Showing papers on "Anticipation (genetics) published in 2014"
TL;DR: Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72-ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9 ORF72 carriers have a higher incidence of bulbar onset disease.
Abstract: The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and ALS–FTLD, as well as contributing to sporadic forms of these diseases. Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72-ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9ORF72 carriers have a higher incidence of bulbar onset disease. In contrast, C9ORF72-FTLD is predominantly associated with behavioural variant FTD, which often presents with psychosis, most commonly in the form of hallucinations and delusions. However, C9ORF72 expansions are not restricted to these clinical phenotypes. There is a higher than expected incidence of parkinsonism in ALS patients with C9ORF72 expansions, and the G4C2 repeat has also been reported in other motor phenotypes, such as primary lateral sclerosis, progressive muscular atrophy, corticobasal syndrome and Huntington-like disorders. In addition, the expansion has been identified in non-motor phenotypes including Alzheimer’s disease and Lewy body dementia. It is not currently understood what is the basis of the clinical variation seen with the G4C2 repeat expansion. One potential explanation is repeat length. Sizing of the expansion by Southern blotting has established that there is somatic heterogeneity, with different expansion lengths in different tissues, even within the brain. To date, no correlation with expansion size and clinical phenotype has been established in ALS, whilst in FTLD only repeat size in the cerebellum was found to correlate with disease duration. Somatic heterogeneity suggests there is a degree of instability within the repeat and evidence of anticipation has been reported with reducing age of onset in subsequent generations. This variability/instability in expansion length, along with its interactions with environmental and genetic modifiers, such as TMEM106B, may be the basis of the differing clinical phenotypes arising from the mutation.
154 citations
TL;DR: Findings confirm anticipation as a true biological phenomenon, also in FAP ATTRV30M, and have important clinical implications in genetic counselling of offspring and in follow-up of mutation carriers.
Abstract: Background Early-onset (≤40 years) and later-onset (≥50 years) cases of familial amyloid polyneuropathy (FAP) ATTRV30M are not different entities, often coexisting in the same family, and showing anticipation (earlier age-at-onset (AO) in younger generations, usually associated with more severe phenotype). Historically, anticipation has been ascribed to ascertainment biases. Our aim was to study anticipation in a very large number of FAP kindreds, removing possible biases, and gain further insight into parent-of-origin effects. Methods We analysed 926 parent-offspring pairs (from the Unidade Clinica de Paramiloidose roster, collected in 70 years), both clinically observed and had well-established AO, correcting for intrafamilial correlations. Results Women had a significantly higher AO, either for daughters (mean: 33.70, SD: 6.84) vs sons (29.43, 6.08); or mothers (39.57, 11.75) vs fathers (35.62, 11.62). Also, 291 pairs showed marked anticipation (≥10 years); the transmitting parent was the mother in 203 pairs. Mother-son pairs showed larger anticipation (10.43, 9.34), while father-daughter pairs showed only a residual anticipation (1.23, 9.77). Gender of offspring and parents was highly significant (with no interaction). To remove possible biases, we repeated analyses: (1) excluding the proband; (2) removing pairs with simultaneous onset; and (3) excluding offspring born after 1960. Anticipation was found in all subsamples, with the same trend for a parent-of-origin effect. Noteworthy, parents with AO ≤40 years never had offspring with AO ≥50. Conclusions These findings confirm anticipation as a true biological phenomenon, also in FAP ATTRV30M. Acknowledgment of anticipation may have important clinical implications in genetic counselling of offspring and in follow-up of mutation carriers.
55 citations
TL;DR: It is suggested that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias, and guidelines for future studies claiming statistical evidence for anticipation are suggested.
Abstract: Anticipation is the phenomenon whereby age of onset in genetic disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob disease (CJD) caused by the c.598G>A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation’s 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested.
43 citations
TL;DR: No evidence of increased rates of CNVs is found in two successive generations of TP53 mutation carriers and in successive Generations of Trp53-deficient mice, and in multigeneration families, cancer onset was delayed in older compared with recent generations, supporting an alternative model for apparent anticipation.
