Genetic Modifiers of Hereditary Neuromuscular Disorders and Cardiomyopathy.
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ABSTRACT:
SUBMITTER: Bazrafshan S
PROVIDER: S-EPMC7915259 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neuromuscular diseases, which encompass disorders that affect muscle and its innervation, are highly heritable. Genetic diagnosis now frequently pinpoints the primary mutation responsible for a given neuromuscular disease. However, the results from genetic testing indicate that neuromuscular disease phenotypes may vary widely, even in individuals with the same primary disease-causing mutation. Clinical variability arises from both genetic and environmental factors. Genetic modifiers can now be identified using candidate gene as well as genomic approaches. The presence of genetic modifiers for neuromuscular disease helps define the clinical outcome and also highlights pathways of potential therapeutic utility. Herein, we will focus on single gene neuromuscular disorders, including muscular dystrophy, spinal muscular atrophy, and amyotrophic lateral sclerosis, and the methods that have been used to identify modifier genes. Animal models have been an invaluable resource for modifier gene discovery and subsequent mechanistic studies. Some modifiers, identified using animal models, have successfully translated to the human counterpart. Furthermore, in a few instances, modifier gene discovery has repetitively uncovered the same pathway, such as TGFβ signaling in muscular dystrophy, further emphasizing the relevance of that pathway. Knowledge of genetic factors that influence disease can have direct clinical applications for prognosis and predicted outcome.
| S-EPMC4339951 | biostudies-literature
Project description:Repeat expansion disorders (REDs) are monogenic diseases caused by a sequence of repetitive DNA expanding above a pathogenic threshold. A common feature of the REDs is a strong genotype-phenotype correlation in which a major determinant of age at onset (AAO) and disease progression is the length of the inherited repeat tract. Over a disease-gene carrier's life, the length of the repeat can expand in somatic cells, through the process of somatic expansion which is hypothesised to drive disease progression. Despite being monogenic, individual REDs are phenotypically variable, and exploring what genetic modifying factors drive this phenotypic variability has illuminated key pathogenic mechanisms that are common to this group of diseases. Disease phenotypes are affected by the cognate gene in which the expansion is found, the location of the repeat sequence in coding or non-coding regions and by the presence of repeat sequence interruptions. Human genetic data, mouse models and in vitro models have implicated the disease-modifying effect of DNA repair pathways via the mechanisms of somatic mutation of the repeat tract. As such, developing an understanding of these pathways in the context of expanded repeats could lead to future disease-modifying therapies for REDs.
| S-EPMC10754329 | biostudies-literature
Project description:ObjectiveDilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset.MethodsA multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up.ResultsPatients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027).ConclusionsWe report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.
| S-EPMC4626372 | biostudies-literature
Project description:With the wider deployment of massively-parallel, next-generation sequencing, it is now possible to survey human genome data for research and clinical purposes. The reduced cost of producing short-read sequencing has now shifted the burden to data analysis. Analysis of genome sequencing remains challenged by the complexity of the human genome, including redundancy and the repetitive nature of genome elements and the large amount of variation in individual genomes. Public databases of human genome sequences greatly facilitate interpretation of common and rare genetic variation, although linking database sequence information to detailed clinical information is limited by privacy and practical issues. Genetic variation is a rich source of knowledge for cardiovascular disease because many, if not all, cardiovascular disorders are highly heritable. The role of rare genetic variation in predicting risk and complications of cardiovascular diseases has been well established for hypertrophic and dilated cardiomyopathy, where the number of genes that are linked to these disorders is growing. Bolstered by family data, where genetic variants segregate with disease, rare variation can be linked to specific genetic variation that offers profound diagnostic information. Understanding genetic variation in cardiomyopathy is likely to help stratify forms of heart failure and guide therapy. Ultimately, genetic variation may be amenable to gene correction and gene editing strategies.
