Showing papers on "Anticipation (genetics) published in 2019"

The global epidemics of diabetes in the 21st century: Current situation and perspectives.

Abstract: Diabetes is on the rise worldwide, with a global prevalence in adults in 2017 being 8.8% of the world population, with the anticipation of a further increase to 9.9% by 2045. In total numbers, this...

Genetic Counseling in Huntington's Disease: Potential New Challenges on Horizon?

Abstract: Huntington’s disease (HD) is a rare, hereditary, neurodegenerative and dominantly transmitted disorder affecting about 10 out of 100,000 people in Western Countries. The genetic cause is a CAG repeat expansion in the huntingtin gene (HTT), which is unstable and may further increase its length in subsequent generations, so called anticipation. Mutation repeat length coupled with other gene modifiers and environmental factors contribute to the age at onset in the offspring. Considering the unpredictability of age at onset and of clinical prognosis in HD, the accurate interpretation, a proper psychological support and a scientifically sound and compassionate communication of the genetic test result are crucial in the context of Good Clinical Practice and when considering further potential disease-modifying therapies. We discuss various genetic test scenarios that require a particularly careful attention in psychological and genetic counseling and expect that the counseling procedures will require a constant update.

The remarkable phenotypic variability of the p.Arg269HiS variant in the TRPV4 gene.

Abstract: Introduction Mutations in the TRPV4 gene are associated with neuromuscular disorders and skeletal dysplasias, which present a phenotypic overlap. Methods Next-generation sequencing and Sanger sequencing were used to analyze the TRPV4 gene. Results We present 2 Polish families with TRPV4-related disorder harboring the same p.Arg269His mutation. The disease phenotypic expression was extremely variable (from mild scapular winging to severe hypotonia, global weakness, inability to walk unaided, congenital contractures, scoliosis, and respiratory insufficiency), but did not suggest anticipation. The 2 most severely affected patients showed congenital distal contractures of the upper limbs and involvement of cranial nerves (manifesting as facial asymmetry and strabismus). The disease course seemed to be stable, although in later stages it caused respiratory insufficiency and progression of physical disability. Discussion The phenotypic variability observed in p.Arg269His carriers suggests that an additional modifier or a more complex pathogenic mechanism exists. Muscle Nerve 59:129-133, 2019.

Selective Forces Related to Spinocerebellar Ataxia Type 2

Abstract: Spinocerebellar ataxia type 2 (SCA2) is caused by an unstable expanded CAG repeat tract (CAGexp) at ATXN2. Although prone to selective forces such as anticipation, SCA2 frequency seems to be stable in populations. Our aim was to estimate reproductive success, segregation patterns, and role of anticipation in SCA2. Adult subjects from families with molecular diagnosis provided data about all his/her relatives. Affected and unaffected sibs older than 65.7 years of age were used to estimate reproductive success and segregation patterns. Twenty-one SCA2 families were studied, including 1017 individuals (164 affected) who were born from 1840 to 2012. The median number of children of the non-carriers and carriers, among 99 subjects included in the reproductive success analysis, were 2 and 3 (p < 0.025), respectively. Therefore, the reproductive success of carriers was 1.5. There were 137 non-carriers (59.6%) and 93 carriers (40.4%) (p = 0.04), among subjects included in the segregation analysis. Age at onset across generations pointed to anticipation as a frequent phenomenon. We raised evidence in favor of increased reproductive success related to the carrier state at ATXN2, and segregation distortion favoring normal alleles. Since majority of normal alleles analyzed carried 22 repeats, we propose that this distortion segregation can be related to the high frequency of this allele in human chromosomes.

The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect

Abstract: BACKGROUND: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. METHODS: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. RESULTS: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. CONCLUSIONS: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. IMPACT: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.

A novel homozygous RTEL1 variant in a consanguineous Lebanese family: phenotypic heterogeneity and disease anticipation.

