4), is characterized by the development of vascular malformations (VMs). Patients with HHT may present with mucocutaneous telangiectasia, as well as organ arteriovenous malformations (AVMs) of the central nervous system, lungs, and liver. Genotype-phenotype correlations have been well described in adults with HHT. We aimed to investigate genotype-phenotype correlations among pediatric HHT patients. Demographic, clinical, and genetic data were collected and analyzed in 205 children enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. A chi-square test was used to determine the association between phenotypic presentations and genotype. Among 205 patients (age range: 0-18 years; mean: 11 years), ENG mutation was associated with the presence of pulmonary AVMs (p < 0.001) and brain VM (p < 0.001). The presence of a combined phenotype-defined as both pulmonary AVMs and brain VMs-was also associated with ENG mutation. Gastrointestinal bleeding was rare (4.4%), but was associated with SMAD4 genotype (p < 0.001). We conclude that genotype-phenotype correlations among pediatric HHT patients are similar to those described among adults. Specifically, pediatric patients with ENG mutation have a greater prevalence of pulmonary AVMs, brain VMs, and a combined phenotype.
| S-EPMC7565052 | biostudies-literature
Project description:Background: Linking genotype to phenotype is a major aim of genetics research, yet the underlying biochemical mechanisms of many complex conditions continue to remain elusive. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID. Methods: Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical manifestations of complex vs. simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment patterns within subgroups. Results: Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to gene set. Conclusions: These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.
| S-EPMC6217001 | biostudies-literature
Project description:IntroductionIn clinical and animal studies, Hypertrophic Cardiomyopathy (HCM) shares many similarities with non-inherited cardiac hypertrophy induced by pressure overload (hypertension). This suggests a potential role for mechanical stress in priming tissues with mutation-induced changes in the sarcomere to develop phenotypes associated with HCM, including hypercontractility and aberrant calcium handling. Here, we tested the hypothesis that heterozygous loss of function of Myosin Binding Protein C (MYBCP3 +/- , mutations in which account for almost 50% of inherited HCM) combines with environmental stiffness to drive HCM phenotypes.MethodsWe differentiated isogenic control (WTC) and MYBPC3 +/- iPSC into cardiomyocytes using small molecule manipulation of Wnt signaling, and then purified them using lactate media. The purified cardiomyocytes were seeded into "dog bone" shaped stencil molds to form micro-heart muscle arrays (μHM). To mimic changes in myocardial stiffness stemming from pressure overload, we varied the rigidity of the substrates μHM contract against. Stiffness levels ranged from those corresponding to fetal (5 kPa), healthy (15 kPa), pre-fibrotic (30 kPa) to fibrotic (65 kPa) myocardium. Substrates were embedded with a thin layer of fluorescent beads to track contractile force, and parent iPSC were engineered to express the genetic calcium indicator, GCaMP6f. High speed video microscopy and image analysis were used to quantify calcium handling and contractility of μHM.ResultsSubstrate rigidity triggered physiological adaptation for both genotypes. However, MYBPC3 +/- μHM showed a lower tolerance to substrate stiffness with the peak traction on 15 kPa, while WTC μHM had peak traction on 30 kPa. MYBPC3 +/- μHM exhibited hypercontractility, which was exaggerated by substrate rigidity. MYBPC3 +/- μHM hypercontractility was associated with longer rise times for calcium uptake and force development, along with higher overall Ca2+ intake.ConclusionWe found MYBPC3 +/- mutations cause iPSC-μHM to exhibit hypercontractility, and also a lower tolerance for mechanical stiffness. Understanding how genetics work in combination with mechanical stiffness to trigger and/or exacerbate pathophysiology may lead to more effective therapies for HCM.Supplementary informationThe online version contains supplementary material available at (10.1007/s12195-021-00684-x).
| S-EPMC8548480 | biostudies-literature
Project description:Genotype-Phenotype Correlations of Late Infantile Neuronal Ceroid Lipofuscinosis - LDN 6716
| PRJNA449798 | ENA