The role of tissue-specific imprinting as a source of phenotypic heterogeneity in human disease

Genomic imprinting is an epigenetic phenomenon affecting a small number of genes that leads to expression from only one parental allele. Several imprinted genes are important for neurologic development and function and several neurobehavioral disorders are caused by genetic defects involving imprinted genes. For some genes, the imprinting is tissue specific, leading to biallelic expression in some tissues and monoallelic expression in other tissues. Defects involving these genes may produce one restricted phenotype due to loss of expression of the gene product in tissues where the gene is imprinted and, in some instances, a second phenotype due to haploinsufficiency of the gene product in tissues where it is biallelically expressed.     

Behavioural and cognitive abnormalities in an imprinting centre deletion mouse model for Prader–Willi syndrome

The genes in the imprinted cluster on human chromosome 15q11–q13 are known to contribute to psychiatric conditions such as schizophrenia and autism. Major disruptions of this interval leading to a lack of paternal allele expression give rise to Prader–Willi syndrome (PWS), a neurodevelopmental disorder with core symptoms of a failure to thrive in infancy and, on emergence from infancy, learning disabilities and over‐eating. Individuals with PWS also display a number of behavioural problems and an increased incidence of neuropsychiatric abnormalities, which recent work indicates involve aspects of frontal dysfunction. To begin to examine the contribution of genes in this interval to relevant psychological and behavioural phenotypes, we exploited the imprinting centre (IC) deletion mouse model for PWS (PWS‐IC^+/?) and the five‐choice serial reaction time task (5‐CSRTT), which is primarily an assay of visuospatial attention and response control that is highly sensitive to frontal manipulations. Locomotor activity, open‐field behaviour and sensorimotor gating were also assessed. PWS‐IC^+/? mice displayed reduced locomotor activity, increased acoustic startle responses and decreased prepulse inhibition of startle responses. In the 5‐CSRTT, the PWS‐IC^+/? mice showed deficits in discriminative response accuracy, increased correct reaction times and increased omissions. Task manipulations confirmed that these differences were likely to be due to impaired attention. Our data recapitulate several aspects of the PWS clinical condition, including findings consistent with frontal abnormalities, and may indicate novel contributions of the imprinted genes found in 15q11–q13 to behavioural and cognitive function generally.     

Atp10a, a gene adjacent to the PWS/AS gene cluster, is not imprinted in mouse and is insensitive to the PWS-IC

Mutations affecting a cluster of coordinately regulated imprinted genes located at 15q11-q13 underlie both Prader–Willi syndrome (PWS) and Angelman syndrome (AS). Disruption of the predominately maternally expressed UBE3A locus is sufficient to meet diagnostic criteria for AS. However, AS patients with a deletion of the entire PWS/AS locus often have more severe traits than patients with point mutations in UBE3A suggesting that other genes contribute to the syndrome. ATP10A resides 200 kb telomeric to UBE3A and is of uncertain imprinted status. An initial report indicated bialleleic expression of the murine Atp10a in all tissues, but a subsequent report suggests that Atp10a is predominantly maternally expressed in the hippocampus and olfactory bulb. To resolve this discrepancy, we investigated Atp10a allelic expression in the brain, DNA methylation status, and sensitivity to mutations of the PWS imprinting center, an element required for imprinted gene expression in the region. We report that Atp10a is biallelically expressed in both the newborn and adult brain, and Atp10a allelic expression is insensitive to deletion or mutation of the PWS imprinting center. The CpG island associated with Atp10a is hypomethylated, a result consistent with the notion that Atp10a is not an imprinted gene.     

The prevalence of aggression in genetic syndromes: A review

Research into behavioural phenotypes identifies both environmental and organic factors as influencing aggression in children and adults with genetic disorders associated with intellectual disability. However, in contrast to self-injury there is a paucity of research that compares aggression across relevant syndromes. The primary aim of this review is to examine the association between aggression and genetic syndromes by analysis of prevalence studies. The review also examines the literature on the form of the behaviour and influence of environmental factors.Results imply that certain syndrome groups (Cri du Chat, Smith-Magenis, Prader-Willi, Angelman, Cornelia de Lange, and Fragile X syndromes; estimates over 70%) evidence a stronger association with aggression than others (e.g. Williams and Down syndromes; estimates below 15%). However, the strength of association is difficult to quantify due to methodological differences between studies. The results from examining form and environmental influences highlight the importance of phenotype–environment interactions. Research employing group comparison designs is warranted and future work on the assessment and intervention of aggression in genetic syndromes should consider the importance of phenotype–environment interactions.     

