In the field of autism spectrum disorders (ASDs), diagnostic instruments have been helpful in defining populations,¹ merging samples,² and comparing results across studies.^3,4 Nevertheless, best-estimate clinical (BEC) diagnoses have long been the gold standard.^5-7 In single-site studies, BEC diagnoses have added information to standardized instruments to predict later diagnoses^8,9 and classify children according to developmental trajectories of adaptive and language functioning.^10,11 However, researchers have recently expressed skepticism about the scientific and clinical value of categorical ASD groupings in the DSM-IV-TR¹² and the International Statistical Classification of Diseases, 10th Revision¹³ (ie, autistic disorder, pervasive developmental disorder–not otherwise specified [PDD-NOS], Asperger syndrome), on which BEC diagnoses are based.^5,14,15

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

The 600-kilobase (kb) break points 4 and 5 (BP4-BP5) 16p11.2 deletion and duplications (chr16; 29.6-30.2 megabase) are among the most frequent genetic causes of autism spectrum disorder (ASD), schizophrenia, and other neurodevelopmental disorders.^1-5 These reciprocal copy number variants (CNVs) are associated with mirror phenotypes of obesity and being underweight and with increased and decreased global and regional brain volumes in deletion and duplication carriers, respectively.^6-8 Previous studies^5,9 have demonstrated that ASD is diagnosed in approximately 18% of deletion carriers and that this CNV affects global cognition by shifting the IQ approximately 2 SDs without altering the variance. To our knowledge, such studies have not been conducted for the reciprocal duplication. Akin to duplications of other genomic regions, case series^10-18 have reported variable expressivity and suggested incomplete penetrance; however, incomplete penetrance was recently ruled out after recalling carriers identified in unselected populations.¹⁹ This phenotypic variability and the limited available data underscore the need to systematically characterize the clinical impact of the duplication with standardized assessments in large numbers of carriers.