Showing papers on "Anticipation (genetics) published in 2012"
TL;DR: Genetic anticipation is likely an artifact of incomplete time of observation of kindreds with HPAH due to BMPR2 mutations, and inclusion of currently unaffected mutation carriers strengthens the observation that bias of ascertainment exists when recent generations are included.
Abstract: Rationale: Analysis of the age of onset in heritable pulmonary arterial hypertension (HPAH) has led to the hypothesis that genetic anticipation causes younger age of onset and death in subsequent generations. With accrual of pedigree data over multiple decades, we retested this hypothesis using analyses that eliminate the truncation of data that exists with shorter duration of follow-up.Objectives: To analyze the pedigrees of families with mutations in bone morphogenetic protein receptor type 2 (BMPR2), afflicted in two or more generations with HPAH, eliminating time truncation bias by including families for whom we have at least 57 years of data.Methods: We analyzed 355 individuals with BMPR2 mutations from 53 families in the Vanderbilt Pulmonary Hypertension Registry. We compared age at diagnosis or death in affected individuals (n = 249) by generation within families with multigenerational disease. We performed linear mixed effects models and we limited time-truncation bias by restricting date of birth...
164 citations
TL;DR: Best practice guidelines for clinical molecular genetic analysis and reporting in myotonic dystrophy type 1 and 2 are described, including presymptomatic and prenatal testing.
Abstract: Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to late-onset baldness and cataract. In adult patients, cardiac conduction abnormalities may occur and cause a shorter life span. In subsequent generations, the symptoms in DM1 may present at an earlier age and have a more severe course (anticipation). In myotonic dystrophy type 2 (DM2), no anticipation is described, but cardiac conduction abnormalities as in DM1 are observed and patients with DM2 additionally have muscle pain and stiffness. Both DM1 and DM2 are caused by unstable DNA repeats in untranslated regions of different genes: A (CTG)n repeat in the 3'-UTR of the DMPK gene and a (CCTG)n repeat in intron 1 of the CNBP (formerly ZNF9) gene, respectively. The length of the (CTG)n repeat expansion in DM1 correlates with disease severity and age of onset. Nevertheless, these repeat sizes have limited predictive values on individual bases. Because of the disease characteristics in DM1 and DM2, appropriate molecular testing and reporting is very important for the optimal counseling in myotonic dystrophy. Here, we describe best practice guidelines for clinical molecular genetic analysis and reporting in DM1 and DM2, including presymptomatic and prenatal testing.
117 citations
TL;DR: Age at diagnosis in 2 generations of families with known mutations to investigate for earlier onset in subsequent generations of women with high risk of developing breast and ovarian cancers.
Abstract: Hereditary breast and ovarian cancer syndrome (HBOC) related to the breast cancer (BRCA) genes initially was identified in families with the use of genetic linkage analysis1–3 Since then, over 5000 different mutations in these genes have been identified that are inherited in an autosomal-dominant fashion and are responsible for approximately 5% to 10% of breast cancer diagnoses4 Carriers of this mutation have an elevated risk of developing both breast and/or ovarian cancer, and a meta-analysis estimate of the lifetime risk of breast cancer was 47% to 66% in BRCA1 carriers and 40% to 57% in the BRCA2 carriers, and the risk of developing ovarian cancer was 35% to 46% and 13% to 23%, respectively, in the same analysis5 One of the major risk factors for HBOC is the development of breast cancer at a very young age, Thus, the National Comprehensive Cancer Network (NCCN) guidelines panel has recommend initiating screening at ages 20 to 25 years, or 5 to 10 years earlier than the youngest age at diagnosis in the family6 Implementing screening techniques is meant to identify cancers at the earliest time possible; therefore, estimating the onset of disease is vital in timing the initiation of screening and interventions
Anticipation has been described as a phenomenon observed in inherited diseases such as Fragile X syndrome and Huntington disease, in which the disease occurs at younger ages or with increased severity of disease in subsequent generations7,8 The cause of this anticipation has been identified as DNA instability, such as nucleotide repeats that change in length in subsequent generations, altering the phenotype of the disease However, changes in disease phenotype in subsequent generations also have been identified in other disorders, such as in colon cancer, Alzheimer disease, and diabetes9,10 With the increase in BRCA1 and BRCA2 testing, there also has been an increase in families being evaluated and screened for HBOC
There have been several reports of anticipation in breast cancer To date, these reports have been based on very small cohorts; those studies indicated an earlier age at diagnosis and examined the absolute differences between matched pairs Dagan and Gershoni-Baruch reported a statistically significant difference of approximately 4 years in BRCA2 mutation carriers and a statistically nonsignificant numerical difference in BRCA1 carriers11 In addition, Peixoto et al and Paltiel et al also observed similar patterns of earlier age of diagnosis for subsequent generations in breast cancer registries12,13
When discussing appropriate screening interventions for women with a known deleterious BRCA1 or BRCA2 mutation, potential interventions include clinical breast examination, magnetic resonance imaging, and mammography14 Evaluating for patterns of inheritance like anticipation in families with known deleterious BRCA mutations may help promote understanding of these genes and provide further insight into the timing of screening initiation and starting other interventions The objective of the current analysis was to evaluate any trends in age at diagnoses in families with known deleterious BRCA mutations at a single institution to add to the growing evidence of genetic anticipation in patients with HBOC We evaluated families who were referred to the Clinical Cancer Genetic Program at our institution and analyzed age at diagnosis across 2 generations
70 citations
TL;DR: It is found that CpG methylation in human ATXN2 gene promoter is associated with pathogenic CAG expansions in SCA2 patients and this points to a novel regulatory mechanism of ATXn2 expression involving an epigenetic event resulting in differential disease course in SCa2 patients.
