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Summary of Advances Cover 2012

Summary of Advances

In Autism Spectrum Disorder Research


Question 3: What Caused This to Happen and Can It Be Prevented?

Autism after infection, febrile episodes, and antibiotic use during pregnancy: An exploratory study – Atladóttir HO, Henriksen TB, Schendel DE, Parner ET. Pediatrics. 2012 Dec;130(6):e1447-54. [PMID: 23147969]

Exposure to certain environmental factors during pregnancy has long been implicated in the potential development of ASD in offspring. Findings from animal studies suggest that the stimulation of a woman's immune system during pregnancy caused by events such as infection may be associated with abnormal brain development in the fetus. Studies in human populations, however, have yielded conflicting results concerning the relationship between maternal infection during pregnancy and ASD. Data generated from the Danish National Birth Cohort (DNBC) was used to investigate the relationship between the occurrence of common infections, episodes of fever, and the use of antibiotics during pregnancy and the risk for ASD in children. The DNBC included 96,736 children born between 1997 and 2003 whose mothers participated in telephone interviews at approximately 17 and 32 weeks into their pregnancy as well as about 6 months after birth. According to the Danish Psychiatric Central Register, 1% of the children in the DNBC had been diagnosed with ASD at the time of the study. Interviewers asked mothers participating in the study about the occurrence of infections, fever, and the use of antibiotics during their pregnancies. In general, the researchers found little evidence that various types of mild common infection or short episodes of fever during pregnancy were strong risk factors for ASD. However, evidence suggested that maternal report of influenza infection during pregnancy was associated with a doubled risk of infantile autism, a diagnosis indicating that ASD is apparent in the first 3 years of life. In addition, prolonged episodes of fever tripled the risk of infantile autism, and use of different antibiotics during pregnancy was also associated with a small increase in risk of ASD. While the authors emphasized the importance of further research to validate their findings due to the limitations of their methodology, the large scale of this population-based cohort study makes it a key finding, potentially linking ASD with maternal influenza infection, fever, and the use of antibiotics during pregnancy. Further research will be needed to confirm these potential relationships and to investigate whether immune changes in mothers may have an impact on brain development in humans.

Rate of de novo mutations and the importance of father's age to disease risk – Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K. Nature. 2012 Aug 23;488(7412):471-5. [PMID: 22914163]

Results of a recent study suggest that a father's age may be a larger contributor to autism risk than previously thought. Researchers from deCODE genetics in Iceland conducted a large-scale study in which they evaluated whole-genomes of 78 Icelandic families (consisting of DNA drawn from two parents and an offspring) and examined them for mutations, or changes, in the DNA.  Of the 78 children included, 44 were diagnosed with ASD and 21 with schizophrenia. Results from the study demonstrated that the older the father was at the time of a child's conception, the greater the risk of having a child who developed ASD or schizophrenia. This increasing risk correlated strongly with the number of de novo mutations in the child's DNA, which are non-inherited changes in DNA that usually occur prior to conception in eggs or sperm and can result in the development of genetic disorders in children despite the absence of the disorder in either parent. Previous research on de novo mutations had been restricted to specific genes or small samples of whole-genome sequences, but the sample size in this study allowed researchers to more accurately quantify the risk of mutation across the whole genome. The study found an effective increase of more than two mutations for every year in paternal age, or a doubling in the number of mutations every 16.5 years. Such mutations can be caused by environmental influences or by errors in maintaining DNA integrity that accumulate over time. While the genetic risks to offspring of older mothers has been documented for some time, the results of this study point to the importance that a father's age plays in the occurrence of genetic mutations that can lead to disorders such as ASD and schizophrenia. Intriguingly, this study's findings also suggest that changes in demographics favoring later parenthood may be contributing to the rise in prevalence of ASD.

Patterns and rates of exonic de novo mutations in autism spectrum disorders – Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH Jr, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Nature. 2012 Apr 4;485(7397):242-5. [PMID: 22495311]

Mutations in particular genes are believed, in many instances, to contribute to the risk of developing ASD. However, to date only a small fraction of ASD cases have been linked to known genetic risk factors. This is thought to be largely due to the lack of comprehensive scientific knowledge available on risk-determining genes that may play a role in ASD. Researchers have confronted this issue by examining the rate of de novo mutations—those arising spontaneously in reproductive cells but absent from the non-reproductive cells of either parent—in the DNA of individuals with ASD. With this approach, scientists examined the gene-rich regions of DNA known as exomes from people with ASD and their parents and identified de novo point mutations—or mutations in a single letter in the DNA code—that correlated with increased risk for ASD. They discovered that the number of de novo mutations in an individual with ASD is highly correlated with the age of both the mother and the father at the time of the child's conception, pointing to elevated risk as a parent ages and accumulates more mutations in their reproductive cells' DNA. Furthermore, the researchers found that de novo mutations in individuals with ASD are distributed across many genes and each mutation appears to contribute only modestly to the occurrence of ASD, indicating that any one mutation is unlikely to be the sole cause of ASD in an individual. Although in general it does not appear that families with a member affected by ASD have a particularly elevated rate of de novo mutation that would suggest special vulnerability to mutations, researchers found that the genes carrying de novo point mutations are highly related and share common biological pathways, and they are often linked to genes closely associated with ASD and other intellectual disabilities. Based on this discovery, researchers examined variations in two genes (CHD8 and KATNAL2) in 935 individuals with ASD and 870 controls and found significant evidence that mutations within these genes indicated susceptibility for ASD. Investigators concluded that while the role of a single de novo mutation is limited in its ability to implicate a specific gene as a risk factor for ASD, predictive models that can assess de novo mutations in multiple genes at once in large data samples are important in the identification of genuine autism risk factors.

Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations – O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE.  Nature. 2012 Apr 4;485(7397):246-50. [PMID: 22495309]

Despite scientific evidence linking genetics to the development of ASD, more than 70% of ASD cases still have no known genetic cause. It is suggested that de novo mutations—those arising spontaneously in the DNA of reproductive cells and absent in the DNA of non-reproductive cells of either parent—may be involved in the incidence of ASD in families with no history of the disorder, also known as “sporadic” families. While previous studies have found that de novo copy number variations (CNVs), or large duplications or deletions in DNA, contribute to autism risk, this study focused on understanding the contribution of point mutations (or single nucleotide variants – SNVs) and other small mutations to the incidence of ASD in sporadic families. Researchers analyzed gene-rich regions of DNA (exomes) from 209 sporadic families consisting of children with ASD and their parents (who do not have ASD) and found that de novo mutations are four times more likely to be contributed by the father than by the mother. Furthermore, it was observed that the number of de novo mutations increases with the age of the father at the time of the child's conception. Researchers were able to determine that 39% of the most disruptive de novo mutations (those most negatively affecting normal gene expression) were in genes that belonged to a highly interconnected network of genes associated with aspects of brain development or previously linked to ASD. The two specific genes containing the most recurring mutations among the 209 sporadic families were CHD8, a gene involved in remodeling chromatin (the DNA and protein complex that makes up chromosomes) to regulate gene expression, and Netrin-G1 (NTNG1), a gene that helps guide growing neurons and has been associated with atypical cases of Rett syndrome. Further genetic screening of 2,500 individuals identified additional disruptive de novo mutations in genes also implicated in ASD and other neurodevelopmental disorders (GRIN2B, LAMC3, and SCN1A). Based on these and other similar findings delineating the genetic distribution of de novo mutations in relation to ASD, researchers conclude that there is overwhelming diversity in the range and location of such mutations on the genome. Thus, scientists emphasize the need to continue using multiple techniques and large sample cohorts to identify additional genetic risk factors with the potential to lead to development of diagnostic biomarkers and new therapeutic approaches for ASD. 

De novo mutations revealed by whole-exome sequencing are strongly associated with autism – Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. Nature. 2012 Apr 4;485(7397):237-41. [PMID: 22495306]

De novo gene mutations that arise spontaneously in reproductive cells or embryos are a key target of interest in the exploration of non-inherited causes of ASD in which neither parent has the disorder. Previous research has indicated that spontaneous or de novo copy number variations (CNVs), in which large sections of DNA are altered, contribute to risk for ASD. Less is known about whether spontaneous alterations in single base pairs within the DNA code, called de novo point mutations or single nucleotide variants (SNVs), may also play a role in elevating ASD risk. In this study, through sequencing of gene-rich regions of DNA (exomes) in a cohort of 928 individuals with ASD and their unaffected parents/siblings, scientists have uncovered compelling evidence on the contribution of de novo SNVs to risk for ASD. The researchers examined highly disruptive de novo SNVs (those most negatively affecting normal gene expression) and determined that such mutations in genes specific to the brain were significantly associated with ASD. To specify which genes contribute relatively greater risk, scientists estimated that the probability of two or more disruptive de novo mutations occurring in the same genes in unrelated individuals was highly unlikely. According to this measurement threshold, scientists identified SCN2A—a gene associated with epilepsy and ASD—as the only gene within the cohort that contains a disruptive de novo SNV in two individuals with ASD. In a combined analysis with genetic data from another cohort of 414 individuals with ASD, an additional two genes (KATNAL2 and CHD8) were further identified as significantly associated with ASD. Researchers noted that although there is overwhelming genetic diversity in the frequency and location of de novo events throughout the genome, the technique of assessing disruptive de novo events clustered within the genes of unrelated individuals can reliably identify risk-contributing gene variants. This research will prove crucial in the continued exploration of genetic risk factors in ASD. 

Question 3

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