Copy number variations in neurodevelopmental disorders

Common neurodevelopmental disorders (including autism, speech and language delay, schizophrenia, epilepsy and intellectual disability) have complex aetiology, which is predominantly genomic, but also environmental in origin. They share a paradox, in that high heritability is matched by lowered fecundity, placing them under negative genetic selection. This implicates variants of recent origin, such as de novo mutations or common, very low-risk polymorphisms that escape negative selection. High or moderate risk variants have been discovered by chromosome analysis, genome sequencing and copy number variant (CNV) detection, including a 3Mb deletion causing 22q11.2 deletion syndrome (Velo-Cardio-Facial Syndrome) that has penetrance of up to 50% for schizophrenia. More recently, rare, recurrent and often de novo pathogenic CNVs, including deletions at NRXN1, 1q21.2, 15q11.2 and 15q13.3, 16p11.2 and duplications at VIPR2 and 16p13.11, have also been discovered. These have several unique features that differentiate them from Mendelian disease mutations in that they have incomplete penetrance, with moderate-to-high odds ratios for risk, and show diagnostic pleiotropy, increasing risk across the neurodevelopmental disorder spectrum. Some are also syndromic, with characteristic features such as facial dysmorphology, and other specific risks such as aortic dissection or obesity, implying that they might be better classified as distinct diagnoses. The discovery of pathogenic CNVs provide new opportunities for translation leading to patent benefit, including improvements in clinical genetic diagnosis and genetic counselling, the possibility of clinician decision-making tools for risk prediction, and the identification of drug targets and implementation of personalised medicine using stratification by genotype.