Copy Number Variations

Schizophrenia Shares Genetic Links with Autism, Genome Study Shows

Source: 
Scientific American
Date Published: 
May 10, 2010
Abstract: 

Schizophrenia involves some of the same genetic variations as autism and attention deficit disorders, a new whole-genome study has confirmed. In an effort to assess some of the common genetic variations that might underpin this fairly common but thorny mental illness, researchers sequenced DNA from 1,735 adults with schizophrenia and 3,485 healthy adults. Across the patients that had the disease, the researchers found many frequent variations related to copying or deleting genes, known as copy-number variations.

Better Genetic Test for Autism?

Source: 
Science Daily
Date Published: 
March 15, 2010
Abstract: 

A large study from Children's Hospital Boston and the Boston-based Autism Consortium finds that a genetic test that samples the entire genome, known as chromosomal microarray analysis, has about three times the detection rate for genetic changes related to autism spectrum disorders (ASDs) than standard tests.

The Top 10 Everything of 2009.# 7: New Research on Autism

Source: 
Time Magazine
Date Published: 
December 8, 2009
Abstract: 

TIME recognized New Research on Autism as #7 of its Top 10 Medical Breakthroughs of 2009.

Autism-Risk Gene Rewires the Brain in a Way That Disrupts Learning and Language Acquisition

Source: 
Medical News Today
Date Published: 
November 3, 2010
Abstract: 

Researchers at UCLA have discovered how an autism-risk gene rewires the brain, which could pave the way for treatments aimed at rebalancing brain circuits during early development. Dr. Geschwind and team examined the variations in brain function and connectivity resulting from two forms of the CNTNAP2 gene - one form of the gene increases the risk of autism. The researchers suspected that CNTNAP2 might have an important impact on brain activity. They used fMRI (functional magnetic resonance imaging) to scan 32 children's brains while they were performing tasks related to learning. Only 16 of them had autism.

The imaging results confirmed their suspicions. All the children with the autism-risk gene showed a disjointed brain, regardless of their diagnosis. Their frontal lobe was over-connected to itself, while connection to the rest of the brain was poor, especially with the back of the brain. There was also a difference between how the left and right sides of the brain connected with each other, depending on which CNTNAP2 version the child carried.

The authors believe their findings could help identify autism risk earlier, and eventually lead to interventions that could enhance connections between the frontal lobe and the left side of the brain.

Genome Wide Study of Autism Published in Nature

Source: 
EurekAlert
Date Published: 
October 7, 2009
Abstract: 

In one of the first studies of its kind, an international team of researchers has uncovered a single-letter change in the genetic code that is associated with autism. The finding, published in the October 8 issue of the journal Nature, implicates a neuronal gene not previously tied to the disorder and more broadly, underscores a role for common DNA variation. In addition, the new research highlights two other regions of the genome, which are likely to contain rare genetic differences that may also influence autism risk.

Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

Source: 
PLOS Genetics, Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, et al.
Date Published: 
June 2009
Year Published: 
2009

The study identified 27 different genetic regions where rare copy number variations - missing or extra copies of DNA segments - were found in the genes of children with autism spectrum disorders, but not in the healthy controls. The researchers, including geneticists from the University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia (CHOP) compared genetic samples of 3,832 individuals from 912 families with multiple autistic children against genetic samples of 1,070 disease-free children. Besides the identification of 27 regions harboring rare variants in children with ASDs, the study also uncovered two novel genes where variations were found, BZRAP1 and MDGA2 - thought to be important in synaptic function and neurological development, respectively. Interestingly, key variants on these genes were passed down in some, but not all, of the affected individuals in families.

Newly Found Genetic Variation Linked to Autism

Source: 
Nature
Date Published: 
April 2009
Year Published: 
2009

A newly identified genetic variant could account for up to 15 percent of autism cases, say researchers who studied genes that are important in connecting brain cells.  Researchers say the variant is carried by about 65 per cent of people with autism.
 

Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Source: 
PNAS, Sur, Tropea, Giacometti, et al.
Date Published: 
February 2009
Year Published: 
2009

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.

Strong association of de novo copy number mutations with sporadic schizophrenia.

Source: 
Nature Genetics, Xu, Roose, et al
Date Published: 
2008
Year Published: 
2008

Schizophrenia is an etiologically heterogeneous psychiatric disease, which exists in familial and nonfamilial (sporadic) forms. Here, we examine the possibility that rare de novo copy number (CN) mutations with relatively high penetrance contribute to the genetic component of schizophrenia. We carried out a whole-genome scan and implemented a number of steps for finding and confirming CN mutations. Confirmed de novo mutations were significantly associated with schizophrenia (P = 0.00078) and were collectively approximately 8 times more frequent in sporadic (but not familial) cases with schizophrenia than in unaffected controls. In comparison, rare inherited CN mutations were only modestly enriched in sporadic cases. Our results suggest that rare de novo germline mutations contribute to schizophrenia vulnerability in sporadic cases and that rare genetic lesions at many different loci can account, at least in part, for the genetic heterogeneity of this disease.

Linkage, Association, and Gene Expression Analyses Identify CNTNAP2 as an Autism-Susceptibility Gene

Source: 
American Journal of Human Genetics, Alarcon, Abrahams, et al.
Date Published: 
January 2008
Year Published: 
2008

Autism is a genetically complex neurodevelopmental syndrome in which language deficits are a core feature. We describe results from two complimentary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism. A two-stage association study tested 2758 SNPs across a 10 Mb 7q35 language-related autism QTL in AGRE (Autism Genetic Resource Exchange) trios and found significant association with Contactin Associated Protein-Like 2 (CNTNAP2), a strong a priori candidate. Male-only containing families were identified as primarily responsible for this association signal, consistent with the strong male affection bias in ASD and other language-based disorders. Gene-expression analyses in developing human brain further identified CNTNAP2 as enriched in circuits important for language development. Together, these results provide convergent evidence for involvement of CNTNAP2, a Neurexin family member, in autism, and demonstrate a connection between genetic risk for autism and specific brain structures.