To understand mental disorders, we must quantify the specific effect of each contributing gene mutation.’ — Dr. Sébastien Jacquemont, geneticist.
No autism is alike. This is also true of most mental disorders. “We now understand that each gene mutation has a specific effect, which adds to other effects to draw a unique picture of the disease in each patient,” said Dr. Sébastien Jacquemont, a geneticist who sees on a daily basis children who are referred to him for a potential genetic diagnosis of mental disorder such as autism. To understand this additive effect, a precise quantification of the effect each identified mutation has in these patients is necessary. “We have just discovered, for example, that a missing copy of a region in chromosome 16 results in a 25-point intelligence quotient (IQ) drop in carriers. Addition of a copy in the same genomic region results in an approximate 16-point drop. Strangely enough, even if carriers show much differentiated sets of symptoms – and sometimes no symptoms at all – the specific effect of these two mutations seems to remain the same,” said Jacquemont, who is a clinical researcher at CHU Sainte-Justine, the mother-child hospital affiliated to University of Montreal, where he is also professor. Together with international collaborators, the scientist authored an article in the renowned scientific journal JAMA Psychiatry.
To reach these conclusions, the researchers measured the intelligence of 700 family members who had at least one relative carrying the same genetic mutation on chromosome 16, which is known to predispose to autistic spectrum disorders. Even in study participants whose IQ was considered to be normal, the researchers found a substantial 25 points IQ drop induced by 16p11.2 gene deletions. Indeed, it is quite common for mutation carriers to show no mental health problems.
“Intellectual faculties are the sum of many factors, the majority of which are genetic and inherited from parents. Each first-degree relative – parents and offspring, siblings – has 50% of their genetic code in common and therefore 50% of the genetic factors that partially determine cognition,” said Dr. Jacquemont. Studying families thus enabled the researchers to measure the factors that combine with the mutations which effects they wanted to quantify. “For example, depending on the additional factors involved, a 25-point IQ drop can determine whether or not a person has crossed the threshold of ‘intellectual disability.”
Further studies are needed to quantify the effect of all mutations associated with autism and characterize the additive effects that lead to this psychiatric disorder. “No single mutation can cause the whole set of clinical signs shown by these patients,” concludes the scientist.
Dr. Sébastien Jacquemont is a clinician-geneticist at CHU Sainte-Justine and associate professor in the Department of Pediatrics at the University of Montreal.
Funding: This work is financially supported through a career award from the Swiss National Science Foundation.
Source: William Raillant-Clark – University of Montreal
Image Credit: The image is credited to United States Department of Energy and is in the public domain
Original Research: Abstract for “Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities” by Debra D’Angelo, MS; Sébastien Lebon, MD; Qixuan Chen, PhD; Sandra Martin-Brevet, MS; LeeAnne Green Snyder, PhD; Loyse Hippolyte, PhD; Ellen Hanson, PhD; Anne M. Maillard, PhD; W. Andrew Faucett, MS; Aurélien Macé, MS; Aurélie Pain, MS; Raphael Bernier, PhD; Samuel J. R. A. Chawner, MA; Albert David, MD; Joris Andrieux, MD, PhD; Elizabeth Aylward, MD; Genevieve Baujat, MD; Ines Caldeira, MD; Philippe Conus, MD; Carrina Ferrari, MS; Francesca Forzano, MD; Marion Gérard, MD; Robin P. Goin-Kochel, PhD; Ellen Grant, MD; Jill V. Hunter, MD; Bertrand Isidor, MD, PhD; Aurélia Jacquette, MD; Aia E. Jønch, MD3; Boris Keren, MD; Didier Lacombe, MD; Cédric Le Caignec, MD, PhD; Christa Lese Martin, PhD; Katrin Männik, PhD; Andres Metspalu, PhD; Cyril Mignot, MD; Pratik Mukherjee, MD; Michael J. Owen, PhD; Marzia Passeggeri, MD; Caroline Rooryck-Thambo, MD; Jill A. Rosenfeld, PhD; Sarah J. Spence, MD, PhD; Kyle J. Steinman, MD; Jennifer Tjernagel, MS; Mieke Van Haelst, MD; Yiping Shen, PhD; Bogdan Draganski, MD; Elliott H. Sherr, MD, PhD; David H. Ledbetter, PhD; Marianne B. M. van den Bree, PhD; Jacques S. Beckmann, PhD; John E. Spiro, PhD; Alexandre Reymond, PhD; Sébastien Jacquemont, MD; Wendy K. Chung, MD, PhD ; for the Cardiff University Experiences of Children With Copy Number Variants (ECHO) Study, the 16p11.2 European Consortium, and the Simons Variation in Individuals Project (VIP) Consortium in JAMA Psychiatry. Published online January 2016 doi:10.1001/jamapsychiatry.2015.2123
Abstract
Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities
Importance The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI).
Objectives To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD.
Design, Setting, and Participants This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives.
Main Outcomes and Measures Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data.
Results Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (–22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies.
Conclusions and Relevance The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.
“Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities” by Debra D’Angelo, MS; Sébastien Lebon, MD; Qixuan Chen, PhD; Sandra Martin-Brevet, MS; LeeAnne Green Snyder, PhD; Loyse Hippolyte, PhD; Ellen Hanson, PhD; Anne M. Maillard, PhD; W. Andrew Faucett, MS; Aurélien Macé, MS; Aurélie Pain, MS; Raphael Bernier, PhD; Samuel J. R. A. Chawner, MA; Albert David, MD; Joris Andrieux, MD, PhD; Elizabeth Aylward, MD; Genevieve Baujat, MD; Ines Caldeira, MD; Philippe Conus, MD; Carrina Ferrari, MS; Francesca Forzano, MD; Marion Gérard, MD; Robin P. Goin-Kochel, PhD; Ellen Grant, MD; Jill V. Hunter, MD; Bertrand Isidor, MD, PhD; Aurélia Jacquette, MD; Aia E. Jønch, MD3; Boris Keren, MD; Didier Lacombe, MD; Cédric Le Caignec, MD, PhD; Christa Lese Martin, PhD; Katrin Männik, PhD; Andres Metspalu, PhD; Cyril Mignot, MD; Pratik Mukherjee, MD; Michael J. Owen, PhD; Marzia Passeggeri, MD; Caroline Rooryck-Thambo, MD; Jill A. Rosenfeld, PhD; Sarah J. Spence, MD, PhD; Kyle J. Steinman, MD; Jennifer Tjernagel, MS; Mieke Van Haelst, MD; Yiping Shen, PhD; Bogdan Draganski, MD; Elliott H. Sherr, MD, PhD; David H. Ledbetter, PhD; Marianne B. M. van den Bree, PhD; Jacques S. Beckmann, PhD; John E. Spiro, PhD; Alexandre Reymond, PhD; Sébastien Jacquemont, MD; Wendy K. Chung, MD, PhD ; for the Cardiff University Experiences of Children With Copy Number Variants (ECHO) Study, the 16p11.2 European Consortium, and the Simons Variation in Individuals Project (VIP) Consortium in JAMA Psychiatry. Published online January 2016 doi:10.1001/jamapsychiatry.2015.2123