Abstract: Pathogenic CAG (cytosine-adenine-guanine) expansions beyond certain thresholds in the ataxin-2 (ATXN2) gene cause spinocerebellar ataxia type 2 (SCA2) and were shown to contribute to Parkinson disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Regulation of ATXN2 gene expression and the function of the protein product are not known. SCA2 exhibits an inverse correlation between the size of the CAG repeat and the age at disease onset. However, a wide range of age at onset are typically observed, with CAG repeat number alone explaining only partly this variability. In this study, we explored the hypothesis that ATXN2 levels could be controlled by DNA methylation and that the derangement of this control may lead to escalation of disease severity and influencing the age at onset. We found that CpG methylation in human ATXN2 gene promoter is associated with pathogenic CAG expansions in SCA2 patients. Different levels of methylation in a SCA2 pedigree without an intergenerational CAG repeat instability caused the disease anticipation in a SCA2 family. DNA methylation also influenced the disease onset in SCA2 homozygotes and SCA3 patients. In conclusion, our study points to a novel regulatory mechanism of ATXN2 expression involving an epigenetic event resulting in differential disease course in SCA2 patients.
44 citations
TL;DR: The SCA7 gene encodes a protein of largely unknown function, called ataxin-7, which represents one of the polyglutamine expansion diseases with increase of CAG repeats as mentioned in this paper.
Abstract: Spinocerebellar ataxia type 7 (SCA7) is associated with progressive blindness, dominant transmission, and marked anticipation. SCA7 represents one of the polyglutamine expansion diseases with increase of CAG repeats. The gene maps to chromosome 3p12-p21.1. Normal values of CAG repeats range from 4 to 18. The SCA7 gene encodes a protein of largely unknown function, called ataxin-7. SCA7 is reported in many countries and ethnic groups. Its phenotypic expression depends on the number of expanded repeats. The infantile phenotype is very severe, with more than 100 repeats. The classic type has 50 to 55 repeats and is characterized by a combination of visual and ataxic disturbances lasting for 20-40 years.When the number of CAG repeats is between 36 and 43, the evolution is much slower, with few or no retinal abnormalities. A CAG repeat number from 18 to 35 is asymptomatic but predisposes to the development of the disorder when expanding to the pathological range through transmission. The diagnosis is made by molecular genetics. The neuropathology of the disorder includes atrophy of the spinocerebellar pathways, pyramidal tracts, and motor nuclei in the brainstem and spinal cord, a cone-rod sytrophy of the retina, and ataxin-7 immunoreactive neuronal intranuclear inclusions. The neuropathological features vary as a function of the number of CAG repeats. Present research deals mainly with the study of ataxin-7 in transfected neural cells and transgenic mouse models.
42 citations
TL;DR: Clinical anticipation was observed in four families, which suggests the clinical progression over generation in Japanese BAFME families, and generalized seizures newly appeared in the next generation in those two families and in another family.
Abstract: The clinical anticipation in Japanese benign adult familial myoclonus epilepsy (BAFME), defined as earlier onset age of either cortical tremor or generalized seizures or new appearance of those symptoms in the next generation, remains unknown. The onset age and the degree of both cortical tremor and generalized seizures were investigated in nine patients of four BAFME families (mean age: 46.6 ± 18.7 years). Clinical anticipation in the onset age of cortical tremor or generalized seizures was observed in three families, and generalized seizures newly appeared in the next generation in those two families and in another family. Clinical anticipation was observed in four families, which suggests the clinical progression over generation in Japanese BAFME families.
