Showing papers on "Anticipation (genetics) published in 2013"

Molecular Genetics and Genetic Testing in Myotonic Dystrophy Type 1

Abstract: Myotonic dystrophy type 1 (DM1) is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation, from asymptomatic adults to severely affected neonates. A striking anticipation and parental-gender effect upon transmission are distinguishing genetic features in DM1 pedigrees. It is an autosomal dominant hereditary disease associated with an unstable expansion of CTG repeats in the 3′-UTR of the DMPK gene, with the number of repeats ranging from 50 to several thousand. The number of CTG repeats broadly correlates with both the age-at-onset and overall severity of the disease. Expanded DM1 alleles are characterized by a remarkable expansion-biased and gender-specific germline instability, and tissue-specific, expansion-biased, age-dependent, and individual-specific somatic instability. Mutational dynamics in male and female germline account for observed anticipation and parental-gender effect in DM1 pedigrees, while mutational dynamics in somatic tissues contribute toward the tissue-specificity and progressive nature of the disease. Genetic test is routinely used in diagnostic procedure for DM1 for symptomatic, asymptomatic, and prenatal testing, accompanied with appropriate genetic counseling and, as recommended, without predictive information about the disease course. We review molecular genetics of DM1 with focus on those issues important for genetic testing and counseling.

Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability

Abstract: Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder caused by a noncoding ATTCT pentanucleotide expansion. An inverse correlation between SCA10 expansion size and age at onset has been reported, and genetic anticipation has been documented. Interruptions in the ATTCT expansion are known to occur within the expansion. In order to determine the effect of repeat interruptions in SCA10 expansions, we designed a PCR assay to easily identify ATCCT repeat interruptions in the 5′-end of the expansion. We screened a cohort of 31 SCA10 families of Mexican, Brazilian and Argentinean ancestry to identify those with ATCCT repeat interruptions within their SCA10 expansions. We then studied the effects of ATCCT interruptions on intergenerational repeat instability, anticipation and age at onset. We find that the SCA10 expansion size is larger in SCA10 patients with an interrupted allele, but there is no difference in the age at onset compared with those expansions without detectable interruptions. An inverse correlation between the expansion size and the age at onset was found only with SCA10 alleles without interruptions. Interrupted expansion alleles show anticipation but are accompanied by a paradoxical contraction in intergenerational repeat size. In conclusion, we find that SCA10 expansions with ATCCT interruptions dramatically differ from SCA10 expansions without detectable ATCCT interruptions in repeat-size-instability dynamics and pathogenicity.

Telomere length and genetic anticipation in Lynch syndrome.

Abstract: Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.

Possible anticipation associated with a novel splice site mutation in episodic ataxia type 2

Abstract: Anticipation is a phenomenon characterized by decreasing age at onset and increasing severity of symptoms of a disease in successive generations within a pedigree. Anticipation mostly occurs in neurodegenerative diseases with expansion of unstable trinucleotide repeats. However, it has not been previously pointed out in episodic ataxia type 2 (EA2). Clinical and genetic analyses were performed in nine members from three consecutive generations of a Korean family with EA2. We performed a polymerase chain reaction (PCR)-based direct sequence analysis of all coding regions of CACNA1A using genomic DNA. The clinically affected family members showed recurrent vertigo, interictal nystagmus, and childhood epilepsy. There is a decrease in the age onset (possible genetic anticipation) in three succeeding generations of the family. Genetic analysis identified a splice site mutation (p.Val1465Glyfs13X) and normal trinucleotide repeats in CACNA1A in all clinically affected and one unaffected members. Recognizing anticipation would aid in genetic counseling in EA2.

Increased clinical anticipation with maternal transmission in benign adult familial myoclonus epilepsy in Japan.

Abstract: We recently reported clinical anticipation in Japanese families with benign adult familial myoclonus epilepsy (BAFME). However, it remains unknown whether clinical anticipation is predominantly associated with paternal or maternal transmission. We investigated the relationship between gender of the transmitting parent and clinical anticipation in nine BAFME families. Clinical anticipation regarding either cortical tremor or generalised seizures was observed in all 12 parent/child pairs (8 mother/child pairs and 4 father/child pairs). Moreover, a higher degree of clinical anticipation was associated with maternal transmission than with paternal transmission (p=0.03). Although a causative gene for BAFME still remains unknown, 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.

