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.

Clinical and genetic analysis of spinocerebellar ataxia type 7 (SCA7) in Zambian families

Abstract: To date, 43 types of Spinocerebellar Ataxias (SCAs) have been identified. A subset of the SCAs are caused by the pathogenic expansion of a CAG repeat tract within the corresponding gene. Ethnic and geographic differences are evident in the prevalence of the autosomal dominant SCAs. Few descriptions of the clinical phenotype and molecular genetics of the SCAs are available from the African continent. Established studies mostly concern the South African populations, where there is a high frequency of SCA1, SCA2 and SCA7. The SCA7 mutation in South Africa (SA) has been found almost exclusively in families of indigenous Black African ethnic origin. To present the results of the first clinical description of seven Zambian families presenting with autosomal dominant SCA, as well as the downstream molecular genetic analysis of a subset of these families. The study was undertaken at the University Teaching Hospital in Lusaka, Zambia. Ataxia was quantified with the Brief Ataxia Rating Scale derived from the modified international ataxia rating scale. Molecular genetic testing for 5 types of SCA (SCA1, SCA2, SCA3, SCA6 and SCA7) was performed at the National Health Laboratory Service at Groote Schuur Hospital and the Division of Human Genetics, University of Cape Town, SA. The clinical and radiological features were evaluated in seven families with autosomal dominant cerebellar ataxia. Molecular genetic analysis was completed on individuals representing three of the seven families. All affected families were ethnic Zambians from various tribes, originating from three different regions of the country (Eastern, Western and Central province). Thirty-four individuals from four families had phenotypic features of SCA7. SCA7 was confirmed by molecular testing in 10 individuals from 3 of these families. The age of onset of the disease varied from 12 to 59 years. The most prominent phenotypic features in these families were gait and limb ataxia, dysarthria, visual loss, ptosis, ophthalmoparesis/ophthalmoplegia, pyramidal tract signs, and dementia. Affected members of the SCA7 families had progressive macular degeneration and cerebellar atrophy. All families displayed marked anticipation of age at onset and rate of symptom progression. The pathogenic SCA7 CAG repeat ranges varied from 47 to 56 repeats. Three additional families were found to have clinical phenotypes associated with autosomal dominant SCA, however, DNA was not available for molecular confirmation. The age of onset of the disease in these families varied from 19 to 53 years. The most common clinical picture in these families included a combination of cerebellar symptoms with slow saccadic eye movements, peripheral neuropathy, dementia and tremor. SCA is prevalent in ethnic Zambian families. The SCA7 families in this report had similar clinical presentations to families described in other African countries. In all families, the disease had an autosomal dominant pattern of inheritance across multiple generations. All families displayed anticipation of both age of onset and the rate of disease progression. Further clinical and molecular investigations of the inherited ataxias in a larger cohort of patients is important to understand the natural history and origin of SCAs in the Zambian population.

Earlier age of onset in BRCA carriers-anticipation or cohort effect?: A Countercurrents Series.