25 citations
TL;DR: The genetic background of a family with SCA showed typical findings for a mitochondrial disorder, and both parents were shown to be homozygous for a recessive POLG1 mutation, underlying mitochondrial recessive ataxia syndrome, MIRAS.
19 citations
TL;DR: ATTR Ser50Arg mutation was associated with an early onset, an unbalanced male to female ratio, a more aggressive course in males and possibly displayed anticipation in patients with positive test results.
Abstract: Background: The phenotypic heterogeneity of transthyretin amyloidosis (ATTR) familial polyneuropathy may be linked to the type of mutation and to the environmental factors. A gender difference in relation to the severity of the disease has been suspected. More than 100 different pathogenic variants of hereditary transthyretin (TTR) mutations have been reported. Objective: To describe 32 patients with confirmed TTR Ser50Arg mutation from the same geographical origin. Methods: Seven families with up to four affected generations underwent genetic testing and prospective clinical and laboratory evaluations. Results: The mutation was confirmed in seven patients from different families with clinical symptoms compatible with ATTR amyloidosis, and in 25 (62%) of the 40 direct relatives tested. Of the 32 patients with positive test results, 18 (56%) were men. Only 5 (16%) subjects were disease-free at the time of the genetic test (mean age: 20, range: 18–30-year-old). The rest developed symptoms at a young age, between ages 36 and 41. Symptomatic, histologically positive patients were older than carriers and symptomatic patients without a confirmatory biopsy. The later generation displayed symptoms at a younger age. Initial manifestations in the 27 symptomatic patients were neuropathic in 19 (70%), gastrointestinal in 6 (22%) and autonomic in 1 (4%). Significant differences were demonstrated among genders, where men had a considerably worse outcome. Conclusion: ATTR Ser50Arg mutation was associated with an early onset, an unbalanced male to female ratio, a more aggressive course in males and possibly displayed anticipation.
11 citations
Journal Article•
TL;DR: Assessment of the familial pedigree has revealed anticipation in phenotype and autosomal dominant inheritance, and data in addition to the high conservation of methionine residue in mammalian species suggest that M163V is inherited with an autosome dominant pattern, therefore, the risk of inheritance will increase.
Abstract: Mutations in the GJB2 gene are the most common causes of hereditary hearing loss. This study reveals some facts about the inheritance pattern of M163V in the GJB2 gene. This study was performed on two different families with non-syndromic hearing loss. We screened the GJB2 coding region with direct sequencing. There was a substitution of A to G in exon 2 at nucleotide 487 (M163V). This mutation was heterozygous in fathers and children while mothers were normal. Fathers of both families showed late onset hearing impairment, but there was early onset hearing loss in the children, which was more severe compared to the fathers. M163V has been reported as an unknown heterozygous mutation that leads to failure of the homotypic junctional channel formation. Another mutation in this codon is M163L, with an autosomal dominant inheritance, which impairs trafo cking through the plasma membrane, resulting in cell death. Assessment of the familial pedigree has revealed anticipation in phenotype and autosomal dominant inheritance. These data in addition to the high conservation of methionine residue in mammalian species suggest that M163V is inherited with an autosomal dominant pattern. Therefore, the risk of inheritance will increase. Genetic counselors and otologists should prioritize the evaluation and prevention of this disorder in patients.
11 citations
20 Dec 2012
TL;DR: Once an ATXN7 CAG repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SCA7 are possible and genetic counselingSCA7 is inherited in an autosomal dominant manner.
