Showing papers on "Anticipation (genetics) published in 2021"
TL;DR: The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington's disease (HD), opened up a new era of human genetics and provided explanations for some old problems as discussed by the authors.
Abstract: The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington's disease (HD), opened up a new era of human genetics and provided explanations for some old problems In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders
37 citations
TL;DR: Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area, as well as penetrance, which is increased in case of maternal inheritance and in male patients.
Abstract: INTRODUCTION Hereditary transthyretin (ATTRv) amyloidosis is of autosomal dominant transmission, caused by a spectrum of mutations in the transthyretin (TTR) gene. The ATTRV30M (p.Val50Met) is the most frequent substitution in Europe. Northern Sweden is a known cluster for ATTRV30M amyloidosis patients due to high prevalence of the mutation rate, with homozygous cases. First symptoms occur generally during the 6th decade. Previous studies reported low penetrance in this area and possible anticipation in families. In order to refine our knowledge of the genetic aspects, penetrance and factors that influence the disease's risk, we performed a comprehensive study of ATTRV30M families in Sweden. METHODS To assess anticipation, well-established age at onset (AO) was compared in all informative parent-offspring pairs and in subgroups, after excluding ascertainment biases. Penetrance was estimated using a non-parametric method that enables to study covariates' effect on the disease's risk. RESULTS We analysed 114 ATTRV30M Swedish families, including 12 homozygous individuals. Among 131 parent-offspring pairs, we found an average anticipation of 11.7 [Standard Deviation (SD) =10.03] years, higher in case of maternal transmission (mean ± SD = 13.7 ± 8.4 years), compared to paternal transmission (mean ± SD = 7.9 ± 11.5 years, p < .003). Anticipation remained significant, after exclusion of ascertainment biases. In heterozygous ATTRV30M kindred, penetrance was low, estimated below 10% [95% confidence interval (CI) = 6-10] at 40 years-old, increasing to 71% [95% CI= 65-76] at age 90 years. The risk was found to be higher in male patients (p < .01) and in case of maternal transmission (p < .01), reflecting a parent of origin effect. We observed no difference of penetrance according the geographical origin. Finally, the disease risk was similar in heterozygous and homozygous ATTRV30M amyloidosis individuals. CONCLUSIONS Our study provides new data on the genetics of ATTRV30M families in Sweden, including the occurrence of anticipation and on penetrance. Both are increased in case of maternal inheritance and in male patients. Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area. Clinically, these findings are of importance to guide the management of sibships and the monitoring of mutation carriers.
10 citations
TL;DR: This chapter will address all issues and summarize the recent updates about clinical aspects of C9orf72 disease, focusing on both the common and the less typical phenotypes.
Abstract: The identification of C9orf72 gene has led to important scientific progresses and has considerably changed our clinical practice. However, a decade after C9orf72 discovery, some important clinical questions remain unsolved. The reliable cutoff for the pathogenic repeat number and the implication of intermediate alleles in frontotemporal dementia, amyotrophic lateral sclerosis, or in other diseases are still uncertain. The occurrence of an anticipation phenomenon – at the clinical and molecular levels – in C9orf72 kindreds is still debated as well, and the factors driving age at onset and phenotype variability are largely unknown. All these questions have a significant impact not only in clinical practice for diagnosis and genetic counseling but also in a research context for the initiation of therapeutic trials. In this chapter, we will address all those issues and summarize the recent updates about clinical aspects of C9orf72 disease, focusing on both the common and the less typical phenotypes.
6 citations
TL;DR: The present meta‐analysis concluded that there is a segregation distortion favoring the expanded allele, among children of carriers, and further studies on transmissions and anticipation phenomena as well as more observations about fertility are required to clarify these selective forces over SCA3/MJD.