Abstract: The Li–Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associated with germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been suggested that this apparent anticipation pattern may result from germ-line genomic instability in TP53 mutation carriers, causing increased DNA copy-number variations (CNVs) with successive generations. To address the genetic basis of phenotypic disparities of LFS/LFL, we performed whole-genome sequencing (WGS) of 13 subjects from two generations of an LFS kindred. Neither de novo CNV nor significant difference in total CNV was detected in relation with successive generations or with age at cancer onset. These observations were consistent with an experimental mouse model system showing that trp53 deficiency in the germ line of father or mother did not increase CNV occurrence in the offspring. On the other hand, individual records on 1,771 TP53 mutation carriers from 294 pedigrees were compiled to assess genetic anticipation patterns (International Agency for Research on Cancer TP53 database). No strictly defined anticipation pattern was observed. Rather, in multigeneration families, cancer onset was delayed in older compared with recent generations. These observations support an alternative model for apparent anticipation in which rare variants from noncarrier parents may attenuate constitutive resistance to tumorigenesis in the offspring of TP53 mutation carriers with late cancer onset.
28 citations
TL;DR: Findings indicate that anticipation is present in families with VHL disease and may be helpful for genetic counseling for families withVon Hippel-Lindau disease families and for further understanding the pathogenesis of V HL disease.
Abstract: Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. A phenomenon known as genetic anticipation has been documented in some hereditary cancer syndromes, where it was proved to relate to telomere shortening. Because studies of this phenomenon in VHL disease have been relatively scarce, we investigated anticipation in 18 Chinese VHL disease families. We recruited 34 parent-child patient pairs (57 patients) from 18 families with VHL disease. Onset age was defined as the age when any symptom or sign of VHL disease first appeared. Anticipation of onset age was analyzed by paired t test and the other two special tests (HV and RY2). Relative telomere length of peripheral leukocytes was measured in 29 patients and 325 healthy controls. Onset age was younger in child than in parent in 31 of the 34 parent-child pairs. Patients in the first generation had older onset age with longer age-adjusted relative telomere length, and those in the next generation had younger onset age with shorter age-adjusted relative telomere length (P < 0.001) in the 10 parent-child pairs from eight families with VHL disease. In addition, relative telomere length was shorter in the 29 patients with VHL disease than in the normal controls (P = 0.003). The anticipation may relate to the shortening of telomere length in patients with VHL in successive generations. These findings indicate that anticipation is present in families with VHL disease and may be helpful for genetic counseling for families with VHL disease families and for further understanding the pathogenesis of VHL disease.
27 citations
TL;DR: Preliminary evidence of genetic anticipation of RCC in HLRCC syndrome is reported, which may have practical implications on counseling and timing of surveillance initiation and exploration of the underlying mechanisms of anticipation would be of considerable biological interest.
Abstract: Hereditary leiomyomatosis-renal cell cancer (HLRCC) is an autosomal dominant disorder characterised by cutaneous leiomyomas, symptomatic uterine leiomyomas and aggressive type II papillary renal cell carcinoma It is caused by heterozygous mutations in the fumarate hydratase (FH) gene on chromosome 1q43 We present evidence of genetic anticipation in HLRCC syndrome A comprehensive literature review was performed to determine the potential for genetic anticipation in HLRCC syndrome The normal random effects model was used to evaluate for genetic anticipation to ensure reduction in bias A total of 11 FH kindreds with available multi-generational data were identified for analysis The mean difference in age at diagnosis of RCC between the first and second generation was −186 years (95 % CI −266 to −106, p < 0001) The mean difference in age at diagnosis of RCC between the first and third generation was −362 years (95 % CI −470 to −254, p < 0001) No evidence of anticipation for uterine leiomyomas was observed (p = 0349) We report preliminary evidence of genetic anticipation of RCC in HLRCC syndrome Additional clinical validation is important to confirm this observation, which may have practical implications on counseling and timing of surveillance initiation Exploration of the underlying mechanisms of anticipation in HLRCC would be of considerable biological interest
19 citations
TL;DR: 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.
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.
