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.

Anticipation in Lynch Syndrome: Still Waiting for the Answer

Abstract: Genetic anticipation describes the progressively earlier onset and increased severity of disease in successive generations of a family. For some diseases, genetic anticipation is a well-recognized clinical feature with an elegantly and completely characterized molecular mechanism. Lynch syndrome is not one of these diseases. Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer, was originally described by Aldred Warthin in 1913 as a cancer family syndrome characterized by the early onset of gastrointestinal, uterine, and other cancers. Ninety-five years later, we are still gathering data to understand whether successive generations are truly affected at earlier ages than their ancestors and whether the severity of the disease is more or less pronounced. In this issue of Journal of Clinical Oncology, Nilbert et al revisit the hypothesis of genetic anticipation in Lynch syndrome using the population-based Danish Hereditary Nonpolyposis Colorectal Cancer Registry. Examining data from 290 parent-child pairs from families with Lynch syndrome who are known to carry a mutation in one of three causal genes, they show that the mean age of onset of cancer is lower in children than in their parents. The authors used a statistical method that accounts for the fact that children are always younger than their parents. The younger age of cancer among children also persisted even in analyses that excluded those cancers diagnosed during surveillance. However, their conclusion that this statistically significant difference in age at diagnosis represents biologically meaningful genetic anticipation is not entirely convincing. It is worthwhile to review the molecular genetic basis of syndromes where the evidence for genetic anticipation is crystal clear, to understand just how far we have to go to complete the story of Lynch syndrome. Genetic anticipation is a cardinal feature of more than a dozen neurodegenerative disorders such as Huntington disease, fragile X, myotonic dystrophy, and Friedreich ataxia, among others. The molecular mechanism of each these examples is explained by understanding trinucleotide expansion repeat disorders, where a generational expansion of a repetitive trinucleotide sequence during meiosis leads to disease. For example, the normal number of copies of the DNA sequence CAG that encodes a polyglutamine tract within the HD gene ranges between 9 and 35. More than 40 copies of this CAG repeat, (CAG)40, causes Huntington disease; both the severity and age of onset depend on the number of repeats. Individuals with 40 to 50 repeats are often asymptomatic until late in life, whereas children with 70 to 121 repeats develop severe disease in the juvenile form of the disease. The juvenile form is always paternally inherited, as a consequence of the fact that trinucleotide expansion occurs most frequently during male gametogenesis. This phenomenon also explains the sexspecific inheritance patterns that are frequently observed with genetic anticipation. One might hypothesize that a gene involved in mismatch repair (such as one of the genes that cause Lynch syndrome) might lead to a similar type of generational instability in repetitive sequences of DNA, and that this could serve as a biologic basis of genetic anticipation. The only problem with this hypothesis is that there is little evidence to support it. No studies to date have evaluated generational differences in microsatellite instability in the typical targets of defective mismatch repair. The studies that have examined clinical populations for genetic anticipation have generally led to conflicting conclusions, and none have been accompanied by mechanistic data supporting these diverse interpretations. One might also hypothesize that defective mismatch repair might enhance the generational expansion of trinucleotide repeats in models of Huntington disease. The only problem with this hypothesis is that the opposite appears to be true, at least in animal models. Msh2 is required for (CAG) expansion in a mouse model of Huntington disease, and transgenic mice with a complete absence of Msh2 have perfectly stable polyglutamine tracts. Several studies show that Msh2 deficiency actually inhibits intergenerational trinucleotide expansion. Therefore, if genetic anticipation is shown to be clinically relevant in Lynch syndrome, it is unlikely to occur due to the same type of trinucleotide expansion responsible for anticipation in neurodegenerative disorders. Anticipation has been difficult to study in cancer genetic syndromes. However, intriguing new evidence from studies of LiFraumeni syndrome (LFS) and Dyskeratosis Congenita (DC) suggest that there may be at least one other mechanism that plays a role in modifying the age of onset of some types of cancer susceptibility. Accelerated telomere attrition has been reported in affected carriers with LFS compared with unaffected carriers as well as compared with normal wild-type controls, leading investigators to speculate that defects in TP53 allow cells with shorter telomeres to escape senescence and proliferate. If this type of selection for shorter telomeres applies to both somatic and germline tissues, then one would expect that shorter telomeres would be identified at birth in each successive generation. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 3 JANUARY 2

Genetic anticipation and breast cancer: a prospective follow-up study.

Abstract: Genetic anticipation is characterized by an earlier age of disease onset, increased severity, and a greater proportion of affected individuals in succeeding generations. The discovery of trinucleotide repeat expansion (TRE) mutations as the molecular correlate of anticipation in a number of rare Mendelian neurodegenerative disorders has led to a resurgence of interest in this phenomenon. Because of the difficulties presented to traditional genetics by complex diseases, the testing for genetic anticipation coupled with TRE detection has been proposed as a strategy for expediting the identification of susceptibility genes for complex disorders. In the case of breast cancer, a number of previous studies found evidence consistent with genetic anticipation. It is known that a proportion of such families are linked to either BRCA1 or BRCA2, but no TRE mutations have been identified. It has been shown that the typical ascertainment employed in studies purporting to demonstrate genetic anticipation combined with unadjusted statistical analysis can dramatically elevate the type I error. We re‐examine the evidence for anticipation in breast cancer by applying a new statistical approach that appears to have validity in the analysis of anticipation to data ascertained from a recent follow‐up of a large prospective cohort family study of breast cancer. Using this approach, we find no statistically significant evidence for genetic anticipation in familial breast cancer. We discuss the limitations of our analysis, including the problem of adequate sample size for this new statistical test.

Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Abstract: Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

Instability of trinucleotidic repeats during chromatin remodeling in spermatids.

Abstract: Transient DNA breaks and evidence of DNA damage response have recently been reported during the chromatin remodeling process in haploid spermatids, creating a potential window of enhanced genetic instability. We used flow cytometry to achieve separation of differentiating spermatids into four highly purified populations using transgenic mice harboring 160 CAG repeats within exon 1 of the human Huntington disease gene (HTT). Trinucleotic repeat expansion was found to occur immediately following the chromatin remodeling steps, confirming the genetic instability of the process and pointing to the origin of paternal anticipation observed in some trinucleotidic repeats diseases.