Genomics

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.

Link Between Genetic Defect And Brain Changes In Schizophrenia Demonstrated

Source: 
Science Daily
Date Published: 
October 17, 2009
Abstract: 

Researchers at the University of North Carolina at Chapel Hill School of Medicine have found that the 22q11 gene deletion -- a mutation that confers the highest known genetic risk for schizophrenia -- is associated with changes in the development of the brain that ultimately affect how its circuit elements are assembled.

The researchers would now like to figure out how these alterations in the circuitry of the brain affect the behavior of the mouse. They also hope that understanding the "mis-wiring" of the brain in a genetic animal model of schizophrenia would help them understand the causes of the disease in the general population

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.

A Common Genetic variant in the neurexin superfamily member CNTNAP2 increases Familial Risk of Autism

Source: 
American Journal of Human Genetics, Arking, Cutler, et al
Date Published: 
December 2008
Year Published: 
2008

Autism is a childhood neuropsychiatric disorder that, despite exhibiting high heritability, has largely eluded efforts to identify specific genetic variants underlying its etiology. We performed a two-stage genetic study in which genome-wide linkage and family-based association mapping was followed up by association and replication studies in an independent sample. We identified a common polymorphism in contactin-associated protein-like 2 (CNTNAP2), a member of the neurexin superfamily, that is significantly associated with autism susceptibility. Importantly, the genetic variant displays a parent-of-origin and gender effect recapitulating the inheritance of autism.

Autism: Maternally derived antibodies specific for fetal brain proteins

Source: 
Neurotoxicology, Braunschweig, Ashwood, et al
Date Published: 
2008
Year Published: 
2008

Autism is a profound disorder of neurodevelopment with poorly understood biological origins. A potential role for maternal autoantibodies in the etiology of some cases of autism has been proposed in previous studies To investigate this hypothesis, maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot in 61 mothers of children with autistic disorder and 102 controls matched for maternal age and birth year (62 mothers of typically developing children (TD) and 40 mothers of children with non-ASD developmental delays (DD)). We observed reactivity to two protein bands at approximately 73kDa and 37kDa in plasma from 7 of 61 (11.5%) mothers of children with autism (AU) against fetal but not adult brain, which was not noted in either control group (TD; 0/62 p=0.0061 and DD; 0/40 p=0.0401). Further, the presence of reactivity to these two bands correlated with a diagnosis of behavioral regression in the child when compared to the TD (p=0.0019) and DD (0.0089) groups. Individual reactivity to the 37kDa band was observed significantly more often in the AU population compared with TD (p=0.0086) and DD (p=0.002) mothers, yielding a 5.69-fold odds ratio (95% confidence interval 2.09 - 15.51) associated with this band. The presence of these antibodies in the plasma of some mothers of children with autism, as well as the differential findings between mothers of children with early onset and regressive autism may suggest an association between the transfer of IgG autoantibodies during early neurodevelopment and the risk of developing of autism in some children.

Recurrent 16p11.2 Microdeletions in Autism

Source: 
Human Molecular Genetics, Kumar, KaraMohamed, et al
Date Published: 
2008
Year Published: 
2008

Autism is a childhood neurodevelopmental disorder with a strong genetic component, yet the identification of autism susceptibility loci remains elusive. We investigated 180 autism probands and 372 control subjects by array comparative genomic hybridization (aCGH) using a 19K whole-genome tiling path bacterial artificial chromosome microarray to identify submicroscopic chromosomal rearrangements specific to autism. We discovered a recurrent 16p11.2 microdeletion in two probands with autism and none in controls. The deletion spans approximately 500-kb and is flanked by approximately 147-kb segmental duplications (SDs) that are >99% identical, a common characteristic of genomic disorders. We assessed the frequency of this new autism genomic disorder by screening an additional 532 probands and 465 controls by quantitative PCR and identified two more patients but no controls with the microdeletion, indicating a combined frequency of 0.6% (4/712 autism versus 0/837 controls; Fisher exact test P = 0.044). We confirmed all 16p11.2 deletions using fluorescence in situ hybridization, microsatellite analyses and aCGH, and mapped the approximate deletion breakpoints to the edges of the flanking SDs using a custom-designed high-density oligonucleotide microarray. Bioinformatic analysis localized 12 of the 25 genes within the microdeletion to nodes in one interaction network. We performed phenotype analyses and found no striking features that distinguish patients with the 16p11.2 microdeletion as a distinct autism subtype. Our work reports the first frequency, breakpoint, bioinformatic and phenotypic analyses of a de novo 16p11.2 microdeletion that represents one of the most common recurrent genomic disorders associated with autism to date.

Structural Variation of Chromosomes in Autism Spectrum Disorder

Source: 
American Journal of Human Genetics, Marshall, Noor, et al
Date Published: 
2008
Year Published: 
2008

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.

Association Between Microdeletion and Microduplication at 16p11.2 and Autism

Source: 
New England Journal of Medicine, Weiss, Shen, et al
Date Published: 
2008

We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations. Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor.

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.