Abstract: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a dominant neurodegenerative disease caused by the expansion of a CAG repeat tract in ATXN3. Anticipation and worsening of clinical picture in subsequent generations were repeatedly reported, but there is no indication that SCA3/MJD frequency is changing. Thus, we performed a systematic review and meta-analysis on phenomena with potential effect on SCA3/MJD recurrency in populations: instability of CAG repeat transmissions, anticipation, fitness, and segregation of alleles. Transmission of the mutant allele was associated with an increase of 1.23 CAG repeats in the next generation, and the average change in age at onset showed an anticipation of 7.75 years per generation; but biased recruitments cannot be ruled out. Affected SCA3/MJD individuals had 45% more children than related controls. Transmissions from SCA3/MJD carriers showed that the expanded allele was segregated in 64% of their children. In contrast, transmissions from normal subjects showed that the minor allele was segregated in 54%. The present meta-analysis concluded that there is a segregation distortion favoring the expanded allele, among children of carriers. Therefore, further studies on transmissions and anticipation phenomena as well as more observations about fertility are required to clarify these selective forces over SCA3/MJD.
5 citations
TL;DR: Despite much anticipation of a far better new year, 2021 has started with that deja vu feeling as teachers welcomed pupils in early January but as the COVID 19 virus regained its foothold.
Abstract: Despite much anticipation of a far better new year, 2021 has started with that deja vu feeling. In many countries, teachers welcomed pupils in early January but as the COVID 19 virus regained its g...
5 citations
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10 Apr 2021TL;DR: The autoimmune polyglandular syndromes (APS) are clusters of endocrine abnormalities that occur in discreet patterns in subjects with immune dysregulation and that permit treatment and anticipation of associated systemic or other hormonal deficiencies as mentioned in this paper.
Abstract: The autoimmune polyglandular syndromes (APS) are clusters of endocrine abnormalities that occur in discreet patterns in subjects with immune dysregulation and that permit treatment and anticipation of associated systemic or other hormonal deficiencies. Three major entities are recognized, APS1, APS2 and APS3; the rare X-linked syndrome of immunodysregulation, polyendocrinopathy, and enteropathy due to mutations in the FOXP3 gene also qualifies as an APS. An additional increasingly described category occurs in patients treated with immunoregulatory agents such as checkpoint inhibitors for cancer, so that tumor antigens that have evaded recognition can now be targeted, but at the expense of activating autoimmunity. APS1 is a syndrome characterized by chronic muco-cutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency, as well as ectodermal dystrophy and a host of other endocrine and non-endocrine tissue involvement in autoimmune destructive processes. The underlying cause is a homozygous inactivating mutation in the autoimmune regulator gene AIRE which permits the intra-thymic expression of ectopic antigens normally expressed only in specific peripheral tissues (e.g., insulin), so that T-cells as they mature within the thymus and acquire a receptor for the self- antigen are eliminated (negative selection), thereby avoiding autoimmunity. Recent studies demonstrate that in addition to the classical homozygous mutations, single gene dominant mutations in AIRE play an important role in autoimmune regulation and its disorders. APS2 and APS3 are both due to mutations in the HLA DQ/DR regions which regulate antigen presentation to T-cell receptors; however, their genetic profile is more complex. APS2 is characterized by type 1 diabetes mellitus (T1DM), Addison Disease, and Hypothyroidism, whereas APS3 is similar but without Addison disease. In keeping with other autoimmune disorders, these entities are more frequent in females, whereas APS1 has no sexual predominance. The recent emergence of autoimmune endocrinopathies in patients treated with immunoregulatory agents for cancer adds a new dimension to considerations of autoimmune polyendocrinopathy syndromes. Rapid progress in the immunology and genetics of these entities offers the promise of potential amelioration and eventual reversal via genetic manipulation before organ damage is established. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG .
3 citations
26 May 2021
TL;DR: In this paper, the determinants of bone health in transgender youth in anticipation of or shortly after initiating puberty suppression and/or gender-affirming hormone therapy were studied, and the results showed that bone health was not significantly affected.
Abstract: Purpose: We aimed to study determinants of bone health in transgender youth in anticipation of or shortly after initiating puberty suppression and/or gender-affirming hormone therapy. Methods: This...