Abstract: Is the age of onset of breast cancer in women with a BRCA1 or BRCA2 mutation decreasing? Two recent papers suggested that the effect of mutations is more profound with each successive generation 1,2. In a paper from Spain, the average age of breast cancer diagnosis declined by 6.8 years in BRCA1 carriers and by 12.1 years in BRCA2 carriers in one generation 1. In Texas, the median age of diagnosis declined by 6 years in a single generation, from 48 to 42 years 2. To be fair to others, the same phenomenon has been reported many times, dating back to 1993 3–10. What could be the cause of such an abrupt shift? Perhaps a deteriorating environment coupled with widespread inactivity among women? Perhaps women are being better screened? Or is the nature of the mutation changing? In each study, the authors reviewed the pedigrees of families with a BRCA mutation where women were affected both in the current (“proband”) generation and in the parental generation. The average age of diagnosis in each generation was calculated, compared, and found to be younger in the proband generation. But before examining those studies in detail, it is important to distinguish between genetic anticipation and a cohort effect. “Anticipation” refers to penetrance that increases with the number of generations elapsed since the mutation first arose de novo in a single individual. Anticipation was proposed for retinoblastoma (for which no molecular mechanism has been identified) in the 1970s 11, but better-known examples are Huntington disease 12 and myotonic dystrophy 13 (for which dynamic mutations in trinucleotide repeats underlie the shifts). It is important to note that, in anticipation, a decline in age at diagnosis is observed with subsequent generations within a pedigree, but the average age of diagnosis in the population shows no change with calendar time because each generation contains a mix of first-generation carriers, second-generation carriers, and so on. It is believed that, eventually, the age of onset becomes young enough that reproductive fitness is impaired, and the most harmful alleles are thereby lost in the population (and are replenished by de novo mutations). In a cohort effect, penetrance of the gene depends on the year of birth of the carriers. When a cohort effect is present, a decline in age at diagnosis with subsequent generations within a pedigree is also observed, but the average age at diagnosis in the underlying population is also observed to decline with calendar time, and the age-specific incidence rates are seen to increase with calendar time. Age-specific rates of cancer might also decline with age in a cross-sectional study. The groups from Spain and Texas both invoked anticipation as the likely mechanism for the observed declines in age of onset from generation to generation. But consider the most common BRCA1 mutation, 5382insC. This mutation has been estimated to have arisen some 70 generations ago somewhere in Eastern Europe 14. Does that provenance mean that the average age of diagnosis has been creeping down for each of 70 generations? Or only for the last one, like a dormant volcano that suddenly becomes active? Or is it the case that genetic anticipation acts on Houston mutations, but not on 5382insC mutations? Neither explanation will do. A cohort effect seems much more likely. Problems are inherent in both the Spanish and the Texas studies. Consider two hypothetical nuclear pedigrees: In each family, the mother is 75 and the daughter is 50. In the first family, the mother developed breast cancer at age 60, and the daughter developed breast cancer at age 40. In the second family, the mother developed breast cancer at age 40, and the daughter, healthy at 50, develops breast cancer 10 years later at age 60. In theory, these families should cancel each other out, but only the first family is eligible for the study. A woman in the first generation may have had breast cancer at any age up to 70, but a woman in the proband’s generation can only have early-onset breast cancer. Furthermore, it is critical to consider the criteria for genetic testing. If a young patient is more likely than an elderly patient to be tested, then the proband’s generation will be enriched for early-onset breast cancer. This analysis is pertinent for hospital clinics in which an early age of diagnosis is an explicit testing criterion. Lastly, the proband’s generation will include only bona fide carriers. The mother’s generation will include affected women who have not been tested and may include sporadic cases diagnosed, on average, at older ages. But better studies also support the idea of a cohort effect. One design that does not suffer from ascertainment bias involves studying a large and unselected series of breast cancer cases to identify the BRCA-positive subset, subsequently comparing the lifetime cancer risks in the sisters and mothers. If a cohort effect is present, then the lifetime risk of cancer should be greater in the sisters than in the mothers. Studies of this kind, with the results expected for a cohort effect, have been conducted by Gronwald et al. 8 in Poland and by King et al. 7 in the United States. The breast cancer risk by age 50 was estimated by King and colleagues to be 24% among mutation carriers born before 1940, but to be 67% among those born after 1940. Another approach is to show that the prevalence of BRCA1/2 mutations among incident cases of breast cancer increases with time 14. The assumption here is that the prevalence of mutations in the underlying population is fixed and that the risk of nonhereditary cancer does not change over the study period. In a prospective study of carriers in North America, we recently showed that the annual cancer rate was highest among women aged 25 to 40 years 15 (Table I). For young women, the annual risk reached an astonishing rate of 38% over a 10-year period—almost 4% per year. This effect may be age-related (that is, the cancer risk declines with age), but a cohort effect is also possible: that is, the risk for women born during 1935–1950 is about 1% per year throughout their lives, but the risk for women born during 1970–1985 is almost 4% per year. Either way, the enormous risks that young women with a mutation now face are a matter of concern. It is important that proper epidemiology studies be conducted so that the factors contributing to this risk—and to possible risk increase—can be identified. TABLE I Annual rates of breast cancer in carriers of BRCA1 mutations in North Americaa

Genetic anticipation in a large family with pure autosomal dominant hereditary spastic paraplegia.

Abstract: We have reinvestigated a large kindred identified over 25 years ago segregating for a form of pure autosomal dominant hereditary spastic paraplegia (HSP). We have examined additional relatives in order to refine the clinical and genetic characteristics of this disorder, and performed an analysis to determine if anticipation is present in this family. Analysis of onset ages in parent-to-child transmissions of HSP is consistent with anticipation. These results provide support for dynamic mutation as the underlying mechanism of this form of HSP, and suggest a trinucleotide repeat instability occurring primarily in the female germ line.

Clinical signs and symptoms in a large hereditary spastic paraparesis pedigree with a novel spastin mutation.

Abstract: The most common form of autosomal dominant hereditary spastic paraparesis (HSP), SPG4, is caused by mu- tations in the spastin gene on chromosome 2p. This disease is characterized by intra- and interfamilial phenotypic variation. To determine the predictive values of clinical signs and symp- toms in SPG4, we examined 43 members of a large pedigree with autosomal dominant HSP. We then identified the genetic etiology of the disorder in this family, a novel nonsense muta- tion in exon 1 of spastin, carried by 24 of the examined family members. The best clinical predictors of positive gene status were the presence of hyperreflexia in the lower extremities, 2 beats of ankle clonus, pes cavus, bladder symptoms and in- creased tone in the legs. The mean age of onset was 32.2 7.4 years, but the age of onset was earlier in children from 10 of 12 child-parent gene-positive pairs, with a mean difference of 10.8 3.3 years. The finding of leg weakness was especially common in older-onset affected family member with leg hy- perreflexia. These results suggest that specific clinical signs and symptoms may be of value in differentiating individuals af- fected with SPG4 from family members with nonspecific neu- rological findings. © 2004 Movement Disorder Society