Main Genetic Subtypes Research Articles

Genetic Subtypes and Status of Transmitted Drug Resistance of HIV/AIDS Patients in Sichuan

To investigate the distribution characteristics of the HIV genetic subtypes and the status quo of transmitted drug resistance among HIV/AIDS patients in Sichuan with no previous history of receiving antiretroviral therapy (ART). Adult HIV/AIDS patients who were hospitalized in Sichuan and who had no previous history of exposure to ART drugs exposure were enrolled. In-house sequencing of the HIV gene was done and phylogenetic tree was constructed to analyze the HIV genetic subtypes. The Stanford HIV drug resistance database was used to make online comparison of the drug resistance mutation sites and to determine the presence or absence of drug resistance, and the type and level of drug resistance. A total of 120 patients were enrolled for the study, and 120 blood samples were collected. The genetic subtypes of 87.5% (105/120) of the samples were successfully amplified. The distribution characteristics of HIV genotype were as follows, CRF01_AE accounted for 46.67% (49/105), CRF07_BC accounted for 39.05% (41/105), and the others genetic subtypes, 14.28% (15/105). There were no significant differences between the different genetic subtypes in sex, age, ethnicity, HIV transmission route, drug resistance, baseline HIV RNA and baseline CD4 ( P>0.05). Drug-resistant mutation sites were detected in 25 samples, accounting for 20.83% (25/120) of all samples, with 16.67% (20/120) being potential drug resistance and 4.17% (5/120) being transmitted drug resistance. For the 24 samples found to be resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs), the mutation frequency of V179D/E was the highest. One patient showed resistance to protease inhibitors (PI) and the mutation site was M46I. No nucleoside reverse transcriptase inhibitor (NRTI) or integrase inhibitors (INTI) resistance were found. The main genetic subtypes of HIV/AIDS patients in Sichuan with no previous history of receiving ART were CRF01_AE and CRF07_BC. The incidence of transmitted drug resistance was low. The drug resistance detected in the study was predominantly resistance to NNRTIs. Baseline HIV drug resistance testing is of great significance for formulating effective ART regimens.

Diffuse large B-cell lymphoma genetics - simplifying the subtyping.

Diffuse large B-cell lymphoma genetics - simplifying the subtyping.

Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches.

Prader-Willi syndrome (PWS) is a neuro-developmental genetic disorder due to lack of expression of genes inherited from the paternal chromosome 15q11-q13 region with three main genetic subtypes. These include paternal 15q11-q13 deletion (about 70% of cases), maternal uniparental disomy 15 or both 15s from the mother (20-30% of cases), and defects in the imprinting center (1-3%) which controls the expression of imprinted genes in this chromosome region. Clinical manifestations include infantile hypotonia with a poor suck resulting in failure to thrive, short stature, small hands/feet and hypogonadism/hypogenitalism due to growth and other hormone deficiencies, hyperphagia and excessive weight gain with obesity and cognitive and behavioral problems including obsessive compulsions, tantrums and self-injury. The phenotype is likely related to hypothalamic dysfunction. Hyperphagia and obesity with related complications are major causes of morbidity and mortality in PWS requiring accurate diagnosis, appropriate medical management and treatment; the major objective of our report. An extensive review of the literature was undertaken including genetics, clinical and behavioral aspects, and updated health-related information addressing the importance of early diagnosis and treatment of individuals with Prader-Willi syndrome. A searchable, bulleted and formatted list of topics related to this obesity syndrome was provided utilizing a Table of Contents approach for the clinical practitioner. Physicians and other health care providers can use this review with clinical, genetic and treatment summaries divided into sections that are pertinent in the context of clinical practice. Finally, frequently asked questions by clinicians, families and other interested participants will be addressed.

Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings.

IntroductionPrader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. There are three main genetic subtypes in PWS: paternal 15q11-q13 deletion (65–75 % of cases), maternal uniparental disomy 15 (20–30 % of cases), and imprinting defect (1–3 %). DNA methylation analysis is the only technique that will diagnose PWS in all three molecular genetic classes and differentiate PWS from Angelman syndrome. Clinical manifestations change with age with hypotonia and a poor suck resulting in failure to thrive during infancy. As the individual ages, other features such as short stature, food seeking with excessive weight gain, developmental delay, cognitive disability and behavioral problems become evident. The phenotype is likely due to hypothalamic dysfunction, which is responsible for hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency. Obesity and its complications are the major causes of morbidity and mortality in PWS.MethodsAn extensive review of the literature was performed and interpreted within the context of clinical practice and frequently asked questions from referring physicians and families to include the current status of the cause and diagnosis of the clinical, genetics and endocrine findings in PWS.ConclusionsUpdated information regarding the early diagnosis and management of individuals with Prader-Willi syndrome is important for all physicians and will be helpful in anticipating and managing or modifying complications associated with this rare obesity-related disorder.