3 citations
TL;DR: In this paper, a mouse cell model system of an unstable CAG•CTG trinucleotide repeat was used to investigate the role of functional DNA mismatch repair (MMR) proteins in repeat expansion.
Abstract: More than 30 human disorders are caused by the expansion of simple sequence DNA repeats, among which triplet repeats remain the most frequent. Most trinucleotide repeat expansion disorders affect primarily the nervous system, through mechanisms of neurodysfunction and/or neurodegeneration. While trinucleotide repeat tracts are short and stably transmitted in unaffected individuals, disease-associated expansions are highly dynamic in the germline and in somatic cells, with a tendency towards further expansion. Since longer repeats are associated with increasing disease severity and earlier onset of symptoms, intergenerational repeat size gains account for the phenomenon of anticipation. In turn, higher levels of age-dependent somatic expansion have been linked with increased disease severity and earlier age of onset, implicating somatic instability in the onset and progression of disease symptoms. Hence, tackling the root cause of symptoms through the control of repeat dynamics may provide therapeutic modulation of clinical manifestations. DNA repair pathways have been firmly implicated in the molecular mechanism of repeat length mutation. The demonstration that repeat expansion depends on functional DNA mismatch repair (MMR) proteins, points to MMR as a potential therapeutic target. Similarly, a role of DNA base excision repair (BER) in repeat expansion has also been suggested, particularly during the removal of oxidative lesions. Using a well-characterized mouse cell model system of an unstable CAG•CTG trinucleotide repeat, we tested if expanded repeat tracts can be stabilized by small molecules with reported roles in both pathways: cadmium (an inhibitor of MMR activity) and a variety of antioxidants (capable of neutralizing oxidative species). We found that chronic exposure to sublethal doses of cadmium and antioxidants did not result in significant reduction of the rate of trinucleotide repeat expansion. Surprisingly, manganese yielded a significant stabilization of the triplet repeat tract. We conclude that treatment with cadmium and antioxidants, at doses that do not interfere with cell survival and cell culture dynamics, is not sufficient to modify trinucleotide repeat dynamics in cell culture.
2 citations
TL;DR: In this paper, the authors reviewed the age of onset in all published cases of familial AxD and found that 32 of 34 instances of parent-offspring pairs demonstrated an earlier age onset in offspring compared to the parent.
Abstract: Alexander Disease (AxD) is a rare leukodystrophy caused by missense mutations of glial fibrillary acidic protein (GFAP). Primarily seen in infants and juveniles, it can present in adulthood. We report a family with inherited AxD in which the mother presented with symptoms many years after her daughter. We reviewed the age of onset in all published cases of familial AxD and found that 32 of 34 instances of parent-offspring pairs demonstrated an earlier age of onset in offspring compared to the parent. We suggest that genetic anticipation occurs in familial AxD and speculate that genetic mosaicism could explain this phenomenon.
1 citations
TL;DR: In this article, a whole-exome sequencing was done on DNA of 14 unrelated Iranian AD-HSP probands, and candidate variants were PCR-amplified and sequenced by the Sanger method, subsequently checked in family members to co-segregation analysis.
Abstract: BACKGROUND AND OBJECTIVE Hereditary spastic paraplegia (HSP) is a heterogeneous neurodegenerative disorder with lower-limb spasticity and weakness. Different patterns of inheritance have been identified in HSP. Most autosomal-dominant HSPs (AD-HSPs) are associated with mutations of the SPAST gene (SPG4), leading to a pure form of HSP with variable age-at-onset (AAO). Anticipation, an earlier onset of disease, as well as aggravation of symptoms in successive generations, may be correlated to SPG4. Herein, we suggested that anticipation might be a relatively common finding in SPG4 families. METHODS Whole-exome sequencing was done on DNA of 14 unrelated Iranian AD-HSP probands. Data were analyzed, and candidate variants were PCR-amplified and sequenced by the Sanger method, subsequently checked in family members to co-segregation analysis. Multiplex ligation-dependent probe amplification (MLPA) was done for seven probands. Clinical features of the probands were recorded, and the probable anticipation was checked in these families. Other previous reported SPG4 families were investigated to anticipation. RESULTS Our findings showed that SPG4 was the common subtype of HSP; three families carried variants in the KIF5A, ATL1, and MFN2 genes, while five families harbored mutations in the SPAST gene. Clinical features of only SPG4 families indicated decreasing AAO in affected individuals of the successive generations, and this difference was significant (p-value <0.05). CONCLUSION It seems SPAST will be the first candidate gene in families that manifests a pure form of AD-HSP and anticipation. Therefore, it may be a powerful situation of genotype-phenotype correlation. However, the underlying mechanism of anticipation in these families is not clear yet.
