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16p11.2 duplication, reciprocal deletion have similar effect on cognition

The mean effect of 16p11.2 duplication on cognition was similar to that of reciprocal deletion; however, duplication had significantly higher variance, partly due to additional genetic and familial factors, according to recent findings.

“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. 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,” Debra D’Angelo, MS, of Mailman School of Public Health, Columbia University, New York, and colleagues wrote.

To study the effects of the 16p11.2 duplication on cognitive, behavioral, medical and anthropometric traits, researchers compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers and 244 deletion controls from European and North American cohorts. Full-Scale IQ (FSIQ), Nonverbal IQ and Verbal IQ scores, presence of ASD or other DSM-IV diagnoses, BMI, head circumference and medical data were assessed.

Duplication was associated with a mean FSIQ score that was 26.3 points lower between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2 to 11.4 points) among nonproband carriers.

The mean overall effect of deletion was similar, according to researchers (–22.1 points; P < .001).

Researchers found broad variation in FSIQ, with a 19.4-fold and 2-fold increase in the proportion of very low and higher than the mean FSIQ scores, compared with the deletion group (P < .001).

Part of this variation was predicted by parental FSIQ, according to researchers.

Frequency of ASD was similar among deletion and duplication proband carriers (16% vs. 20%), however, FSIQ was significantly lower (by 26.3 points) among duplication proband carriers with ASD.

Duplication carriers had lower head circumference and BMI, consistent with previous findings.

“One of the most remarkable features of the report is its serious attempt to integrate findings across different areas of assessment. This feat is not even attempted in many reports. The reader not only learns that distributions of IQ in deletions and duplications are shifted downward from intrafamilial control individuals but can follow the associations between decreases in IQ and other features, from ASD to seizures to gross motor delays to BMI to head circumference,” Catherine Lord, PhD, and Jeremy Veenstra-VanderWeele, MD, of Weill Cornell Medical College, New York–Presbyterian Hospital, White Plains, New York, wrote in an accompanying editorial. “As geneticists become more familiar with psychometric data, the need to consider cognitive defects when measuring many behavioral domains and neurologic risk is increasingly being recognized.” – by Amanda Oldt

Disclosure: D’Angelo and colleagues report no relevant financial disclosures. Lord reports receiving royalties from Western Psychological Services for publication of autism-related instruments. All profits are given to charity. Please see the full study for a list of all authors’ relevant financial disclosures.