Given the neuropsychiatric risk and previously identified associations with head circumference
6], a clear next step is to determine if and how brain structure, as measured through
magnetic resonance imaging (MRI), is affected in patients carrying 16p11.2 CNVs. Because
this is a rare variant with high penetrance, it is useful for the study of known broad-spectrum
disease phenotypes in relatively small sample sizes and in largely control populations;
in turn, this has the advantage of enabling researchers to investigate the effect
of the variation without their results being confounded by differences in medication
or the altered environment of a patient. Two studies 1],2] have recently measured macro-scale brain structure via MRI in individuals with 16p11.2
deletion (N?=?27, N?=?14, respectively) and duplication (N?=?17, N?=?17, respectively), most of whom had not been diagnosed with either schizophrenia
or ASD. Given the rarity of the mutation and the hypothesized large effects on the
brain, these should be considered relatively large sample sizes.
Both studies find large global differences in intracranial volume and total white
and gray matter volumes; deletion carriers have larger volumes and duplication carriers
have smaller volumes relative to controls. Both studies find an effect in the same
direction on cortical surface area, but less evidence is found for alterations in
cortical thickness. This dichotomy is consistent with a developmental change in the
formation of the brain. The radial unit hypothesis predicts that this type of abnormality
in cortical surface area could be due to a greater number of neural progenitors being
produced during fetal development in deletion carriers, which then differentiate to
create a cortical plate with a larger surface area 9]. The replicable findings of high effect across two cohorts give strong support to
this developmental mechanism. In addition, these studies identify a phenotype that
stem cell or animal models of the 16p11.2 mutation can attempt to replicate, and subsequently
to correct through drug screening.
When studying chromosomal effects on the structure of specific brain regions, the
picture becomes more complicated. One of the strongest findings was an effect on thalamic
volume, which was greater in deletion carriers and smaller in duplication carriers
in both studies, even after controlling for a global measure of head size (intracranial
volume). Overall cerebellar volume showed the same relationship in one study 1], but specific regions of the cerebellum were found to have the opposite direction
of effect in the other 2]. The volume of regions of the striatum had the same relationship with carrier status
as thalamic volume in one study 2], but this was not significantly replicated in the other study 1]. Regional, rather than global, thickness and area in specific cortical areas were
not evaluated in one study 1], so it is currently not possible to assess the reproducibility of this phenotype.
It should be noted that differences in the method of analysis, age of participants
and genetic variation outside the 16p11.2 region, and within the region in an unaffected
chromosome, could be responsible for the different results seen across the cohorts
in the two studies. Obtaining a clearer picture of the specific regions affected in
patients will take larger cohorts.