NEURODEVELOPMENTAL COPY NUMBER VARIANTS AND CLINICAL RISK: A PEDIATRIC RECORD POPULATION STUDY

Background Chromosomal Copy Number Variants (CNVs) associated with schizophrenia also carry etiological risk for neurodevelopmental disorders, including autism and intellectual deficiency. It is not known however what is their risk for any disorders. Here we applied well-replicated ‘neurodevelopmental’ CNVs (NRXN1 del, MYT1L dup, 15q13.3 del/dup, 16p11.2 del/dup, and 22q11.2 del/dup) and interrogated their frequency and overall clinical penetrance for broad categories of disorder in a general pediatric population. Methods Eight selected CNVs were screened utilizing TaqMan within a population sample of 60,644 pediatric patients. CNV carriers were examined with respect to pre-scored digitized pediatric records and compared to records for a 5:1 non-carrier control group matched for each individual CNV. Prevalence for 12 clinical categories were estimated. Results Seven of these CNVs (NRXN1 (del), MYT1L (dup), 22q11 (dup), 16p11 (dele/dup), and 15q11.3 (del/dup)) were detected in the pediatric population at expected rates based on large control population studies. Having any CNV predicted an increase for two of the 12 disease categories after Bonferroni correction: Nervous system (p=1.43×10-5) and mental/neurodevelopmental disorder (p=2.9×10-10), and were associated with greater cost of medical care. Individual CNVs were examined in relation to their matched non-carriers for previously described associated disorders. As anticipated, 15q13.3 deletion was associated with mental/neurodevelopmental disorders, and 16p11 deletion was associated with congenital deficits, CNS disorders and mental/neurodevelopmental disorders. 16p11 deletion carriers showed more circulatory disorders than their matched non-carriers. Finally, in addition to association with mental and congenital defects, a significant association was found between 22q11 duplication and pediatric gastrointestinal reflux (p=0.0037) which was more likely to be present in the presence of developmental delay (interaction p=0.0362). Discussion These findings extend previous clinically based studies providing a high prediction of risk for 16p11.2 deletion, 15q13.3 deletion and 22q11.2 duplications. A broader concept of overall clinical penetrance is important for understanding the pathophysiology of these disorders and may inform genetic counseling. To our knowledge, this is the first report of a CNV association (22q11 duplication) for pediatric GERD, which may represent a delay in vagal nerve maturation, and first report of a 16p11 deletion associated with circulatory disorders.