Mutations at the SLC20A2 gene and brain resilience in families with idiopathic basal ganglia calcification ("Fahr's disease").

Abstract: Wang et al. (2012) recently identified seven novel mutations at the SLC20A2 gene in families from China, Spain and Brazil, suggesting that Familial Idiopathic Basal Ganglia Calcification (IBGC) might be a phosphate imbalance disorder. Expressing wild-type human SLC20A2 and the mutated variants, using transport assays in Xenopus oocytes, resulted in significant impaired Pi transport. On the other hand, mutants did not have an obvious effect on the Pi transport activity when co-expressed with the wild-type PiT2 protein, encoded by SLC20A2. This suggests that such mutations have an effect through haploinsufficiency (Wang et al., 2012). Additional analysis showed that this gene is responsible for ~50% of the familial cases (Hsu et al., 2013; Lemos et al., 2013). More recently, two French families with IBGC were reported with mutations at the platelet derived growth factor receptor B (PDGFRB) gene, opening now a new venue for the comprehension of this phenotype as being caused by different molecular failures in mechanisms of vascular homeostasis (Nicolas et al., 2013). Familial or sporadic IBGC, often called by the misnomer “Fahr's Disease,” is a neuropsychiatric disorder with variable clinical outcome, including parkinsonism, psychosis, dementia and headaches. The diagnosis criteria include bilateral calcifications, often documented with computerized tomography, in the absence of hormonal and metabolic imbalances. Such subjects are often misdiagnosed as patients with schizophrenia, Parkinson's disease, bipolar Disorder, and Alzheimer's disease (Manyam, 2005; Lemos et al., 2011). Calcifications might also be detected in cerebellum, thalamus and cortex. The mode of inheritance of IBGC is mainly reported in literature as autosomal dominant, sometimes displaying anticipation, a phenomenon widely described in diseases with similar pattern of inheritance and first reported in familial IBGC by Geschwind et al. (1999). Families affected with IBGC also show a variable clinical manifestation and a lack of full penetrance. Recent functional studies aiming to access the expression profiles of SLC20A2 at the kidney, have reported that the expression of this gene is tightly linked to inorganic phosphate (Pi) concentration into the organism. Moreover, together with SLC20A1, these genes act at the Pi uptake under different conditions of pH and dietary Pi (Villa-Bellosta et al., 2009). Calcification is an unspecific biochemical process occurring normally even under physiological conditions, through phosphate deposition and hydroxyapatite crystals formation, similar to the mineral fraction of the bones. However, disturbances in this process, which are often related to phosphate transport alterations at epithelial cells of blood vessels, lead to calcification around these tissues, jeopardizing the vessels' elasticity and leading to arteriosclerosis as well (Villa-Bellosta and Sorribas, 2011). Curiously, Wang et al. (2012) and other authors also reported subjects with calcifications but no symptoms. Brain resilience for such lesions is still the most compelling challenge for the complete understanding of the pathological mechanisms of IBGC and others autosomal dominant neuropsychiatric conditions. Argylean et al. (2009) used neuroimaging techniques to assess the cerebellumthalamocortical connectivity (CbTC) in individuals with dystonia and compared these data with that was yielded by the analysis of this same circuit in control individuals and asymptomatic carriers of mutations for dystonia. Their analysis showed reduced integrity of cerebellothalamocortical fiber tracts, in both clinically manifesting and nonmanifesting mutation carriers. In these subjects, reductions in cerebellothalamic connectivity were associated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Nonmanifesting mutation carriers displayed an additional area of fiber tract disruption, distally situated along the thalamocortical segment, in tandem with a proximal cerebellar outflow abnormality. In individual gene carriers, clinical penetrance was determined by the difference in connectivity measured at these two sites. Other approaches to investigate the lack of full penetrance in genetic traits have been based on functional studies using the one-thousand-cells nematode Caenorhabditis elegans. These analyses state that this phenomenon may occur due to mitigating mechanisms involving “genetic interaction partners,” that is, genes involved in common molecular networks (Burga et al., 2011). On this perspective, two molecular mechanisms have been described: the first one involves a high expression of homologous genes, which because of its similar coding sequence, still bears related functions, enabling them to play the role which should have been done by the damaged gene. The other mechanism involves Heat Shock Proteins, which, by folding proteins into its biologically active conformation, ends up attenuating the effects of mutations along the peptidic sequence (Burga et al., 2011). The haploinsufficiency effect described by Wang et al. (2012) when expressing SLC20A2 mutations in Xenopus oocites lead us to speculate that in asymptomatic carriers of those deleterious mutations must have an altered pattern of expression of paralog genes. This assumption would be in accordance with the first mechanism described by Burga and colleagues (2011). Functional studies in model organisms may be able to test this hypothesis. Previous studies with clinical heterogeneity of familial IBGC shows that ~40% of the patients carrying basal ganglia calcification do not show symptoms. We reported previously that symptoms were present in only 28 patients with IBGC, from a total of 47 subjects with calcifications detected during a linkage analysis of 6 families (Oliveira et al., 2003). This suggests that the brain might have mechanisms to handle calcifications and the first symptoms outcome (resilience), however, we cannot exclude the possibility that we are still missing the precocious detection due to less sensitive clinical findings. On the other hand, it is well established that studies measuring the total volume of calcification shows far more deposits in symptomatic individuals compared to asymptomatic subjects (Manyam, 2005). We suggest considering two levels of penetrance in IBGC: one for the calcification formations and another for the clinical manifestation but only a proper follow-up of asymptomatic subjects with calcifications will detect the exact timing of the appearance the first symptoms and will define the limits of brain resilience to calcifications. An animal model will most likely provide this answer. The concept of brain resilience is intrinsically associated to IBGC pathophysiology, since this is the most probable mechanism underlying the absence of clinical manifestations pathogenic SCL20A2 mutation carriers. This lack of concordance between the genetic and phenotypic statuses, gives rise to the probabilistic concept of penetrance in human genetics, that is, the likelihood of a given damaging genotype turns out to develop a clinical entity in its carriers. As for IBGC, the concept of incomplete penetrance should be further elaborated, in order to better categorize phenotipically the individuals present in a given heredogram. On this perspective, we propose the term “radiological penetrance.” Imaging genetics is a promising strategy to integrate genotypic and phenotypic data and more studies—especially those focusing brain imaging in asymptomatic IBGC carriers—are necessary to properly test such hypotheses.

