One of the central mysteries of autism is how a highly genetic disorder can produce such a strikingly uneven cognitive profile, in which some mental functions — particularly those comprising social cognition — are impaired, while other mental functions are preserved or even enhanced. The 16p11.2 microdeletion in autism encapsulates this challenge: even when the genetic lesion is seemingly homogeneous, the phenotype appears to be highly variable, ranging from a full diagnosis of autism (in about 15% of cases) to no diagnosis (about 5% of cases). However, consistent abnormalities are noted in some cognitive functions, behavior, growth, and body mass index (BMI): about 75% of cases appear to exhibit a deficit along the DSM spectrum, and common phenotypes in deletion cases include larger head circumference, reduction of full scale IQ, language and articulatory disorders, difficulty in motor coordination, seizures, intellectual disability, ADHD, and OCD. Carriers of the 16p11.2 deletion are predisposed to obesity and macrocephaly, whereas a mirror phenotype is observed in 16p11.2 duplication carriers, who present a high risk of being underweight and microcephalic.
The questions that arise from the expanding analysis of 16p11.2 probands include:
- Why is the penetrance of the 16p11.2 deletion so variable in autism? Are there additional risk factors in the genome that contribute to differences in 16p11.2 CNV outcome?
- What are the cognitive and neural phenotypes of the 16p11.2 deletion? Do core features exist that are present in most carriers, including those with an autism diagnosis and those without?
- How do 16p11.2 genes regulate different aspects of brain development, in particular the formation and function of synapses and circuits? How do additional genetic risk factors enhance the effects of 16p11.2 haploinsufficiency?
The goal of the 16p11.2 targeted project is to provide answers to these questions and thus contribute to a mechanistic understanding of how this specific genetic abnormality, and similar CNVs, leads to neurobiological consequences and neural and cognitive phenotypes. Such an understanding is a likely prerequisite for mechanism-based drug targets and pharmacological or behavioral interventions for the 16p11.2 deletion.
Additional genetic risk factors for ASD with CNVs at 16p11.2 (Mark Daly)
16p11.2 duplication or deletion are among the most common, high-impact risk factors for autism spectrum disorders (ASDs). However, phenotypic variability among individuals with the same 16p11.2 genetic risk factor is wide — including all outcomes from profoundly autistic to essentially unaffected individuals. The purpose of this project is to examine the distribution of additional genetic risk factors for ASDs in the presence of CNVs at 16p11.2, using two parallel tracks of inquiry. The first, genomewide analysis, will be approached genetically through common and rare variant burden analyses, and phenotypically by examining familiality and gender patterning. Second, a focused regional analysis will examine whether variation in the intact chromosome is relevant in deletion carriers. Collectively, these analyses will improve understanding of the mechanisms through which 16p11.2 CNVs create risk for ASDs and, more broadly, the manner in which different types of genetic risk for ASD may behave in concert across the genome.
Characterizing the cognitive and neural phenotypes of individuals with 16p11.2 deletions (Nancy Kanwisher)
We propose to address the heterogeneity of autism in both genotype and phenotype by characterizing the cognitive and neural phenotype of individuals with 16p11.2 deletions, both those with an autism diagnosis, and those without. In particular, because the available preliminary evidence suggests that language deficits are the clearest feature of the cognitive phenotype of 16p11.2 deletions (Rosenfeld et al., 2010; Zuffery et al, 2012; Hanson et al., 2010; Shinawi et al., 2010), we will test exactly what aspects of language processing are altered in individuals with 16p deletions (compared to age- and IQ-matched control subjects), using both behavioral measures (Aim I) and neuroimaging measures (Aim II).
Synaptic pathophysiology of the 16p11.2 microdeletion mouse model (Mark Bear)
Autism is a heterogeneous group of neurodevelopmental disorders affecting approximately 1% of the pediatric population. It is characterized by impaired social interaction, deficits in verbal and non-verbal communication, and restricted repetitive and stereotyped patterns of behavior, interests and activities. In addition, it is often associated with other neurological co-morbidities, such as intellectual disability and seizure disorder. Autism can be caused by various genetic abnormalities, one of which is the loss of a small segment of DNA, a condition called a microdeletion. One of the most common microdeletions in autism patients is the loss of part of human chromosome 16. A mouse model mimicking this genetic abnormality has shown behavioral phenotypes that recapitulate autism. However, the molecular mechanisms underlying the behavioral phenotypes are unclear. In the proposed studies, we seek to understand the synaptic abnormalities in a mouse model of autism caused by human chromosome 16 microdeletion. Specifically, we plan to study these mice at biochemical, behavioral, and electrophysiological levels. Our work will provide insight into the mechanism by which autism arises from microdeletion of chromosome 16 and other genetic abnormalities. The knowledge will also help to guide diagnosis and treatment in autism patients.
Role of MVP in regulating synaptic and circuit function (Mriganka Sur)
Major vault protein (MVP) is one of the genes within a 118Kb subset of the 16p11.2 region that likely has a crucial role in specific phenotypes of the 16p11.2 deletion. In vitro, MVP is known to regulate intracellular signaling cascades including PI3K/Akt, MAPK and JAK/STAT pathways, all of which are required for synaptic and cortical plasticity. These pathways, and in particular Ras signaling, have been implicated in autism pathophysiology. The goal of this project is to determine the function of MVP in synaptic and cortical plasticity.