Abstract
Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4–40.1)], 55% for duplication carriers [8.3 (1.4–55.5)]) and anxiety disorders (24% [1.8 (0.4–8.4)] and 55% [10.0 (1.9–71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.
Highlights
The microdeletion and the microduplication at 1q21(chr1: 146.57–147.39; GRCh37/hg19) are enriched in patients with schizophrenia (OR estimate for the deletion: 5.2; for the duplication: 2.9)[1] and in patients with intellectual disabilities (ID)/developmental delay (DD) and autism spectrum disorder (ASD) (OR estimate for the deletion: 35; for the duplication: 18)[2,3]
-duplication at this locus derived from UK Biobank are 0.027% and 0.044%, respectively[4] this may underestimate the true frequency in the population because more severely affected carriers are likely to be underrepresented in a middle-aged research cohort
The most prevalent NDD was ADHD both in children with the deletion (19/50 cases assessed for NDD; 38%) and children with the duplication (21/44 cases assessed for NDD; 47.7%)
Summary
The microdeletion and the microduplication at 1q21(chr1: 146.57–147.39; GRCh37/hg19) are enriched in patients with schizophrenia (OR estimate for the deletion: 5.2; for the duplication: 2.9)[1] and in patients with intellectual disabilities (ID)/developmental delay (DD) and autism spectrum disorder (ASD) (OR estimate for the deletion: 35; for the duplication: 18)[2,3]. The clinical phenotype of 1q21 deletion[5,6] and duplication[6] was originally established in clinical cohorts with intellectual disability, autism or congenital anomalies. A systematic review of 22 studies containing data from 59 children and 48 adults with the 1q21.1 duplication[7] reported high frequencies of neurodevelopmental problems including 50.8% for DD/ID, 35.6% for autism or autistic features and 8.5% for seizures. We wanted to ascertain whether mirror phenotypes—similar to the established dose effect on head size6— occur in the psychological domain and whether—and what type of— psychopathology was prevalent in an adult group largely composed of family carriers and not affected by the ascertainment bias of clinical samples
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