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van den Bree, M.

Publications and source records attributed to van den Bree, M..

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Information and genetic counselling for psychiatric risks in children with rare disorders

BackgroundThe diagnosis of developmental disorders is being transformed by advances in whole genome technologies. However, continuing uncertainties about the individual risks and potential severity of psychiatric impacts attributed to causal genomic variants limits the availability of comprehensive family-oriented information. In addition, there is insufficient evidence about how the parents of children with developmental disorders comprehend the facts and implications of their diagnosis through genetic counselling, nor how they gather developmental and mental health information to guide their understanding. MethodsParents of children (aged 0-17 years) referred to paediatric genetics services completed an anonymous online 46-item survey about: (i) the experience of attending services to receive their childs genetic diagnosis, and (ii) the availability, quality and helpfulness of information about psychiatric and neurodevelopmental conditions associated with genomic disorders. FindingsTwo-hundred and eighty-six families (199 UK and 87 USA) completed the survey. One-in-three UK and one-in-five US respondents were dissatisfied with how their childs genetic diagnosis was communicated. Satisfaction was predicted by face-to-face communication (odds ratio 2{middle dot}91 [95% CI 1{middle dot}43-5{middle dot}94]; p=0{middle dot}003); results being presented by genetics specialists (2{middle dot}97 [1{middle dot}41-6{middle dot}26]; p=0{middle dot}004); receiving clear explanations (5{middle dot}14 [2{middle dot}58- 10{middle dot}26]; p<0{middle dot}001); receiving support (2{middle dot}99 [1{middle dot}21-7{middle dot}36], p=0{middle dot}017); and male gender of the tested child (2{middle dot}56 [1{middle dot}28-5{middle dot}14]; p=0{middle dot}008). Compared to health-related information on developmental delay or intellectual disability, parents were more likely to obtain information about psychiatric manifestations from non-professional lay sources than from clinical specialists (p<0{middle dot}001). This was particularly evident for families in the UK compared to the USA (p<0{middle dot}001). Parents considered information from rare disorder support groups to be more helpful than from genetics specialists (odds ratio 11{middle dot}0 [95% CI 5{middle dot}08-86{middle dot}75]; p<0{middle dot}001), or paediatricians (11{middle dot}0 [1{middle dot}42-85{middle dot}20]; p=0{middle dot}006), or internet sites (15{middle dot}5 [3{middle dot}71-64{middle dot}77]; p<0{middle dot}001), which in turn proved more helpful than information provided by geneticists (2{middle dot}5 [1{middle dot}44-4{middle dot}31]; p=0{middle dot}001). InterpretationPsychiatric comorbidity is a common feature of rare genomic disorders, but the paucity of suitable information available from clinical specialists suggests families are not optimally informed about these challenges. Wider implementation of genomic testing in general medicine should include adequate training in genetic counselling to ensure best practice in communicating and explaining complex test results supported by comprehensive, family-oriented information. FundingThe Waterloo Foundation: Changing Minds Programme (506296); The Medical Research Council (MRC) Research Grant: Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (MR/N022572/1).

genetics

Genotype-phenotype relationships in children with copy number variants associated with high neuropsychiatric risk: Findings from the Intellectual Disability & Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study

BackgroundA variety of copy number variants are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Different ND-CNVs could lead to distinct and specific patterns of cognitive and behavioural outcomes, but supporting evidence is currently lacking. Methods258 children with ND-CNVs (13 CNVs across 9 loci) were systematically assessed for psychiatric disorders as well as broader traits of neurodevelopmental, cognitive and psychopathological origin. A comparison was made with 106 non-carrier control siblings, in order to test the hypothesis that phenotypes would differ by genotype, both quantitatively, in terms of severity, and qualitatively in the pattern of associated impairments. Outcomes79.8% of ND-CNVs carriers met criteria for one or more psychiatric disorders (OR=13.8 compared to controls): the risk of ADHD (OR=6.9), ODD (OR=3.6), anxiety disorders (OR=2.9), and ASD traits (OR=44.1) was particularly high. ND-CNVs carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits relative to controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. In general, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, however the specific genotype accounted for a low proportion of variance in outcome (5-20% depending on trait). InterpretationThe 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Our findings suggest that genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits, and provides important implications for research into genotype-phenotype relationships within psychiatry. FundingThe Medical Research Council and the Medical Research Foundation Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSeveral copy number variants (CNVs) have been associated with high risk of development of child and adult neuropsychiatric disorders. Increasingly young children with developmental delay referred for genetic testing are being diagnosed with neurodevelopmental and psychiatric risk CNVs (referred to as ND-CNVs hereafter). It remains unclear whether different genotypes are associated with specific cognitive and behavioural phenotypes or whether these outcomes are non-specific. We searched PubMed for studies published from database inception until January 10th, 2019 that investigated the relationship between CNVs and cognitive and behavioural outcomes. Search terms included "CNV", "genomics", "1q21.1", "2p16.3", "NRXN1", "9q34", "Kleefstra Syndrome", "15q11.2", "15q13.3", "16p11.2", "22q11.2", "psychiatry", and "cognition". Preliminary studies have indicated that deletions and duplications at the same loci may differ in cognitive and behavioural phenotypes. However, to date, there have been limited studies that contrasted the phenotypes of ND-CNVs across several loci on a range of cognitive and behavioural domains. Added value of this studyWe found that young people carrying a ND-CNV were at considerably increased risk for neuropsychiatric disorder and impairments across a range of neurodevelopmental, psychopathological, cognitive, social, sleep and motor traits. Within ND-CNV carriers, comparisons between genotypes indicated moderate quantitative and qualitative differences in overall phenotypic profile, with evidence that severity of impairment was similar across all genotypes for some traits (e.g. mood problems, sleep impairments, peer problems, and sustained attention) whereas for other traits there was evidence of genotype specific effects on severity (e.g., IQ, spatial planning, processing speed, subclinical psychotic experiences, ASD traits, motor coordination total psychiatric symptomatology, particularly anxiety, ADHD, and conduct related traits). However the proportion of variance explained by genotype was low, 5-20% depending on trait, indicating that overall ND-CNVs lead to similar neurodevelopmental outcomes. It is important that genotype-phenotype relationships are viewed through a developmental lens as some phenotypic outcomes were found to be associated with age. Implications of all the available evidenceChildren who carry a ND-CNV represent a patient group that warrants clinical and educational attention for a broad range of cognitive and behavioural impairments. Although qualitative and quantitative differences exist between ND-CNVs, our findings point to commonalities in clinical outcomes with neurodevelopmental impairments being present across all ND-CNVs. This group of young people could benefit from the development of a general intervention plan, to which genotype-specific recommendations can be added where needed. Our findings do not support a model whereby different ND-CNVs represent discrete forms of neuropsychiatric disorder and suggest that multiple processes and neural circuits are affected by ND-CNVs. The pleiotropic effects of ND-CNVs emphasises that research aiming to identify causal pathways between genetic variation and psychiatric outcomes via intermediary (or endo-)phenotypes needs to take a global perspective and not be narrowly focused on single phenotypes.

genomics