| S-EPMC4605546 | biostudies-other
Project description:Dilated cardiomyopathy (DCM) is the most common cause of heart failure in young adults and up to 50% of idiopathic DCM is thought to be caused by genetic mutations in candidate genes. Although a genetic diagnosis can confirm a clinical diagnosis of hereditary DCM, genetic testing has not been easily accessible due to genetic heterogeneity and complexity. Next-generation sequencing (NGS) technologies have recently been introduced, and genetic testing for multiple genes is currently available and more than 40 different genes have been associated with DCM. In Korea, the government has supported genetic diagnosis for patients with idiopathic DCM. When a targeted gene panel with NGS technology was used, the detection rate was about 40%. MYBPC3, LMNA, and MYH7 were the most frequently identified genes, and the pattern of causative genes was different from previous reports. In the analysis, a significant number of subjects (42.0%) had rare or novel unspecified variants in DCM candidate genes, which should be assessed as potential causative mutations. Developing a more comprehensive test panel with additional DCM genes and whole exome sequencing will improve the detection rate, and allow genetic testing to be an option for patients with idiopathic DCM. However, all genetic variations are not pathogenic mutations, and the majority of reported mutations in DCM are unique to a single family, which makes genetic data interpretation more difficult. Therefore, clinical features and familial history integration are needed to improve clinical decision making.
| S-EPMC5449520 | biostudies-literature
Project description:From early in the study of mammalian genetics, it was clear that modifiers can have a striking influence on phenotypes. Today, several modifiers have now been studied in enough detail to allow a glimpse of how they function and influence our perspective of disease. With respect to diseases of the eye, some modifiers are an important source of phenotypic variation that can elucidate how genes function in networks to collectively shape ocular anatomy and physiology, thus influencing our understanding of basic biology. Other modifiers represent an opportunity for new therapeutic targets, whose manipulation could be used to mitigate ophthalmic disease. Here, we review progress in the study of genetic modifiers of eye disorders, with examples from mice and humans that together illustrate the ubiquitous nature of genetic modifiers and why they are relevant biological variables in experimental design. Special emphasis is given to ophthalmic modifiers in mice, especially those relevant to selection of genetic background and those that might inadvertently be a source of experimental variability. These modifiers are capable of influencing interpretations of many experiments using targeted genome manipulations such as knockouts or transgenics. Whereas there are fewer examples of modifiers of eye disorders in humans with a molecular identification, there is ample evidence that they exist and should be considered as a relevant biological variable in human genetic studies as well.
| S-EPMC5886476 | biostudies-literature
Project description:BackgroundUnderstanding the genetic modifiers of neurodegenerative diseases can provide insight into the mechanisms underlying these disorders. Here, we examine the relationship between the motor neuron disease spinal muscular atrophy (SMA), which is caused by reduced levels of the survival of motor neuron (SMN) protein, and the actin-bundling protein Plastin 3 (PLS3). Increased PLS3 levels suppress symptoms in a subset of SMA patients and ameliorate defects in SMA disease models, but the functional connection between PLS3 and SMN is poorly understood.ResultsWe provide immunohistochemical and biochemical evidence for large protein complexes localized in vertebrate motor neuron processes that contain PLS3, SMN, and members of the hnRNP F/H family of proteins. Using a Caenorhabditis elegans (C. elegans) SMA model, we determine that overexpression of PLS3 or loss of the C. elegans hnRNP F/H ortholog SYM-2 enhances endocytic function and ameliorates neuromuscular defects caused by decreased SMN-1 levels. Furthermore, either increasing PLS3 or decreasing SYM-2 levels suppresses defects in a C. elegans ALS model.ConclusionsWe propose that hnRNP F/H act in the same protein complex as PLS3 and SMN and that the function of this complex is critical for endocytic pathways, suggesting that hnRNP F/H proteins could be potential targets for therapy development.