Abstract: Clinical characteristics Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death. Anticipation in this nucleotide repeat disorder may be so dramatic that within a family a child with infantile or early-childhood onset may be diagnosed with what is thought to be an unrelated neurodegenerative disorder years before a parent or grandparent with a CAG repeat expansion becomes symptomatic. In adolescent-onset SCA7, the initial manifestation is typically impaired vision, followed by cerebellar ataxia. In those with adult onset, progressive cerebellar ataxia usually precedes the onset of visual manifestations. While the rate of progression varies in these two age groups, the eventual result for almost all affected individuals is loss of vision, severe dysarthria and dysphagia, and a bedridden state with loss of motor control. Diagnosis/testing The diagnosis of SCA7 is established in a proband by the identification of a heterozygous abnormal CAG trinucleotide repeat expansion in ATXN7 by molecular genetic testing. Management Treatment of manifestations: Multidisciplinary care involves supportive treatment of: neurologic manifestations – physical and occupational therapy to help maintain mobility and function, and pharmacologic treatment to reduce symptoms; dysarthria – speech and language therapy and alternative communication methods; dysphagia – feeding therapy to improve nutrition and reduce the risk of aspiration; and reduced vision – use of low vision aids and consultation with agencies for the visually impaired. Surveillance: Routine follow up with multidisciplinary care providers. Agents/circumstances to avoid: Avoid: alcohol intake (especially if excessive) as it can further impair cerebellar function; foods identified by a registered dietitian as possible causes of dizziness or disorientation. Therapies under investigation: Several ongoing clinical trials for medications used as treatment for ataxia. Genetic counseling SCA7 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting an abnormal CAG repeat expansion in ATXN7. Once an ATXN7 CAG repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SCA7 are possible.
9 citations
TL;DR: This study confirms the marked anticipation previously observed in SCA7 and extends the small number of patients studied thus far, which is most likely caused by a de novo expansion of a premutated intermediate allele carried by one parent.
Abstract: Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by degeneration of the cerebellum, brainstem and retina. We herein describe a family from southern Italy whose proband was a 49-year-old man presenting with ataxia with progressive gait disturbances, clumsiness and visual impairment. A molecular analysis identified 38 cytosine-adenine-guanine (CAG) repeat expansions within the SCA7 gene. Our study confirms the marked anticipation previously observed in SCA7 and extends the small number of patients studied thus far. In this family, the disease is most likely caused by a de novo expansion of a premutated intermediate allele carried by one parent.
Journal Article•
TL;DR: A patient with essential thrombocythemia (ET) who developed chronic lymphocytic leukemia (CLL) 10 years after his initial diagnosis is described.
Abstract: We describe a patient with essential thrombocythemia (ET) who developed chronic lymphocytic leukemia (CLL) 10 years after his initial diagnosis. The association of ET and CLL is very rare, and only a handful of cases have been described in the literature. Although the association may be one of chance, some evidence suggests that the 2 neoplasms may be related. Such evidence includes the occurrence of B-cell malignancy and ET in different generations of the same family, with anticipation demonstrated in the pedigree.
TL;DR: The genetic, clinical and electrophysiological features of patients belonging to a four-generation Italian family and a novel polymorphism G→T was found in the Berardinelli-Seip congenital lipodystrophy 2 gene on intron 4, calling the clinician attention to this rare and still insufficiently known disease.
Abstract: Previous studies have revealed a wide phenotypic heterogeneity in hereditary motor neuropathy type V in which upper and lower motor neurons and peripheral motor axons are variously affected, even within the same family. In this case series, we describe the genetic, clinical and electrophysiological features of patients belonging to a four-generation Italian family. Because of a possible anticipation phenomenon, the disorder became apparent at an earlier age as it passed to the next generation, with a median age of onset of 65 years for the first 2 generations, 32 for the third, and 13.5 for the fourth. The symptoms at onset varied considerably among the sufferers, with a predominant impairment of the hands in seven cases, the impairment of the four limbs in one patient and only of the lower limbs in another. Also muscle atrophy was variable, from very mild to severe (wasting of the distal muscles of the limbs). Moreover, electrophysiological results were heterogeneous, including cases with isolated and with diffuse axonal motor neuropathy, and one case of motor sensory polyneuropathy. A novel polymorphism G→T was also found in the Berardinelli-Seip congenital lipodystrophy 2 gene on intron 4. This broad phenotypic and genotypic spectrum calls the clinician attention to this rare and still insufficiently known disease.
05 Jun 2012
TL;DR: An RNA-mediated dominant gain-of-function is currently accepted as the pathogenic mechanism to explain features of the myotonic dystrophy type 1 disease.