Distinctiveness and correlates of maladaptive behaviour in children and adolescents with Smith–Magenis syndrome

This two-part study examines the distinctiveness and correlates of maladaptive behaviour in 35 children and adolescents with Smith–Magenis syndrome, a developmental disorder caused by an interstitial deletion of chromosome 17 (p11.2). Study I compares Child Behavior Checklist scores in 35 children with Smith–Magenis syndrome to age- and gender-matched subjects with Prader–Willi syndrome and mixed intellectual disability. Subjects with Smith–Magenis syndrome had significantly higher levels of maladaptive behaviour than the other groups. Although some problems were shared across groups, 12 behaviours differentiated the three groups with 100% accuracy. Study 2 assessed the frequency and correlates of self-injurious and stereotypical behaviours, including unusual features such as nail-yanking, inserting objects into bodily orifices, self-hugging and a ‘lick-and flip’ behaviour. Nail-yanking and bodily insertions were less common than other types of self-injury, and self-hugs and the ‘lick-and flip’ stereotypies were seen in about half the sample. Although age and degree of delay were correlated with problem behaviours, sleep disturbance emerged as the strongest predictor of maladaptive behaviour. The implications are discussed for clinical diagnostic ambiguities between the Smith–Magenis and Prader–Willi syndromes, and for intervention.     

Imprinted gene expression in the brain

In normal mammals, autosomal genes are present in duplicate (i.e. two alleles), one inherited from the father, and one from the mother. For the majority of genes both alleles are transcribed (or expressed) equally. However, for a small subset of genes, known as imprinted genes, only one allele is expressed in a parent-of-origin dependent manner (note that the 'imprint' here refers to the epigenetic mechanism through which one allele is silenced, and is completely unrelated to classical 'filial imprinting' manifest at the behavioural level). Thus, for some imprinted genes expression is only (or predominantly) seen from the paternally inherited allele, whilst for the remainder, expression is only observed from the maternally inherited allele. Early work on this class of genes highlighted their importance in gross developmental and growth phenotypes. Recent studies in mouse models and humans have emphasised their contribution to brain function and behaviour. In this article, we review the literature concerning the expression of imprinted genes in the brain. In particular, we attempt to define emerging organisation themes, especially in terms of the direction of imprinting (i.e. maternal or paternal expression). We also emphasise the likely role of imprinted genes in neurodevelopment. We end by pointing out that, so far as discerning the precise functions of imprinted genes in the brain is concerned, there are currently more questions than answers; ranging from the extent to which imprinted genes might contribute to common mental disorders, to wider issues related to how easily the new data on brain may be accommodated within the dominant theory regarding the origins and maintenance of imprinting, which pits the maternal and paternal genomes against each other in an evolutionary battle of the sexes.     

Developmental aspects of sleep in Prader Willi Syndrome

Background : Children with Prader Willi syndrome (PWS) are at risk of sleep disordered breathing involving central and obstructive components. PWS patients are known to have abnormal responses to hypoxia and hypercapnoea, an increased incidence of Obstructive Sleep Apnoea [OSA] and hypersomnolence when older. As infants, many present with delay in central control of breathing during sleep and resultant hypoxia. This may have long term consequences for the phenotype. Methods : Polysomnography (PSG) and multiple sleep latency testing [MSLT] was performed on PWS children attending a multidisciplinary clinic. Sleep disorders and age of presentation were identified. EEG spectral analysis on infants was undertaken and compared to a group of typically developing infants. Genotype was established. Results : Results suggest that in children less than 2 years central hypoventilation is present in 100%. 10% of children older than five had normal studies and the rest had OSA+/central hypoventilation. 10% had central hypoventilation and hypersomnolence. Twenty‐five children under 12 months of age were analysed separately. Improvements in central hypoventilation were seen in some infants as they matured. The relationship between this and development of mature EEG patterns was examined and is significantly different to EEG spectral analysis of normal infants studied at 3, 6 and 12 months. This was also related to the genotype of each infant. Conclusion : Infants with Prader Willi have a delay in neural maturity as reflected by EEG development of defined EEG sleep stages. All infants with Prader Willi should have a sleep study in infancy and appropriate therapy instigated if required. Hypersomnolence is generally associated with other sleep disorders.     

Prader-Willi and Angelman syndromes: update on genetic mechanisms and diagnostic complexities

Significant advances have been made in determining the genetic basis of the Prader-Willi and Angelman syndromes; disorders in which genomic imprinting is abnormal. These advances will be instrumental in unravelling the pathogenesis that underlies these neurobehavioural disorders.     

Affective psychosis and Prader–Willi syndrome

Previous studies have demonstrated that maladaptive behaviours are common amongst adults with Prader–Willi syndrome (PWS). Case reports have also previously demonstrated that psychosis can occur amongst adults with PWS. The present study was undertaken in order to gain a better understanding of the psychopathology of the psychosis of PWS. Twentythree out of 25 adults identified with PWS living in Northamptonshire, UK, agreed to participate. Comprehensive psychiatric assessments (using the PPSLD), and measures of adaptive and maladaptive behaviours (using the AAMR-ABS) were completed. Comparisons were made for the prevalence of psychiatric disorders against those from a previous epidemiological study of adults with intellectual disability of other aetiologies from a neighbouring county. The PWS group was found to have higher rates of affective disorders (a point prevalence of 17.4%), in which psychotic symptoms were common, but similar rates of schizophrenia/delusional disorders (4.3%) compared with the comparison group. Behaviour disorders were also common. Surprisingly, none of the PWS group was found to have generalized anxiety or phobic disorders. The diagnostic criteria for the episodes including psychotic symptoms are explored. The high rates of affective disorders is of clinical (i.e. treatment) importance as well as being of academic interest with regard to the genetics of psychiatric disorders.