Genetic heritability and shared environmental factors among twin pairs with autism – Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N. Arch Gen Psychiatry. 2011 Nov;68(11):1095-102. [PMID: 21727249]

Recent research suggests that environmental factors may play a much greater role in autism risk than previously suspected and could even be more influential than genetic factors. These findings stem from a study of autism in twins, the largest of its kind, designed to model the genetic and environmental factors that contribute to the development of autism. Because identical twins share 100 percent of their DNA, researchers can assess the degree to which a disorder is genetic by studying the number of cases where both twins are affected (called concordance). Fraternal twins share 50 percent of their DNA, similar to siblings, so by comparing concordance rates among fraternal twins and siblings, researchers can study the influence of environmental factors, particularly those in the womb. In the study, researchers looked at concordance among 192 pairs of identical and fraternal twins and found that 77 percent of male identical twins and 50 percent of female twins were both affected by autism. Previous studies with smaller numbers of twins suggested a much greater genetic contribution, as high as 90 percent. The fraternal twins in the study had a 35 percent concordance rate – much lower than rates among identical twins but higher than rates among siblings, estimated to range from 3 to 19 percent. Using mathematical modeling, the researchers propose that environmental factors accounted for 55 percent of autism risk, while genetic heritability contributed less than 40 percent. The difference in rates among fraternal twins and siblings, who share similar amounts of DNA, suggests that environmental factors in the womb may be an important area of future study.

Rare de novo and transmitted copy-number variation in autistic spectrum disorders – Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, Marks S, Lakshmi B, Pai D, Ye K, Buja A, Krieger A, Yoon S, Troge J, Rodgers L, Iossifov I, Wigler M. Neuron. 2011 Jun 9;70(5):886-97. [PMID: 21658582]

A study of the genetic causes of autism confirmed that spontaneous or de novo mutations are present in a substantial number of families with only one child on the spectrum. These de novo mutations are not inherited from parents' DNA, arising instead in their egg or sperm or very early in embryonic development. Researchers compared the DNA of children with ASD to that of their unaffected sibling(s) and identified a diverse array of rare genetic abnormalities that may contribute to autism. Recent advances in technology have allowed researchers to identify genetic mutations on a finer scale than was previously possible. Some of the de novo mutations, known as copy number variations (CNVs) because they contain deleted or duplicated sections of DNA, were located in regions known to be associated with ASD, while others implicate new regions. Many of the mutations are thought to affect genes or gene networks involved in brain development. The study confirmed that these non-inherited CNVs are more common in children with ASD compared to their non-affected siblings; however, each unique variant is exceedingly rare, some found in only one family. In addition, researchers found evidence that inherited "ultrarare" genetic duplications may also contribute to autism. Based on the results of the study, the authors note that females have a greater resistance to autism from genetic causes, raising questions about the fate of female carriers. The study findings emphasize the diversity of rare genetic variations that contribute to ASD and suggest the possibility that a treatment for one form of autism may not have value for the majority of cases. The DNA samples analyzed in the study were part of the Simons Simplex Collection, a repository of over 1,000 families in the U.S. and Canada with only one child on the spectrum.

Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations – O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE. Nat Genet. 2011 Jun;43(6):585-9. [PMID: 21572417]