| S-EPMC7495824 | biostudies-literature
Project description:The complex genetics underlying human cardiac disease is evidenced by its heterogenous manifestation, multigenic basis and sporadic occurrence. These features have hampered disease modelling and mechanistic understanding. Here, we show that two structural cardiac diseases, left ventricular non-compaction (LVNC) and bicuspid aortic valve (BAV), can be caused by a combined set of inherited heterozygous mutations. We used CRISPR-Cas9 gene editing to generate mice harboring two mutations in the NOTCH ligand regulator MINDBOMB1 identified in LVNC families. One Mib1 mutation causes LVNC only in heteroallelic combination with a conditional Mib1 allele, while the other leads to BAV in a NOTCH-sensitized genetic background. These data suggest that the LVNC phenotype may be influenced by genetic modifiers present in these families, while valve defects are very sensitive to NOTCH haploinsufficiency. Whole-exome sequencing revealed single-nucleotide variants in the ASXL3, APCDD1 and TMX3, CEP192 and BCL7A genes, co-segregating with the MIB1 mutations and LVNC. We generated mice harboring the orthologous variants in the corresponding Mib1 backgrounds. Triple heterozygous Mib1 Apcdd1 Asxl3 mutants show LVNC, while quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a mice show BAV and other valve-associated defects. Biochemical assays suggest interactions between CEP192, BCL7A and NOTCH. Gene profiling of murine hearts and human induced pluripotent stem cell-derived cardiomyocytes reveals defective metabolic maturation. These findings provide evidence for a common genetic substrate for LVNC and BAV involving MIB1 and genetic modifiers
2023-09-18 | GSE185395 | GEO
Project description:We studied the effects of LTBP4 and SPP1 polymorphisms on age at loss of ambulation (LoA) in a multiethnic Duchenne muscular dystrophy (DMD) cohort.We genotyped SPP1 rs28357094 and LTBP4 haplotype in 283 of 340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Median ages at LoA were compared by Kaplan-Meier analysis and log-rank test. We controlled polymorphism analyses for concurrent effects of glucocorticoid corticosteroid (GC) treatment (time-varying Cox regression) and for population stratification (multidimensional scaling of genome-wide markers).Hispanic and South Asian participants (n?=?18, 41) lost ambulation 2.7 and 2 years earlier than Caucasian subjects (p?=?0.003, <0.001). The TG/GG genotype at SPP1 rs28357094 was associated to 1.2-year-earlier median LoA (p?=?0.048). This difference was greater (1.9 years, p?=?0.038) in GC-treated participants, whereas no difference was observed in untreated subjects. Cox regression confirmed a significant effect of SPP1 genotype in GC-treated participants (hazard ratio?=?1.61, p?=?0.016). LTBP4 genotype showed a direction of association with age at LoA as previously reported, but it was not statistically significant. After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p?=?0.024). Median age at LoA with the protective LTBP4 genotype in this cohort was 15.0 years, 16.0 for those who were treated with GC.SPP1 rs28357094 acts as a pharmacodynamic biomarker of GC response, and LTBP4 haplotype modifies age at LoA in the CINRG-DNHS cohort. Adjustment for GC treatment and population stratification appears crucial in assessing genetic modifiers in DMD.
| S-EPMC4403971 | biostudies-literature
Project description:Methods employed in genome-wide association studies are not feasible ways to explore genotype-phenotype associations in rare disorders due to limited statistical power. An alternative approach is to examine relationships among specific single nucleotide polymorphisms (SNPs), selected a priori, and behavioural characteristics. Here, we adopt this strategy to examine relationships between three SNPs (5-HTTLPR, MAOA, COMT) and specific clinically-relevant behaviours that are phenotypic of fragile X syndrome (FXS) but vary in severity and frequency across individuals. Sixty-four males with FXS participated in the current study. Data from standardised informant measures of challenging behaviour (defined as physical aggression, property destruction, stereotyped behaviour, and self-injury), autism symptomatology, attention-deficit-hyperactivity-disorder characteristics, repetitive behaviour and mood/interest and pleasure were compared between each SNP genotype. No association was observed between behavioural characteristics and either 5-HTTLPR (serotonin) or MAOA (monoamine oxidase) genotypes. However, compared to the COMT (dopamine) AG and GG genotypes, the AA genotype was associated with greater interest and pleasure in the environment, and with reduced risk for property destruction, stereotyped behaviour and compulsive behaviour. The results suggest that common genetic variation in the COMT genotype affecting dopamine levels in the brain may contribute to the variability of challenging and repetitive behaviours and interest and pleasure in this population. This study identifies a role for additional genetic risk in understanding the neural and genetic mechanisms contributing to phenotypic variability in neurodevelopmental disorders, and highlights the merit of investigating SNPs that are selected a priori on a theoretical basis in rare populations.
| S-EPMC7852869 | biostudies-literature