Age at Death of Creutzfeldt-Jakob disease in subsequent family generation carrying the E200K mutation of the prion protein gene.

Abstract: Background The E200K mutation of the prion protein gene (PRNP) is the most frequent amino acid substitution in genetic Creutzfeldt-Jakob disease and is the only one responsible for the appearance of clustered cases in the world. In the Israel and Slovakian clusters, age of disease onset was reduced in successive generations but the absence of a clear molecular basis raised the possibility that this event was an observational bias. The aim of the present study was to investigate possible selection biases or confounding factors related to anticipation in E200K CJD patients belonging to a cluster in Southern Italy.

Dunnigan-type familial partial lipodystrophy associated with the heterozygous R482W mutation in LMNA gene — case study of three women from one family

Abstract: Lipodystrophies are a heterogeneous group of diseases affecting adipose tissue distribution. Familial partial lipodystrophy of the Dunnigantype (FPLD) is a rare autosomal, dominant disorder caused by missense mutations in lamin A/C (LMNA) gene where selective loss of subcutaneous adipose tissue from the limbs and trunk, and accumulation of fat in the neck and face, is usually associated with a variety of metabolic disorders including insulin resistance, diabetes mellitus, dyslipidemia, hepatic steatosis and high blood pressure.In this report we present clinical and molecular features of three Polish women with FLPD phenotype coming from one family (a motherand her two daughters). FPLD was recognised under the circumstances of diabetes treatment, where sequencing of LMNA gene revealed heterozygous R482W mutation. In order to be able to recognise monogenic diabetes associated with lipodystrophy, it is important to bevery precise in physical examination while diagnosing diabetes and to be aware of the necessity of performing genetic testing. Diabetes appropriate differential diagnosis is essential for the treatment strategy, anticipation of the disease progression, and determination of the prognosis. It is necessary for an individual mutation carrier to look carefully at the patient's family.

