Marianne B.M. van den Bree
Psychological Medicine and Clinical Neurosciences, Cardiff University, UK
Genetic conditions with high risk of neurodevelopmental disorder.
1) The complex phenotypic presentation: Comparisons between young people with ND-CNVs and controls indicate considerably increased risk of psychiatric disorder (OR=13.8, p<.001), including ADHD (OR=6.9, p<.001), anxiety disorder (OR=2.9, p=.015) and oppositional defiant disorder (OR=3.6, p=.012). Furthermore, these young people are considerably more likely to screen positive for autism spectrum disorder (OR=44.1, p<.001).
Difficulties in other domains such as cognition, motor coordination and sleep are also common and a complex phenotypic presentation involving multiple domains is present in many of these young people. In those not meeting diagnostic criteria for a neurodevelopmental condition, subthreshold difficulties are still likely to be present. For example, we found that 32% of young people with deletion or duplication of 16p11.2 or 22q11.2 meet criteria for autism, but that an additional 38% meet the clinical cut-off for at least one of the three domains measured to establish an autism diagnosis.
2) The longitudinal development of mental health: These mental health problems tend persist over time. For young people with 22q11.2 deletion (one of the strongest known biological risk factors for developing schizophrenia) certain childhood traits (e.g., anxiety and difficulties with attention and executive function) predict the emergence of prodromal psychotic features in adolescence.
3) Comparison of the phenotypic presentation across different ND-CNVs: Certain phenotypic domains are particularly impaired across all ND-CNVs, in comparison to controls, including ADHD and autism-related traits, motor coordination and general functioning. Degree of impairment is more variable across ND-CNVs in other domains, such as cognition, mood, sleep and anxiety. Overall, our findings point towards greater convergence than divergence in the phenotypic presentation, possibly indicating different ND-CNVs impact on similar brain pathways.
Conclusion: Children tend to be diagnosed with a ND-CNV at a young age and given their high risk of development of mental health and other problems, early monitoring and timely intervention is warranted.
Marianne van den Bree is a Professor in Psychological Medicine in the School of Medicine at Cardiff University. She initiated and leads a large longitudinal research programme of individuals with rare Copy Number Variants (CNVs; chromosomal micro-deletions or - duplications) associated with greatly increased risk of neurodevelopmental and psychiatric conditions (ND-CNVs) and their family members. This research programme has been supported by funding from the Wellcome Trust, Medical Research Council UK, National Institutes of Mental Health USA, and the European Union, amongst others.
Professor van den Bree has a background is in psychology, human genetics and epidemiology/methodology. Her longitudinal ND-CNV research programme combines detailed wide-ranging multi-informant assessments with genetic, pharmacological and brain imaging studies to investigate risk of development of mental health disorder. Patients are recruited through all UK Medical Genetics clinics.
Professor van den Bree has extensive experience playing lead roles in international consortia, including the 22q11.2DS International Brain and Behavior Consortium (IBBC)(Leader of one of Five Coordinating Sites, Executive Committee Member), the International Genes to Mental Health (G2MH) Consortium, and the pan-EU MINDDS Consortium (Leader of one of five Working Groups). She leads one of two Work Packages of the IMAGINE-ID study (>3,400 UK families affected by ND-CNV recruited). She is also a PI within the Mental Health NIMH Rare Genetic Disease Network (MHRGDN) Steering Committee, Wales National Centre for Mental Health (NCMH) and MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG).