Copy number variants and autism

Last year Autism Diva had a blog entry called: How many copies make you you?

Here's more information on copy number variants and de novo mutations in autism from Nature Medicine:

Autism: highly heritable but not inherited

Arthur L Beaudet

The author is in the Department of Molecular and Human Genetics,
Baylor College of Medicine ...

The genetic basis of autism is beginning to come to light. De novo
mutations in gene copy number may have a big role.

Until recently, only 5–10% of autism cases were traceable to an underlying genetic cause. Two studies now change this. Jacquemont et al.1 and Sebat et al.2 suggest that this number is actually 10–20%, and it may grow to 30–40% with further research. The advance is based primarily on the use of a recently developed high-resolution genome analysis technique to identify de novo genomic deletions and duplications of tens to thousands of kilobases (kb).

...

Autism is thought to be highly heritable, largely because of a very high concordance in monozygous twins—although the concordance in dizygous twins is low, and most cases occur as isolated individuals in a family.

Autism occurs in children with sex chromosome abnormalities and with chromosomal deletion and duplication syndromes that affect every autosomal chromosome4. Individuals with autism are often divided into two groups: a syndromic, or complex, group in whom autism is accompanied by malformations or dysmorphic features (dysmorphic refers to an abnormal morphology, frequently an unusual facial appearance, as shown in Jacquemont et al.1) and an essential group who have a normal appearance. In addition, autism can be seen in individuals with
single-gene disorders such as tuberous sclerosis and fragile X mental retardation. More recently, mutations in MECP2, PTEN, SHANK3 and NLGN4X have been reported to cause a small percentage of autism cases. Some of these genes regulate chromatin structure and gene expression (MECP2). Others are important in synaptic function (SHANK3, NLGN4X), which probably is abnormal in autism5.

The two studies1, 2 greatly strengthen the growing awareness that a substantial fraction of autism is caused by genomic rearrangements. Particularly in the case of deletions, loss-of-function point mutations in genes in these regions are likely to be important as well. Most of these are de novo mutations not present in the parents.
The children with identifiable genetic abnormalities are often in the syndromic group, and the sex ratio for these individuals tends to be 1:1, except for X-linked disorders6, 7.

The new reports1, 2 come at a time when there is a new appreciation for human genomic variation, which can entail deletions and duplications of tens to thousands of kilobases. The extent of such copy number variation (CNV) is enormous, encompassing at least 12% of the genome and hundreds of genes 8, 9. During nonallelic homologous recombination at meiosis, low copy repeats in the genome can mediate these deletions and duplications 10. CNVs are extremely common under normal circumstances, but also are an important aspect of what are now
frequently called genomic disorders, which are diseases caused by an alteration of the genome causing complete loss of copy, gain of copy or disruption of a dosage-sensitive gene 10.

To identify CNVs associated with autism, Jacquemont et al. used a technique called array comparative genomic hybridization (array CGH)1. ... The relative intensity of the two dyes identifies differences in genomic copy number between the two samples. The investigators used an array of 3,500 large insert (80–240 kb) clones covering the genome at 1 Mb intervals. They detected eight presumed causative abnormalities in 29 autism patients (28%) regarded as 'syndromic,' meaning that their autism was accompanied by malformations or dysmorphic features. Seven of the eight presumed pathogenic abnormalities were de novo; in the remaining
individual, there was an X chromosome duplication inherited from the healthy mother who was a 'carrier' for the duplication. Jacquemont et al. concluded that array CGH should be usef ul for genetically analyzing individuals when autism is accompanied by malformations or dysmorphic features1.

Sebat et al. performed array CGH using 85,000 oligonucleotide probes, and found de novo deletions or duplications in 12 out of 118 (10%) families with a single affected child and in 2 out of 196 (1.0%) controls 2. .... Since de novo variants occurred in only 1% of the control population, it is highly likely that most of the de novo variants in individuals with autism are the primary cause of their autism. Sebat et al. emphasize that the deletions and duplications may point to genes in which point mutations may lead to autism2. Recently, this approach was successfully applied to identify autism-causing mutations in SHANK3 (ref. 11).

All of these genetic causes of autism have extremely high heritability, meaning that the mutation causes the autism, but the mutations are not inherited. This is analogous to trisomy 21, which causes Down syndrome—...

...

Many of the lesions found in the Jacquemont et al.1 and Sebat et al.2 studies had not been previously reported, suggesting that not all regions of abnormality have been detected as yet. ... De novo point mutations in such genes could explain the advanced paternal age association that has been reported for autism13. There is no evidence, however, that the risk of a de novo CNV is related to the age of either parent.
...

Could de novo CNVs and point mutations explain the whole of autism? Probably not, because one would expect more frequent parent-to-child transmission than is observed for mutations of strong effect, since many individuals with autism reproduce, especially the more mildly affected Asperger patients. In addition, the male predominance would remain unexplained, because these mutations generally affect both sexes about equally, and the 'unknown' residual group of patients is predominantly male (Fig. 1).

The patients without identifiable genetic lesions tend to have a normal physiognomy and, on average, higher cognitive function, and to be even more predominantly male—with a 7–8:1 male:female ratio. Our view is that epigenetic abnormalities of chromatin that are not associated with nucleotide sequence changes might contribute to the etiology in this group; particularly given the male predominance, epigenetic abnormalities affecting the X or Y chromosome might be hypothesized. We have proposed a mixed epigenetic and genetic and mixed de novo and inherited model for autism, in which individual patients could have a genetic (mutation) or epigenetic (epimutation) etiology and these components could be inherited in some cases and de novo in others 14. The de novo aspect is proving to be important, but an epigenetic component, if one exists, remains elusive.

Dosage-sensitive genes—the very genes conveying phenotypes when duplicated or deleted—might be particularly susceptible to epigenetic defects. These defects might explain the relative lack of parent-to-child transmission, since such errors might be erased and reset as part of germline transmission. It is noteworthy that neither de novo events nor epigenetic events can be detected by extensive genome-wide studies currently underway to find genetic transmission or genetic linkage effects using trios of parents and children or affected pairs of siblings.

Interesting stuff. One can only hope that it doesn't turn into a quick and easy way to select against embryos that might end up being autistic.

Please also read this recent NYT article, Prenatal Test Puts Down Syndrome in Hard Focus Amy Harmon wrote it. Autism Diva once explained to Amy Harmon during a telephone interview why a prenatal test for autism would be a very bad idea (thanks goes to Jane Meyerding for sharing this article with the autistic advocacy Yahoo! group).

Video of Amy Harmon and the families and Down's people.
Another video here.


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