Genetics of Dyskeratosis Congenita

Abstract: Dyskeratosis congenita (DC) is a rare, inherited, skin and bone marrow failure disease. It is a multisystem disorder which is heterogeneous at the genetic and clinical levels. Genetically, nine genes have so far been identified whose mutation causes DC, and inheritance of the disease can be X linked, autosomal dominant or recessive. Clinically, the disease can present in childhood as classical DC with a characteristic triad of nail dystrophy, leukoplakia and abnormal skin pigmentation along with progressive bone marrow failure. More severe forms presenting in infancy and milder forms in adults, as aplastic anaemia or pulmonary fibrosis, exist. All forms of the disease with known pathogenesis are due to failure of telomere maintenance, often leading to stem cell exhaustion. Recent progress in the identification of mutations in human syndromes has revealed that DC overlaps clinically and genetically with a number of other rare syndromes. Key Concepts: The major cause of death in DC is bone marrow failure. The most common form of DC is X linked. In the X-linked form, females are not, or very mildly, affected, but they show extremely skewed X-inactivation, with cells expressing the mutated gene being outgrown by cells expressing the wild type gene. Dyskeratosis congenita is a disease caused by defective telomere maintenance. Nine genes have been discovered to cause dyskeratosis congenita when mutated, and their products are involved in telomerase and its assembly or as part of the telomere. When the disease is caused by mutations in the core components of telomerase, TERT and TERC families show an increase in severity of the disease in later generations, a phenomenon known as genetic anticipation. Genetic anticipation is due to shortening of telomeres from one generation to the next. Some DC mutations are also known causes of pulmonary fibrosis, liver fibrosis and Coats retinopathy. Now that genes responsible for rare syndromes are being discovered, it is becoming evident that there is overlap between DC and several other rare syndromes that have been described. Keywords: telomerase; telomere; dyskerin; TERC; TIN2; Hoyeraal Hreidarsson; anticipation; pulmonary fibrosis; aplastic anaemia; telomere length

Multiple endocrine neoplasia type 2A: case report.

Abstract: Multiple endocrine neoplasia type 2A (MEN 2A) is a complex autosomal dominant inherited syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary parathyroid hyperplasia. In patients with only one or two clinical features, identification of a germline RET(REarranged in Transfection) mutation or the identification of the clinical features of MEN 2A in other first degree relatives is required to make the diagnosis. We present the case of a family with MEN 2A syndrome confirmed by genetic analysis which identified RET gene mutation in 634 codon in father - DV - aged 48 years and also in daughter DM -aged 20 years. The specific feature in this case is that the index case was the daughter (diagnosed and operated for pheochromocytoma at the age of 19 years), the father being diagnosed later with medullary thyroid carcinoma by mutational screening in all family members. This family supports the phenomenon of anticipation, in which severity increases and the age of onset decreases in successive generations, the syndrome being discovered earlier and with a worse prognostic in the daughter.

A Novel DYT-5 Mutation with Phenotypic Variability within a Colombian Family.

Abstract: Background : DYT‐5 dystonia usually presents as a dopa‐responsive dystonia (DRD) with early or late parkinsonian manifestations and/or dystonic features. Genetically, these patients have been described as having a wide array of independent mutations in the guanosine triphosphate cyclohydrolase 1 gene (GCH1), and these patients may also have a wide array of clinical manifestations. Methods : A Colombian family with six affected female members was characterized. Results : Three members, including the index case, revealed mild parkinsonism, whereas three granddaughters of the index case showed severe generalized dystonia. No men were affected. There was anticipation, and a female predominance was uncovered. Treatment with levodopa was generally effective except in a case with severe skeletal deformities and contractions. Detailed genetic analysis in the index case revealed a new mutation in exon 1 of GCH1 (c.159delG). Discussion : This study revealed a new mutation of GCH1 that resulted in heterogeneous clinical presentations of DRD within a large family.

Apparent anticipation in SOD1 familial amyotrophic lateral sclerosis.