1 citations
TL;DR: In this article, the authors describe a rare neurological disorder that causes degeneration of upper and lower motor neurons and their axons, called Amyotrophic lateral sclerosis (ALS), which is mostly sporadic, but there are familial forms.
Abstract: Amyotrophic Lateral Sclerosis (ALS) is a rare neurological disorder that causes degeneration of upper and lower motor neurons and their axons. ALS is mostly sporadic, but there are familial forms. ...
TL;DR: Anticipation is an inheritance pattern where disease severity increases and/or age of onset decreases in successive generations as discussed by the authors, and it has been documented in neurodegenerative disorders, auto-immune disorders, and cancer.
Abstract: Anticipation is an inheritance pattern where disease severity increases and/or age of onset decreases in successive generations. It has been documented in neurodegenerative disorders [1,2], autoimm...
21 May 2021
TL;DR: A medical diagnosis system is presented for predicting the risk of cardiovascular disease by combining the relative advantages of genetic algorithm and neural network.
Abstract: Medical Diagnosis Systems play a vital role in medical practice and are used by medical practitioners for diagnosis and treatment. In this paper, a medical diagnosis system is presented for predicting the risk of cardiovascular disease. This system is built by combining the relative advantages of genetic algorithm and neural network. Multilayered feed forward neural networks are particularly suited to complex classification problems. The weights of the neural network are determined using genetic algorithm because it finds acceptably good set of weights in less number of iterations. The dataset provided by University of California, Irvine (UCI) machine learning repository is used for training and testing. It consists of 303 instances of heart disease data each having 14 attributes including the class label. First, the dataset is preprocessed in order to make them suitable for training. Genetic based neural network is used for training the system. The final weights of the neural network are stored in the weight base and are used for predicting the risk of cardiovascular disease. The classification accuracy obtained using this approach is 94.17%.
TL;DR: Data suggest that SCA2 lineages may tend to disappear eventually, due to strong anticipation phenomena, and whether or not the novel cases come from common haplotypes associated with a predisposition to further expansions is a question that needs to be addressed by future studies.
Abstract: Dominant diseases due to expanded CAG repeat tracts, such as spinocerebellar ataxia type 2 (SCA2), are prone to anticipation and worsening of clinical picture in subsequent generations. There is insufficient data about selective forces acting on the maintenance of these diseases in populations. We made a systematic review and meta-analysis on the effect of the CAG length over age at onset, instability of transmissions, anticipation, de novo or sporadic cases, fitness, segregation of alleles, and ancestral haplotypes. The correlation between CAG expanded and age at onset was r2 = 0.577, and transmission of the mutant allele was associated with an increase of 2.42 CAG repeats in the next generation and an anticipation of 14.62 years per generation, on average. One de novo and 18 sporadic cases were detected. Affected SCA2 individuals seem to have more children than controls. The expanded allele was less segregated than the 22-repeat allele in children of SCA2 subjects. Several ancestral SCA2 haplotypes were published. Data suggest that SCA2 lineages may tend to disappear eventually, due to strong anticipation phenomena. Whether or not the novel cases come from common haplotypes associated with a predisposition to further expansions is a question that needs to be addressed by future studies.
TL;DR: In this paper, the role of defensive reactivity to anticipated unpleasant symptoms in panic disorder was investigated in 73 patients with a primary diagnosis of panic disorder with agoraphobia and 52 healthy controls (HC).