Abstract: Myotonic dystrophy protein kinase (DMPK) is a member of the AGC super family of serine/threonine protein kinases (Caenepeel et al, 2004; Manning et al, 2002) The DMPK human gene encodes several alternative spliced protein products believed to be involved in remodeling of the actin cytoskeleton, mitochondrial dynamics, ion homeostasis and nuclear envelope stability DMPK and its isoforms are mainly expressed in skeletal, heart and smooth muscle, and brain, the main targets of myotonic dystrophy type 1 (DM1) (Groenen et al, 2000; Ueda et al, 2000) DM1 is the most common form of muscular dystrophy in adults with a frequency of 1 in 8,000 individuals worldwide It is a multisystem dominantly inherited disorder characterized by myotonia, progressive muscular weakness and wasting, cardiac defects, cataracts and frontal balding, as well as several central nervous system (CNS) manifestations (Harper et al, 2002) The disease is caused by the expansion of an unstable (CTG)n repeat in the 3’-untranslated region (3’-UTR) of the DMPK gene (Brook et al, 1992; Fu et al, 1992; Mahadevan, M et al, 1992) In healthy population the CTG tract is polymorphic with alleles ranging from 5 to 37 in length Individuals carrying the DM1 premutation, a tract between 38 and 49 CTG repeats, generally are asymptomatic but are at risk of transmitting a pathological expanded mutation In contrast, a CTG expansion between 50 and 4000 CTG repeats results in DM1 disease Affected families show the phenomenon of anticipation; longer expansions correlate with an earlier age of onset and more severe course in subsequent generations Based on their clinical presentation DM1 is classified into four subtypes: late onset, classic DM1, childhood onset and congenital DM1 (CDM) (Harley et al, 1992) An RNA-mediated dominant gain-of-function is currently accepted as the pathogenic mechanism to explain features of the DM1 DMPK toxic transcripts accumulate as nuclear foci (Davis et al, 1997; Taneja et al, 1995), interfering with the activity of RNA-interacting proteins and altering RNA metabolism, notably the splicing programme (Ranum & Day, 2004) Although reduced DMPK protein levels in DM1 tissues
TL;DR: Congenital myotonic dystrophy (CDM) is classified as the most severe form of DM1, and its phenotype, with severe hypotonia, neonatal respiratory distress and feeding difficulties, is completely different from that of adult-onset type.
Abstract: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder with variable expression. DM1 results from a trinucleotide expansion in the 3' untranslated region or the gene for myotonic dystrophy protein kinase (DMPK). Severity tends to increase and it shows a younger onset age with vertical transmission, a phenomenon known as anticipation. Congenital myotonic dystrophy (CDM) is classified as the most severe form of DM1, and its phenotype, with severe hypotonia, neonatal respiratory distress and feeding difficulties, is completely different from that of adult-onset type. Involvement of respiratory muscles may be the major cause of mortality in affected infants. Facial weakness with a tented upper lip is often recognized. If infants survive the neonatal period, muscle involvement symptoms gradually improve and most children do not require respiratory support or tube feeding. As CDM patients grow older, mental retardation or a developmental disorder becomes prominent. Furthermore, the main problems in childhood-onset DM, with an onset age under 10 years, are developmental disorders or learning disabilities, rather than muscle symptoms. Early meticulous support and cooperation with teachers are necessary. Medications such as methylphenidate may be helpful in DM1 children with attention deficit/hyperactivity disorder.
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TL;DR: In most families, age of onset tends to be similar, but in some families the disease occurs progressively earlier in successive generations, a phenomenon called anticipation.
Abstract: Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, which encodes an abnormally long polyglutamine repeat in the huntingtin protein. The disease is inherited in an autosomal dominant manner with age-dependent penetrance. CAG repeat lengths of 40 or more are associated with nearly full penetrance by age 65 years. HD typically occurs between 35 and 50 years of age. About 6% of cases have juvenile HD, defined as disease onset before the age of 20 (see Chap. 68). In most families, age of onset tends to be similar, but in some families the disease occurs progressively earlier in successive generations, a phenomenon called anticipation.
Journal Article•
TL;DR: In this family, the age of onset varies from 50 years to 50 years, and decreased in average 22,5 years over three generations, suggesting the phenomenon of anticipation.
Abstract: Introduction: Hereditary spastic paraplegia is a heterogeneous group of inherited neurodegenerative diseases, with a prevalence of 2/100000 in the Portuguese population. It is mainly characterized by progressive and insidious spasticity of the lower limbs due to degeneration of corticospinal tracts. Case Report: We present a child with progressive spasticity and hyperrefl exia of lower limbs, with several relatives of the paternal line with similar symptoms, suggesting the diagnosis of hereditary spastic paraplegia. A causing mutation of hereditary spastic paraplegia type 4 was identifi ed in the proband. Conclusion: In this family, the age of onset varies from fi ve to 50 years, and decreased in average 22,5 years over three generations. The clinical presentation and progression apparently tended to be more severe in successive generations, witch these suggests the phenomenon of anticipation.