Another study of spontaneous mutations identified four genes that are likely to play a causal role in the development of autism. Instead of searching more broadly for copy number variants throughout the genome, researchers focused exclusively on the protein-coding region of the genome called the exome. This approach has a greater potential to identify single candidate genes for ASD. The study sequenced the exomes of 20 people with autism and their parents and identified 21 spontaneous or de novo mutations. Of the 21 mutations, four were determined to be potentially causative (FOXP1, GRIN2B, SCN1A, and LAMC3). Of note, the four participants carrying these mutations were profoundly affected by autism. Three of the four genes identified in the study had previously been associated with autism, intellectual disability without autism, and epilepsy. The fourth mutation, LAMC3, had never before been linked to autism and represents a potential new avenue of research. Within the study, two of the four children had been hit with a "genetic double-whammy" – both inheriting a harmful gene mutation from his parent and having a de novo mutation. For example, the child with a FOXP1 mutation also inherited a defective copy of CNTNAP2, believed to be involved in language development. This child had severe autism and the most profound language deficits of any participant. Another child with autism and epilepsy had both an inherited deletion putting him at risk for epilepsy and a de novo mutation of a gene associated with epilepsy, SCN1A. These two cases support the 'multi-hit' theory of autism – that a combination of mutations in the same pathway is necessary to cause severe autism or related disorders. The authors note that the study supports the role of de novo mutations as a major genetic contributor to autism and demonstrates the great potential of whole exome sequencing to identify candidate genes.

Recurrence risk for autism spectrum disorders: A Baby Siblings Research Consortium study – Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, Bryson S, Carver LJ, Constantino JN, Dobkins K, Hutman T, Iverson JM, Landa R, Rogers SJ, Sigman M, Stone WL. Pediatrics. 2011 Sep;128(3)e488-95. [PMID: 21844053]

For parents with an autistic child, the risk of having another child with autism may be greater than previously thought, according to findings from the largest prospective study of baby siblings conducted to date. Earlier studies suggested that 3 to 10 percent of infants who had an older sibling with autism would go on to develop the disorder themselves – new findings suggest that the risk of recurrence is substantially higher, at approximately 19 percent. This risk is even greater if the younger sibling is a boy or if he or she has more than one older sibling with ASD – male siblings have a 1 in 4 chance of developing autism while those from multiplex families have almost a 1 in 3 chance. Other factors, such as the severity of symptoms in the older sibling, older sibling's gender, parental age, or birth order were not shown to have any effect on recurrence risk. In this study, researchers recruited 664 infants and tracked them from around 8 months of age to 36 months when they were tested for autism. Ultimately, 132 children were diagnosed with autism spectrum disorder using gold-standard direct assessment methods. The research was conducted through the Baby Siblings Research Consortium, an international network that pools data to learn more about children at high risk for developing autism. The researchers note that the increased risk of autism recurrence for siblings suggests that families and pediatricians should take special care tracking their development and refer them for early intervention should concerns arise. These findings also have important implications for genetic counseling and family planning purposes.

Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism – Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Davis Wright NR, Dhodapkar RM, Dicola M, Dilullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS,Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O'Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH Jr, Geschwind D, Roeder K, Devlin B, State MW. Neuron. 2011 Jun 9;70(5):863-85. [PMID: 21658581]

A recent collaborative study identified six genetic mutations that are strongly associated with autism spectrum disorder, including an area of DNA that likely holds clues to understanding the nature of human social behavior. The researchers estimate that these mutations represent only a few of the hundreds of spontaneously arising variants that are likely to increase autism risk. Using gene chip or microarray technology, the researchers analyzed the genomes of over 1,100 families with a single child on the autism spectrum, and compared the results of affected and unaffected siblings. The DNA samples analyzed in the study were part of the Simons Simplex Collection. The scan revealed a variety of copy number variants (CNVs) – genetic mutations that can range from micro-deletions and duplications to large sequences of missing or additional DNA. Notably, one of the non-inherited or de novo CNVs was located on a genetic region linked to Williams-Beuren syndrome, a rare disorder that causes people to be extremely social, overly trusting, and highly empathetic.While loss of DNA from the area results in Williams-Beuren syndrome, gain of extra DNA in this area is associated with autism, which is marked by difficulty with social interaction and lack of empathy. This region's connection with both disorders suggests its importance in understanding the nature of the social brain. The study also supports earlier findings of higher rates of de novo CNVs in people with autism compared to their unaffected siblings. Uncovering the genetic basis of autism is critical to understanding the neurobiology underlying the disorder and may aid in developing targeted treatment approaches for different subtypes.