19 citations
TL;DR: A patient with infantile-onset spinocerebellar ataxia type 2 who inherited the disease from his father (47 CAG repeats) is described to help treating clinicians to suspect this disorder and to offer timely genetic counseling for a currently potentially untreatable disorder.
Abstract: Autosomal dominant cerebellar ataxia type I is a heterogeneous group of spinocerebellar ataxias with variable neurologic presentations, with age of onset varying from infancy to adulthood Autosomal dominant cerebellar ataxia type I is composed mainly of 3 prevalent spinocerebellar ataxia types with different pathogenic loci, specifically spinocerebellar ataxia 1 (6p24-p23), spinocerebellar ataxia 2 (12q241), and spinocerebellar ataxia 3 (14q321) The shared pathogenic mutational event is the expansion of the CAG repeat that results in polyglutamine extended stretches in the encoded proteins CAG repeat disorders generally show the phenomenon of anticipation, which is more often associated with paternal transmission In this report, we describe a patient with infantile-onset spinocerebellar ataxia type 2 (~320 CAG repeat) who inherited the disease from his father (47 CAG repeats) We have summarized the clinical, neuroimaging, electroencephalographic (EEG), and molecular data of previous cases and attempt to highlight the most consistent findings Our intent is to help treating clinicians to suspect this disorder and to offer timely genetic counseling for a currently potentially untreatable disorder
15 citations
TL;DR: Genetic counseling and early screening should be provided to women whose parent had a breast or ovarian cancer diagnosis, and BRCA mutation status did not influence the generational difference in age at diagnosis.
8 citations
TL;DR: This study includes members of a single family known to carry an MLH1 gene mutation who are proven germline mutation carriers or obligate carriers (based on their offspring’s mutation status) and could not identify any evidence of genetic anticipation in mutation carriers from a singlefamily with Lynch syndrome.
Abstract: Lynch syndrome is the commonest inherited cause of colorectal cancer (CRC). Genetic anticipation occurs when the age of onset of a disorder decreases in successive generations. It is controversial whether this occurs in Lynch syndrome. Previous studies have included heterogenous groups of subjects from multiple families, including subjects with a clinical diagnosis (based on family history) as well as those with proven germline mismatch repair gene mutations. The purpose of this study was to determine whether genetic anticipation occurs in mismatch repair gene carriers from a single Lynch syndrome family. This study includes members of a single family known to carry an MLH1 gene mutation who are proven germline mutation carriers or obligate carriers (based on their offspring's mutation status). Evidence of genetic anticipation (determined by age of onset of first CRC) was sought in two ways: Firstly, subjects were grouped as parent-child pairs and individuals were compared with their own offspring; secondly they were grouped by generation within the family tree. The Kaplan-Meier technique was used to adjust for variable follow up times. The family tree consisted of 714 subjects. Ninety-two subjects over five generations were included in the study. There was no evidence of genetic anticipation over the generations. (P = 0.37). Similarly, in the 75 parent-child pairs identified, age of onset of CRC was similar for parents and children (P = 0.51). We could not identify any evidence of genetic anticipation in mutation carriers from a single family with Lynch syndrome.
7 citations
TL;DR: Recent key insights into the cellular pathogenesis and therapy of HD are outlined, including a novel role for mitochondrial fission and excitotoxicity and elegant studies probing signaling pathways that impinge on striatal neuron dysfunction and degeneration.
TL;DR: The clinical characteristics of JOAG in this family were 1) genetics anticipation; 2) high IOP; 3) temporay response to anti-glaucoma drugs; 4) filtering surgery produced thin-walled and saccate filtering blebs, helping maintain lower IOP.
Abstract: AIM
To describe the anticipation and anti-glaucoma drugs response of a Chinese family with juvenile-onset open angle glaucoma (JOAG) caused by the Pro370Leu myocilin (MYOC) mutation.
TL;DR: The purpose of this study was to determine the effect of age of diagnosis of colorectal cancer on lifetime fertility in Lynch syndrome, and whether this can falsely create the appearance of genetic anticipation.
