Following A.Reymond’s article (Copy number variations and cognitive phenotypes in unselected populations. JAMA 313(20):2044–2054), an other article mentioning his group’s researches was recently published in AJMG:
original publication: http://www.ncbi.nlm.nih.gov/pubmed/26010633
COPY NUMBER VARIANTS LINKED TO INTELLECTUAL DISABILITY, LESS EDUCATION
Study shows even moderate genetic duplications, deletions can affect cognitive ability
Some 10% of people carry medium- sized duplications or deletions of DNA that can lower cognitive ability, according to an observational study by Swiss researchers.
A genome-wide evaluation of rare duplications and deletions—also called copy number variants (CNVs)— conducted on presumptively healthy individuals from an Estonian population biobank found that 10.5% of 7,877 people studied had CNVs of between 250 and 499 thousand base pairs (kb), reports a recent study in JAMA (Männik et al., 2015).
These carriers had increased prevalence of intellectual disability and a lower than average level of academic achievement. Overall, 33.5% of deletion carriers and 39.1% of duplication carriers did not graduate from high school, compared with 25.3% of the Estonian population at large.
In contrast to many studies on the genetics of neurodevelopmental disorders that involve acutely affected clinic patients and large CNVs of 1 million base pairs (1 Mb) or more, this study looked for smaller CNVs in a large, randomly selected sample of presumptively healthy individuals, says the study’s senior author, Alexandre Reymond, PhD, Associate Professor of Genomics at University of Lausanne in Switzerland.
“The way you look for carriers of variants impacts severity of cases you get,” says Dr. Reymond. “Carriers of CNVs known to be associated with disease in general population in many cases do have phenotypes.”
Dr. Reymond’s team used a database of more than 50,000 Estonians who provided blood samples and answered more than 1,000 health and lifestyle questions during routine visits with physicians. In all, the researchers identiﬁed 56 carriers of recurrent, large CNVs associated with known syndromes, or one of every 141 people studied.
The researchers identiﬁed many CNV carriers who had milder versions of phenotypic features found in symptomatic individuals in previous clinical studies. For example, the researchers found 11 individuals who carried CNVs in 16p11.2 and had mild versions of an associated phenotype including abnormal head circumference and body mass index, lower IQ, and neurodevelopmental symptoms.
Overall, 5% of carriers of deletions of at least 250 kb and 5.9% of carriers of duplications of at least l Mb had an intellectual disability, compared with 1.7% of the Estonian cohort without detected CNVs, the study notes.
To support the association between rare, intermediate-size CNVs and lower educational attainment, the researchers analyzed additional nonclinical cohorts, including a group of intellectually high- functioning Estonians and distinct populations in the United Kingdom and the United States. In the United Kingdom population, intermediate-size and large CNVs were associated with lower scores on tests of English and math skills given to 13 and 14 year olds, while the U.S. study found lower IQ scores for siblings and twins with such CNVs.
Children who are carriers of copy number variants of DNA, which can affect intellectual ability, are less likely to achieve higher levels of education, recent research suggests.
Carriers of CNVs may not really be asymptomatic, notes Dr. Reymond. In many cases, people who harbor medium- sized CNVs may represent the least severe end of a phenotypic spectrum, he explains. This ﬁnding may call for a shift in thinking about CNV carriers.
“The presence of measurable deleterious phenotypes in the identiﬁed individuals suggests that the assumption that carriers of known syndromic CNVs identiﬁed in health population cohorts are asymptomatic may not be appropriate,” says an editorial by James R. Lupski, MD, PhD, Professor in the Program in Translational Biology & Molecular Medicine at Baylor College of Medicine in Houston.
Christian Schaaf,MD,PhD,postulates that someone with a medium-sized CNV inherited from a parent could end up with a more severe phenotype if he or she has a second mutation, especially in a gene that affects brain development. That parent may, upon closer examination, have mild clinical features, says Dr. Schaaf, Assistant Professor in the Department of Molecular and Human Genetics at Baylor College of Medicine.
“Someone may have cognitive or psychological issues, but he or she can deal with them and are considered normal,” adds Santhosh Girirajan, MBBS, PhD, Assistant Professor, Department of Biochemistry and Molecular Biology, Pennsylvania State University in State College. “Sometimes you need another mutation within the same region or a different region in the genome to get a more serious phenotype.”
Gender-Based Mutational Burden Researchers found that females were not only more likely than males to carry deletions but also carried larger deletions, in general, than males. The ﬁnding supports what other studies have called the “female- biased mutational burden” (Jacquemont et al., 2014). The term refers to females’ need to accumulate more genetic damage than males to show apparent neurodevelopmental defects, allowing females to be enrolled in general population cohorts even if they carry rare CNVs. Males with similar mutations are likely excluded from such studies because they are part of neurodevelopmental clinical populations, Reymond et al. write.
The studies by Dr. Reymond’s team and Jacquemont et al. underscore the importance of gathering detailed family histories from parents, particularly mothers who appear phenotypically normal but upon closer examination may exhibit the same features as their children but in very mild form, Dr. Girirajan suggests.
“Ask parents if there’s any family history of neurodevelopmental or psychiatric disorders,” adds Dr. Girirajan. “A parent may be surviving below the threshold [for a disorder. But] if a kid has the same mutation and another mutation nearby, the child may be more greatly affected.”
Jacquemont S, Coe BP, Hersch M, Duyzend MH, Krumm N, Bergmann S, Beckmann JS, Rosenfeld JA, Eichler EE. 2014. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am J Hum Genet 94(3): 415–425.
Männik K, Mägi R, Macé A, Cole B, Guyatt AL, Shihab HA, Maillard AM, Alavere H, Kolk A, Reigo A, Mihailov E, Leitsalu L, Ferreira AM, Nõukas M, Teumer A, Salvi E, Cusi D, McGue M, Iacono WG, Gaunt TR, Beckmann JS, Jacquemont S, Kutalik Z, Pankratz N, Timpson N, Metspalu A, Reymond
2015. Copy number variations and cognitive phenotypes in unselected populations. JAMA 313(20):2044–2054.
DOI: 10.1002/ajmg.a. 37284
2015 Wiley Periodicals, Inc.