Abstract: Although anticipation has been previously reported in the copper/zinc superoxide dismutase-1 (SOD1) associated familial amyotrophic lateral sclerosis (FALS), some have argued that this may represent ascertainment bias. Consequently, the aim of the present study was to determine whether anticipation was a feature in SOD1 FALS. From a cohort of 112 individuals, the clinical and genetic history of 34 SOD1 patients was assessed. Clinical history was collected with the age of death and disease duration determined in successive generations (generation 1, grandparent; generation 2, parents; generation 3, children), from five large SOD1 families. Results showed that the age of death was significantly less in generation 3 (40.1 ± 2.8 years) compared to generation 2 (46.2 ± 2.0 years, p < 0.05) and generation 1 (56.7 ± 4.5 years, p < 0.01). Furthermore, disease duration was longer in generation 1 (18.4 ± 3.7 months) compared to the disease duration in generation 2 (12.6 ± 2.6 months) and generation 3 (12.3 ± 1.9 months, p = 0.08). Positive intergenerational differences were evident in 92% of parent-offspring transmissions in the present SOD1 FALS cohort (c(2) = 70.6, p < 0.001). In conclusion, the present study supports anticipation as a phenomenon in FALS, possibly due to co-inheritance of modifier genes.

Spinocerebellar ataxia type 7: Report of an Indian family

Abstract: Spinocerebellar ataxia type 7 (SCA7) is a form of autosomal dominant cerebellar ataxia which is associated with pigmentary retinal degeneration. It is known for its world-wide rarity except in the Scandinavian countries. It is very rarely reported from India and the neighbouring Asian countries . The present report describes the neurogenetic findings of a family of SCA7, from the northern part of Karnataka in South India. It documents the wide intrafamilial phenotypic variability, which could be correlated with the CAG repeat counts and phenomenon of anticipation. Genotype phenotype correlation highlighted certain disparities in comparison with the previous studies. The report highlights the need for multiethnic population studies and the role of genetic counseling and prenatal testing in SCA7 patients.

Investigating parent of origin effects (POE) and anticipation in Irish Lynch Syndrome kindreds.

Abstract: 431 Background: Genetic diseases associated with dynamic mutations often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Genetic anticipation describes the progressively earlier onset and increased severity of disease in successive generations of a family. Previous studies have provided limited evidence for and against both POE effect and anticipation in Lynch syndrome. We sought evidence for a specific POE effect and anticipation in Irish Lynch syndrome families. Methods: Affected parent-child pairs (APCPs) (N = 53) were evaluated from kindreds (N = 20) from two hospital-based registries of MMR mutation carriers. POE were investigated by studying the ages at diagnosis in the offspring of affected parent-child pairs. Anticipation was assessed using the bivariate Huang and Vieland model. Results: Paired t-test revealed anticipation with children developing cancer mean 11.8 years earlier than parents, and 12.7 ...

Anticipación genética en familias cubanas con acné conglobata. Genetic anticipation in Cuban families with acne conglobata.

Abstract: Acne conglobata is a serious acne variant having a multifactorial etiology. The identification of this disease in five families of the eastern Cuban region contributed evidences of its genetic anticipation existence; though, its frequency, intensiveness, or those factors influencing or determining it are unknown. This work was aimed at characterizing the genetic anticipation phenomenon in Cuban families having acne conglobata. A descriptive study in a 37 patients sample with acne conglobata was carried out. The disease was diagnosed based on clinical criteria. Meaningful differences were found for the starting age of the disease for patients among generations (χ2= 12,86; p=0,025). The anticipation showed a 100 % frequency and its value varied between 2 and 32 years with a mean value equal to 13,04±8,85 years. Neither the sex of the progenitor transmitter of the disease (p=0,801), nor his/her conceptional age (p=0,197), nor the sex of the offspring (p=0,20), significantly influenced on genetic anticipation. The genetic anticipation in Cuban families affected by acne conglobata was demonstrated and also that it was neither influenced by the sex of the diseasetransmitter progenitor, nor by his/hers conceptional age or the offspring sex.

Location, interaction, and anticipation of aneurysm formation.

Abstract: It is well established that family members of those individuals with intracranial aneurysm are at high risk of intracranial aneurysms. In the past several years, more information on the heritability of location, familial susceptibility to cigarette smoking, and whether “anticipation” of aneurysm formation has been published. We review these three topics in detail and summarize what we gathered from this information.