Relationship between the IQ of people with Prader–Willi syndrome and that of their siblings: evidence for imprinted gene effects

Genetic disorders occasionally provide the means to uncover potential mechanisms linking gene expression and physical or cognitive characteristics or behaviour. Prader-Willi syndrome (PWS) is one such genetic disorder in which differences between the two main genetic subtypes have been documented (e.g. higher verbal IQ in one vs. higher performance IQ in the other; slower than normal reaction time in one vs. normal in the other). In a population study of PWS, the IQ distribution of people with PWS was approximately normal. This raises the question of whether this distribution arose from a systematic effect of PWS on IQ (hypothesis 1) or whether it was the fortuitous result of random effects (hypothesis 2). The correlation between PWS and sibling IQ was determined in order to discriminate between the two hypotheses. In the first case we would expect the correlation to be similar to that found in the general population (0.5); in the second case it would be zero. It was found that the overall PWS-sibling IQ correlation was 0.3 but that the two main genetic subtypes of PWS differed in their familial IQ relationships. As expected, the IQs of normal siblings correlated 0.5, and this was also the case with one genetic subtype of PWS (uniparental disomy) and their siblings, while the other subtype IQ correlated -0.07 with sibling IQ. This is a potentially powerful result that gives another clue to the role of genes on chromosome 15 in the determination of IQ. It is another systematic difference between the genetic subtypes of PWS, which needs an explanation in terms of the very small genetic differences between them.

Dorsal and ventral stream mediated visual processing in genetic subtypes of Prader–Willi syndrome

Previous work has suggested that there are specific deficits in dorsal stream processing in a variety of developmental disorders. Prader-Willi syndrome (PWS) is associated with two main genetic subtypes, deletion and disomy. Relative strengths in visual processing are shown in PWS, although these strengths may be specific to the deletion subtype. We investigated visual processing in PWS using an adapted Simon task which contrasted location (dorsal stream) and shape identity (ventral stream) tasks. Compared to a group of typically developing children, children with PWS deletion showed a greater degree of impairment in the dorsal stream task than in the ventral stream task, a pattern similar to that shown in a group of boys with Fragile-X syndrome. When matched on a measure of non-verbal ability, children with PWS disomy showed the opposite pattern with better performance in the location compared to the shape task, although these task performance asymmetries may have been linked to executive control processes. It is proposed that children with PWS deletion show a relative strength in visual processing in the ventral stream along with a specific deficit in dorsal stream processing. In contrast, children with PWS disomy show neither effect.

Individuals with Prader-Willi Syndrome and Their Perceptions of Skin-Picking Behaviour

(2008). Individuals with Prader-Willi Syndrome and Their Perceptions of Skin-Picking Behaviour. The British Journal of Development Disabilities: Vol. 54, No. 107, pp. 123-130.

Survival of Genetic Subtypes of Relapsed Myeloma May Be Modulated by Secondary Events.

The biological heterogeneity of myeloma can be largely explained by genetic subtypes characterized by primary translocations (t(4;14), t(11;14), and t(14;16)) or trisomies of odd-numbered chromosomes (hyperdiploid myeloma). In newly diagnosed patients, it is well established that these genetic subtypes have different survival. However, the prevalence and survival of the main genetic subtypes in relapse patients is unknown. In this study, we examined the prevalence and survival according to TC classes (a gene expression-based classification system which identifies the main genetic subtypes of myeloma) in patients with relapsed myeloma entered into bortezomib trials who had gene expression profiling (GEP) performed as part of a pharmacogenomics study (Bortezomib cohort). In comparison, we analyzed a large publicly available GEP dataset of newly diagnosed patients treated with total therapy II from the University of Arkansas for Medical Science (UAMS cohort, GEP data available on Gene Expression Omnibus, Zhan et al Blood 2006 epub). GEP was performed using the U133A and B chip for the bortezomib cohort and U133plus chip for the UAMS cohorts (Affymetrix, Santa Clara, CA). For both dataset, raw gene expression were log-transformed, median centered and analyzed using Genespring 7.0 (Agilent Technologies, Palo Alto, CA). A proliferation index (PI) based on the expression of 7 genes (TYMS, TOP2A, CCNB1, KIAA0101, CKS1B, UBE2C, TRIP13) was also calculated. As shown previously (Mulligan et al ASH 2005 abstract) the prevalence of the different TC classes in relapse patients was very similar to newly diagnosed patients (Chi-square p=0.25). In the bortezomib cohort, patients with t(11;14) had the worst survival when compared to patients with t(4;14), maf translocation and hyperdiploidy who had similar survival (survival of t(11;14) versus others, log-rank p=0.036). In contrast, among newly diagnosed patients (UAMS cohort) those with t(4;14) and maf translocations had the worst prognosis, whereas t(11;14) and hyperdiploid patients had the best prognosis (log-rank p=0.02). This interesting contrast in the prognosis within these main genetic subtypes of myeloma at diagnosis and relapse suggest that at relapse, the survival of these patients may be modulated by secondary events or possibly the treatment received. Indeed, a greater proportion of relapsed t(11;14) have a high PI (Chi-square p = 0.04) than newly diagnosed t(11;14). In contrast, there is no difference between the PI of newly diagnosed and relapsed hyperdiploid MM (TC D1, p=0.19). Our observations suggest that although the composition of the various genetic subtypes at diagnosis and relapse appear similar, the prognosis of some subtypes (especially t(11;14)) can be markedly different at relapse when modulated by secondary events (e.g. increase proliferation) whereas others (such as hyperdiploid MM) appear to behave similarly at diagnosis and relapse. Our observation also has important therapeutic implications as it suggests relapsed t(11;14) should be treated aggressively and drug combinations or addition of new agents may be more appropriate. Conversely, bortezomib seemed to be an effective therapy in relapse t(4;14) patients, improving the prognosis of these patients to that of genetic subgroups with good prognosis. Our study highlights the fact that different treatment strategies may be needed for newly diagnosed and relapsed patients even within same genetic subtypes.

