Anticipation (genetics)

About: Anticipation (genetics) is a research topic. Over the lifetime, 669 publications have been published within this topic receiving 21784 citations. The topic is also known as: Genetic Anticipation & Anticipation, Genetic.

Cag Repeat Expansion in Autosomal Dominant Pure Spastic Paraplegia Linked to Chromosome 2p21–p24

Abstract: CAG repeat expansions have been identified as the disease-causing dynamic mutations in the coding regions of genes in several dominantly inherited neurodegenerative disorders, including spinobulbar muscular atrophy, Huntington's disease, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1, 2 and 6 and Machado-Joseph disease. The CAG repeat expansions are translated to elongated polyglutamine tracts and an increased size of the polyglutamine tract correlates with anticipation, the cardinal feature, seen in all these diseases. Autosomal dominant pure spastic peraplegia (ADPSP) is a degenerative disorder of the central motor system clinically characterized by slowly progressive and unremitting spasticity of the legs, hyperreflexia and Babinski's sign. Like the established CAG repeat diseases ADPSP is characterized by both inter- and intrafamilial variation and anticipation. Using the Repeat Expansion Detection (RED) method, we have analyzed 21 affected individuals from six Danish families with the disease linked to chromosome 2p21-p24. We found that 20 of 21 affected individuals showed CAG repeat expansions versus two of 21 healthy spouses, demonstrating a strongly statistically significant association between the occurrence of the repeat expansion and the disease (Fisher's test, P or = 60 CAG repeat copies in the affected individuals. The CAG repeat expansion is very likely translated and expressed as indicated by the detection of a polyglutamine-containing protein in an ADPSP patient.

Clinical evidence of disease anticipation in families segregating a C9orf72 repeat expansion

Abstract: Importance Patients carrying a C9orf72 repeat expansion leading to frontotemporal dementia and/or amyotrophic lateral sclerosis have highly variable ages at onset of disease, suggesting the presence of modifying factors. Objective To provide clinical-based evidence for disease anticipation in families carrying a C9orf72 repeat expansion by analyzing age at onset, disease duration, and age at death in successive generations. Design, Setting, and Participants This cohort study was performed from June 16, 2000, to June 1, 2016, in 36 extended Belgian families in which a C9orf72 repeat expansion was segregating. The generational effect on age at onset, disease duration, and age at death was estimated using a mixed effects Cox proportional hazards regression model, including random-effects terms for within-family correlation and kinship. Time until disease onset or last examination, time from disease onset until death or last examination, or age at death was collected for for 244 individuals (132 proven or obligate C9orf72 carriers), of whom 147 were clinically affected (89 proven or obligate C9orf72 carriers). Main Outcomes and Measures Generational effect on age at onset, disease duration, and age at death. Results Among the 111 individuals with age at onset available (66 men and 45 women; mean [SD] age, 57.2 [9.1] years), the mean (SD) age at onset per generation (from earliest-born to latest-born generation) was 62.5 (8.3), 57.1 (8.2), 54.6 (10.2), and 49.3 (7.5) years. Censored regression analysis on all affected and unaffected at-risk relatives confirmed a decrease in age at onset in successive generations ( P Conclusions and Relevance The clinical data provide supportive evidence for the occurrence of disease anticipation in families carrying a C9orf72 repeat expansion by means of a decrease in age at onset across successive generations. This finding may help clinicians decide from which age onward it may be relevant to clinically follow presymptomatic individuals who carry a C9orf72 repeat expansion.

Why children with inflammatory bowel disease are diagnosed at a younger age than their affected parent

Abstract: BACKGROUND Genetic anticipation has been proposed to explain observed age differences at diagnosis of Crohn’s disease in affected parents and offspring. AIMS To compare affected parent-child pairs with Crohn’s disease and ulcerative colitis with a control group of non-familial patients with inflammatory bowel disease (IBD) in order to quantify whether ascertainment bias could account for this effect. METHODS 137 affected parent-child pairs from 96 families and 214 patients with sporadic IBD were studied. Age at onset of symptoms and diagnosis were ascertained by interview and disease confirmed from clinical records. RESULTS Of the 137 affected parent-child pairs, 50 had Crohn’s disease only, 51 had ulcerative colitis only, and in 36, one had Crohn’s disease and the other ulcerative colitis. The median age of parents at diagnosis was 17.5 years older, 16 years older, and 18 years older in the Crohn’s disease, ulcerative colitis, and mixed disease families respectively (p CONCLUSIONS There was no evidence of genetic anticipation or genomic imprinting of age at diagnosis in this sample of IBD families. Ascertainment bias is responsible for the age differences at diagnosis between affected parents and children.

Exploring the correlates of intermediate CAG repeats in Huntington disease.

Abstract: Objective: To explore the clinical phenotype in individuals with huntingtin gene CAG repeat lengths between 27 and 35, a range that is termed “intermediate” and below one traditionally considered diagnostic of Huntington disease (HD). Background: The Prospective Huntington Disease At-Risk Observational Study (PHAROS) found that patients with intermediate CAG lengths overlapped with those diagnosed as HD (≤ 37 CAG repeats) on the Unified Huntington's Disease Rating Scale (UHDRS) behavioral measures. Furthermore, several patients with intermediate CAG repeats demonstrating clinical (and pathological) evidence of HD have been reported. Methods: We reviewed all cases with intermediate CAG repeats who have presented to our clinic, as well as those reported in the literature. Results: We describe 4 patients with intermediate repeats evaluated at our center whose clinical features were highly suggestive of HD. Investigations for HD phenocopies were negative. Anticipation was demonstrated in 1 case with s...

The myotonic dystrophies.

Abstract: Myotonic dystrophy, or dystrophia myotonica (DM), is the most common inherited muscle disorder in adults. DM is a multisystem disease in which the most disabling feature is muscle wasting that begins in the distal limb and cranial muscles. The genetic basis for DM is an expanded CTG repeat in the DMPK gene on chromosome 19. The size of the expanded repeat, and the severity of the disease, tend to increase in successive generations. The mechanism by which this unusual mutation leads to muscle wasting, myotonia, cataracts, heart block, and neurobehavioral abnormalities has not been clearly defined. Identification of the DM gene has made it easier to delineate other DM-like disorders that are clinically and genetically distinct. The most common of these is proximal myotonic myopathy (PROMM), which is characterized by early involvement of proximal limb muscles. The genetic locus for another DM-like disorder, called DM type 2, was recently mapped to chromosome 3.