Abstract: Phenotypic heterogeneity is often observed in patients with telomeropathies caused by pathogenic variants in telomere biology genes. However, the roles of recessive variants in these different phenotypes are not fully characterized. Our goal is to describe the biological roles of a novel homozygous RTEL1 variant identified in a consanguineous Lebanese family with unusual presentation of telomeropathies. A proband was screened for germline variants in telomere biology genes by whole exome sequencing. Leukocytes’ telomere length was measured in the proband and eight relatives. We identified a novel homozygous p.E665K RTEL1 variant in the proband, his mother, and seven siblings that associated with telomere shortening and a broad spectrum of clinical manifestations, ranging from mild unspecific findings to severe phenotypes. Consanguinity in at least three family generations led to increased frequency of the homozygous p.E665K variant in the youngest generation and progressive telomere shortening. The increased frequency of the homozygous RTEL1 variant due to consanguinity in this Lebanese family allowed us to infer novel behaviors of recessive RTEL1 variants, as the expressivity and penetrance of this gene are very heterogenous between inter- and intra-generations. Progressive telomere shortening was associated with disease anticipation, first reported in recessive autosomal telomeropathies. Both genetic testing and telomere length measurement were critical for the clinical diagnosis of this family with telomere diseases marked by phenotypic heterogeneity.

Predicting Alzheimer's Disease Onset

Abstract: Recently, a method for assigning the probability of disease onset to all people, those clinically ill as well as those without prevalent disease has been described and termed the Oxidative Stress Index (OSI). The OSI, as originally formatted, does not predict which disease will more likely develop, only that further disease is predicted with increased OSI. It is hypothesized here that the OSI may be used to demonstrate which parameters are more contributory to the onset of a particular disease if it is measured at the time of onset of that disease. To test this hypothesis, the OSI has been reformatted to serve in that capacity for Alzheimer's disease (AD) with the anticipation that the OSI could serve to predict not only the likelihood of onset, but also identify those parameters that are most contributory to AD.

Familial periodicity in a multigenerational family of cluster headache: A case report:

Abstract: I describe an unusual phenotypic phenomenon in two members of a multigenerational family of cluster headache (CH) with anticipation features. The index case, a 44-year-old woman, and her sister, a ...

Gene Therapy and Gene Editing for Myotonic Dystrophy

Abstract: Myotonic dystrophy is one of the most common dominant neuromuscular disorders that results in muscle dysfunction. Myotonic dystrophy type 1 (DM1) or Steinert’s disease is caused by an expanded CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene, whereas myotonic dystrophy type (DM2) is caused by expanded CCTG repeats in the first intron of the CCHC-type zinc finger, nucleic acid-binding protein (CNBP) gene. The clinical manifestations worsen with each generation (anticipation) consistent with an expansion of the repeats. The tri- or tetranucleotide repeat expansion results in gain-of-function pathogenic RNAs which are retained in the nuclei and sequester RNA-binding proteins such as MBNL and CUGBP that interfere with splicing. Unfortunately, there is currently no cure available for these dominant neuromuscular diseases. Nevertheless, some promising therapeutic strategies have been developed that are aimed at directly tackling the genetic cause of the disease. In particular, antisense oligonucleotide technologies, gene therapy, and gene editing or small molecules are being explored. Recently, a phase 1/2a clinical trial has been completed that is based on the premise of promoting RNase-H-mediated degradation of the expanded CUG transcripts using antisense oligonucleotides. In this review, we summarize the current progress on different cellular and animal models as well as various therapeutic strategies for DM with specific emphasis on gene therapy and gene editing approaches using TALENs and CRISPR/Cas9. Lastly, translational challenges and future promising therapeutic avenues are discussed.

Pathogenetical Peculiarities of Arterial Hypertension with Weight Increasing on Psychological Stress Background

Abstract: The article examines the pathogenetic features of the rearrangement of body functional state, against the background of psychological stress. At the present time the steady increasing of flow of information and emotional stress lead to load increasу of the central nervous system. It is necessary to increase the nutrient substrate – glucose and, for its aerobic catabolism the necessary amount of oxygen, to meet the intensification of the activity of the сentral nervous system. The increasing of energy costs of the central nervous system is accompanied by anticipation, which leading to change in eating behavior, and turning on a stress-hunger-food mechanism. Above mentioned factors lead to body weight increasing, and respectively, to increasing of the absolute circulating blood volume. At the same time, the relative circulating blood volume (ml/kg body weight) decreases, which leads to a shortage of blood coming to vital organs, including the central nervous system. Blood deficiency compensated by centralizing blood circulation, which is achieved by peripheral vascular spasm. In addition, there is psychological stress affect human body, that is constantly present in the modern lifestyle. Chronic psychological stress, leading to permanent activity of the sympathetic-adrenal system, is a concomitant factor of peripheral vascular spasm. Against this background, the conditions for the development of hypertension are created.