Abstract: Genetic anticipation is the phenomenon in which age of onset of an inherited disorder decreases in successive generations. Inconsistent evidence suggests that this occurs in Lynch syndrome. A possible cause for apparent anticipation is fecundity bias, which occurs if the disease adversely affects fertility. The purpose of this study was to determine the effect of age of diagnosis of colorectal cancer (CRC) on lifetime fertility in Lynch syndrome, and whether this can falsely create the appearance of genetic anticipation. A computer model simulated age of diagnosis of CRC in hypothetical Lynch syndrome carriers and their offspring. The model assumed similar age distribution of CRC across generations (i.e. that there was no true anticipation). Age distribution of CRC diagnosis, and lifetime fertility rates (grouped by age of diagnosis of CRC) were determined from the Australasian Colorectal Cancer Family Registry (ACCFR). Apparent anticipation was calculated by comparing ages of diagnosis of CRC in affected parent–child pairs. A total of 1,088 patients with CRC were identified from the ACCFR. Total lifetime (cohort) fertility was related to age of diagnosis of CRC (correlation coefficient 0.13, P = 0.0001). In the simulation, apparent anticipation was 1.8 ± 0.54 years (P = 0.0044). Observed apparent anticipation in the ACCFR cohort was 4.8 ± 1.73 years (P = 0.0064). There was no difference in apparent anticipation between the simulate d and observed parent–child pairs (P = 0.89). The appearance of genetic anticipation in Lynch syndrome can be falsely created due to changes in fertility.
07 Mar 2014
TL;DR: The findings suggest that a progressive increase of cortical hyperexcitability causes exaggeration of cortical tremor in BAFME and diseases with unstable expanding repeats including those in non-coding regions might share a similar molecular mechanism.
Abstract: Benign adult familial myoclonus epilepsy (BAFME) is an adult onset, autosomal dominant disease characterized by cortical tremor and infrequent generalized seizures. BAFME was considered as non-progressive, but cortical tremor worsened in some of the aged patients. We investigated the disease progression of BAFME. Cortical tremor significantly worsened and amplitudes of giant somatosensory evoked potential significantly increased with age in BAFME. These findings suggest that a progressive increase of cortical hyperexcitability causes exaggeration of cortical tremor. The clinical anticipation, defined as earlier onset age of either cortical tremor or generalized seizures or new appearance of those symptoms in the next generation, was observed in all studied BAFME families. In addition, a higher degree of clinical anticipation was associated with maternal transmission than with paternal transmission. Despite a unknown causative gene for BAFME, our finding suggests that BAFME and diseases with unstable expanding repeats including those in non-coding regions, might share a similar molecular mechanism because such diseases often show clinical anticipation with maternal transmission. As mentioned above, at least some part of the symptoms and pathophysiology progress with aging or over generation in BAFME.
TL;DR: Two probably related Swedish families are presented with a characteristic and novel clinical syndrome of cerebellar ataxia and sensory polyneuropathy and the study serves as a basis for the mapping of the underlying genetic cause.
TL;DR: This work reviews the current knowledge about stable mutations or amplification of DNA tandem repeats sequences that cause hereditary diseases and finds that in most cases, the severity of the symptoms is positively correlated with the size of the amplification.
Abstract: Unstable mutations or amplification of DNA tandem repeats sequences constitute a new kind of genetic alteration discovered in the 90´s that cause hereditary diseases. This mutation has been found inside or near important genes involved in the normal neurological function in human beings. In some cases, the presence of the amplification causes altered expression of the genes, their inactivation or the synthesis of a protein with new functions. Some common characteristics of these diseases are that they affect the central nervous system and are degenerative in nature. Most of them show genetic anticipation meaning that the severity of the manifestations increases in each generation and appear at an earlier age. In most cases, the severity of the symptoms is positively correlated with the size of the amplification. Twenty illnesses caused by this kind of mutations have been identified so far. Briefly, this work reviews the current knowledge about this topic.
TL;DR: A decrease in the age of onset in three consecutive generations in the family of the proband, indicating possible genetic anticipation in this familial EPPK.