Changing rates of genetic subtypes of Prader–Willi syndrome in the UK

The genetically determined neurodevelopmental disorder, Prader-Willi syndrome (PWS), has two main genetic subtypes: a 15q11-q13 deletion affecting the paternally inherited chromosome 15 and chromosome 15 maternal uniparental disomy (mUPD) in which two maternal copies of chromosome 15 are inherited but no paternal copy. It has been accepted that these subtypes occur in approximately 70 and 25% of cases, respectively. This is the first report of a greater proportion (50%) of those with PWS due to mUPD in children presently under 5 years living in the UK. Increasing maternal age at conception is likely to explain the changing proportions in this generation of mothers.

An investigation of executive function abilities in adults with Prader–Willi syndrome

Prader-Willi syndrome (PWS) is a genetic disorder caused by the absence of expression of maternally imprinted genes on the long arm of chromosome 15 (15q 11-13). There are two main genetic sub-types: (1) deletion, caused by the absence of paternally derived genetic material; and (2) uniparental disomy (UPD), where two copies of maternally derived chromosome 15 are present. In addition to generally mild/borderline intellectual disability (ID) and the almost universal feature of hyperphagia, PWS is associated with high rates of behaviour problems including temper tantrums, compulsive behaviour, perseverative speech, skin picking and rigid thinking. The present study seeks to explore whether these behaviours are associated with relative deficits in executive function (EF), which comprises the set of non-automatic processes utilized by an individual when faced with a novel situation. Eighteen adult participants with a clinical diagnosis of PWS (12 with deletion sub-type, 6 with UPD) were recruited from a UK Health Service PWS clinic, and compared with 15 participants of similar age and verbal ability on a series of EF tasks and also Digit Span Forwards. An informant completed two ratings of behaviour, the Aberrant Behavior Checklist (ABC) and the Dysexecutive Questionnaire (DEX). The PWS group had significantly higher scores on the ABC but not on the DEX. There were no significant differences between the whole PWS group and the comparison group on any of the EF tasks. The deletion sub-type group was significantly poorer at a non-executive task, Digit Span Forwards. There was an unexpected trend for the deletion sub-type group to show more efficient performance on a visuospatial planning task, the Tower of London (TOL), but this trend did not reach significance. The lack of relative deficits in EF task performance does not support the hypothesis that EF differences could account for the high levels of behaviour problems found in PWS. Applying the Baddeley and Hitch model of working memory it is suggested that the PWS group have a relatively intact central executive and visuospatial sketchpad but a relative impairment in the phonological loop, perhaps relating to the capacity of the phonological store. This latter finding seems to be particularly salient for those with a deletion. As differences in EF ability were not found, it is suggested that a region of the brain involved in the modulation of emotion but not particularly with EF, the orbitofrontal cortex (OFC), may be implicated in the behaviour problems reported in PWS.

Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by extreme floppiness at birth, impaired sexual development, short stature, severe over-eating, characteristic physical features and learning disabilities (LD). Impaired social cognition, literal mindedness and cognitive inflexibility are also present. The syndrome has two main genetic subtypes that both result in the failure of expression of maternally imprinted genes on chromosome 15 at the locus q11-13. Through multiple sources, we attempted to identify all people with PWS living in one health region in the UK. Additional people with PWS identified in other regions were also recruited to augment the study sample. A comparison group of people with LD as a result of aetiologies other than PWS was also identified. All people from these three groups, over age three, who gave their consent, were assessed using tests of ability and attainment. In addition, their main carers were interviewed using a semistructured interview. Blood samples for genetic diagnosis were obtained from all consenting participants. The IQ distribution of the population sample was approximately normal with a mean IQ 40 points below that of the general population. There were systematic differences between the two main genetic subtypes. Those with disomies differed in cognitive profiles from both those with deletions and the comparison LD group (the latter two groups were very similar) in terms of better verbal abilities and impaired coding ability. Some people with PWS deletions had strong visuospatial skills. We propose that the normal distribution of IQ, shifted downwards relative to that of the general population, is the result of a global effect on IQ of the PWS gene(s), and that the different cognitive profile seen in those with chromosome 15 maternal disomies is a specific effect of a gene, or genes, on chromosome 15 which is differentially either expressed or not expressed in those with disomies relative to those with deletions. One hypothesis is that these subtle cognitive differences are a manifestation of the genetic influences of gender-specific imprinted genes on cerebral lateralization. This requires further investigation.