Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density, and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.

Assessment of emotions and behaviour by the Developmental Behaviour Checklist in young people with neurodevelopmental CNVs

Background A number of genomic conditions caused by copy number variants (CNVs) are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Although these patients also tend to have cognitive impairments, few studies have investigated the range of emotion and behaviour problems in young people with ND-CNVs using measures that are suitable for those with learning difficulties. Methods A total of 322 young people with 13 ND-CNVs across eight loci (mean age: 9.79 years, range: 6.02–17.91, 66.5% male) took part in the study. Primary carers completed the Developmental Behaviour Checklist (DBC). Results Of the total, 69% of individuals with an ND-CNV screened positive for clinically significant difficulties. Young people from families with higher incomes (OR = 0.71, CI = 0.55–0.91, p = .008) were less likely to screen positive. The rate of difficulties differed depending on ND-CNV genotype (χ2 = 39.99, p < 0.001), with the lowest rate in young people with 22q11.2 deletion (45.7%) and the highest in those with 1q21.1 deletion (93.8%). Specific patterns of strengths and weaknesses were found for different ND-CNV genotypes. However, ND-CNV genotype explained no more than 9–16% of the variance, depending on DBC subdomain. Conclusions Emotion and behaviour problems are common in young people with ND-CNVs. The ND-CNV specific patterns we find can provide a basis for more tailored support. More research is needed to better understand the variation in emotion and behaviour problems not accounted for by genotype.

Emotional and behavioural phenotypes in young people with neurodevelopmental CNVs

BackgroundA number of disorders caused by copy number variants (CNVs) are associated with a high risk of neurodevelopmental and psychiatric disorders and cognitive impairments (ND-CNVs). Few studies of ND-CNVs have investigated the emotional and behavioural problems that are important outcomes in young people with developmental and intellectual disabilities using appropriate measures.Methods322 young people with 13 ND-CNVs across eight loci (mean age:9.79 years, range:6.02-17.91, 66.5% male) took part in the study. Primary carers completed the Developmental Behaviour Checklist (DBC).ResultsSixty-seven percent of individuals with an ND-CNV screened positive for clinically significant difficulties. Young people from families with higher incomes (OR=0.71, CI=0.55 – 0.92, p=.009) were less likely to screen positive. Young people born after prolonged labour (OR=2.87, CI=1.18-8.13, p=.030) were more likely to screen positive. The rate of difficulties differed depending on ND-CNV genotype (Deviance=25.83, p=.011), with the lowest rate in 22q11.2 deletion (46%) and the highest in 1q21.1 deletion (87.5%). Individuals with inherited ND-CNVs had greater difficulties (F=6.54, df=1, p=.012, ηp2=.050), including higher self-absorbed (F=5.01, df=1, p=.027, ηp2=.039) and communication disturbance scores (F=9.13, df=1, p=.003, ηp2=.068). Specific patterns of strengths and weaknesses were found for different ND-CNV genotypes. However, ND-CNV genotype explained no more than 7-16% of variance, depending on subdomain.ConclusionsBehavioural and emotional problems are common in young people with ND-CNVs. The ND-CNV specific patterns we find can provide a basis for more tailored support. More research is needed to better understand the variation in behavioural and emotional problems not accounted for by genotype.