Abstract: Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant disease characterized by diffuse hyperkeratosis of the epidermis of the palm and sole with an erythematous margin. The Keratin 9 (KRT9) and Keratin 1 genes are responsible for EPPK. Several previous studies have focused on the genetic basis of EPPK; however, genetic anticipation has not yet been reported. We described a four-generation family with EPPK and identified a p.R163W mutation of KRT9. We observed a decrease in the age of onset in three consecutive generations in the family of the proband, indicating possible genetic anticipation in this familial EPPK. Further studies are needed to elucidate the mechanisms of anticipation in EPPK.
TL;DR: The entire coding region of GJB2 should be checked in hearing-impaired patients by Sanger sequencing, rather than examination only of the two most prevalent mutations, regardless of mode of inheritance or ethnicity.
Abstract: Background: Connexin 26 ( GJB2 ) mutations are associated with various types of hearing loss, either without associated symptoms or with skin disease, constituting a form of syndromic hearing loss. These mutations can lead to deafness in either a recessive or a dominant autosomal form of inheritance. Methods: Ascertainment of a Jewish Ashkenazi family with nonsyndromic hearing loss led to the construction of a pedigree for a four-generation family, with hearing loss detected in three successive generations. The entire coding region of the GJB2 gene was amplified and sequenced by Sanger sequencing. Results: Audiological analysis revealed that the age of onset and severity of hearing loss were earlier and more severe, respectively, in each successive generation of an Ashkenazi Jewish family. A mutation, c.224G > A, leading to missense p.Arg75Gln was detected only in the affected members of the family. Conclusions: The entire coding region of GJB2 should be checked in hearing-impaired patients by Sanger sequencing, rather than examination only of the two most prevalent mutations, regardless of mode of inheritance or ethnicity. Furthermore, predictions regarding phenotype based on genotype can be difficult to make due to clinical variability in multigenerational families, as demonstrated in the family presented in this study.
Journal Article•
TL;DR: The study of patients with early-onset bipolar disorder may throw light on the "extended phenotype" of mood disorders, as well as the genetic and epigenetic mechanisms involved in the phenomena of anticipation and phenotypic variation.
Abstract: Anticipation is a phenomenon in which successive generations within a family experience an earlier age of onset and a more severe form of a given illness. It has been observed in various neurological and psychiatric conditions, including bipolar disorder. The molecular basis of anticipation involves trinucleotide repeat expansions in genes, but this has not been conclusively demonstrated in bipolar disorder. The histories of 3 father-son pairs are presented. In each pair, the son presented with an early-onset bipolar disorder, and the father developed severe depression after the age of 50 years. No female relatives were affected. The implications of these observations are discussed. Genetic, epigenetic, and environmental mechanisms that may have contributed to this phenomenon are briefly described. The study of such patients may throw light on the "extended phenotype" of mood disorders, as well as the genetic and epigenetic mechanisms involved in the phenomena of anticipation and phenotypic variation.
01 Jan 2014
TL;DR: Although the genes involved in these disorders are widely expressed throughout the body, symptoms are usually confined to the nervous system (Huntington's disease and Fragile X) or muscles (myotonic dystrophy).
Abstract: Triplet repeat disorders are a category of disease caused by the lengthening of repetitive DNA sequence elements in particular genes. These unusual sequences, while normal in certain lengths, are prone to errors during DNA replication that result in their expansion. At some threshold length, the expansion causes disease, either by altering the structure of the protein (when the expansions are in coding regions) or by disrupting some unknown regulatory process (when the expansions are outside coding regions). Although the genes involved in these disorders are widely expressed throughout the body, symptoms are usually confined to the nervous system (Huntington's disease and Fragile X) or muscles (myotonic dystrophy).
TL;DR: The report of sudden death in calves related to anticipation of feeding reminded me of an incident that occurred when I was a (preclinical) veterinary student.
Abstract: THE report of sudden death in calves related to anticipation of feeding ( VR , April 12, 2014, vol 174, pp 374-377) reminded me of an incident that occurred when I was a (preclinical) veterinary student. Young calves, which were fed milk substitute from buckets, …