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Rare Truncating Mutations Linked with Autism

You may have noticed that S.O.A.C. has been slow for the last few weeks. Well, I’m pleased to reported that my husband and I have just moved shop to Greenville, South Carolina, where we’ve started work at an extended campus of the University of South Carolina, in conjunction with the Greenville Health System. We’re both excited for the change and are super-anxious to get settled in and working on more research. Hopefully I’ll have some good work to report on in future!

Anyways, this week I want to report on a recent article that appeared in Nature Genetics by Krumm et al. (2015), addressing trends in rare copy number and single nucleotide variants. While I won’t completely summarize the work, the team did report a few interesting findings.

Krumm et al. studied genetic trends from the Simons Simplex Collection (SSC), which includes only families with single cases of autism. Though they found no significant differences in the transmission of likely gene-disrupting (LGD) and missense mutations when comparing those with autism and their unaffected siblings, when they looked at genes that tend to be more intolerant to mutation events, there were significant differences between autistics and their siblings and between affected and unaffected families. In short, though the overall rate of LGDs didn’t vary between autistics, siblings, and controls, when looking at certain genes that show stronger conservation rates throughout the human population, LGDs in these genes definitely showed links with simplex autism.

Interestingly, the team also looked at mutational burden related to diagnosis. Those with either a diagnosis of “autism” or “pervasive developmental disorder” were more likely to carry LGDs than those with a diagnosis of Asperger’s Syndrome, suggesting that LGD mutations may have strong links with autism severity. In support of this, those autistic individuals with an IQ between 70-100 showed a statistically significant genetic burden, whereas those with IQ 100+ did not.

Though these were all cases of simplex autism, there were families in which siblings rated similarly to their autistic brothers or sisters on the social responsiveness scale (SRS) even though they did not have a diagnosis of autism. When Krumm et al. stratified their analysis in order to compare pairs of siblings with similar SRS scores with those who were more discordant, they found that autistic children from the discordant pairs had higher rates of LGDs. This agrees well with previous work that suggests that simplex cases of autism may exhibit higher rates of gene-disrupting mutations and may be more severe symptomologically compared to multiplex cases.

The team went on to study copy number variant (CNV) deletions and duplications, finding that, as previously reported, autistic children showed higher rates of CNVs compared to their unaffected siblings, which was driven primarily by deletion events. De novo (new) CNVs tended to be larger in autistics than in siblings and more often included genes that were less tolerant to mutations (i.e., more deleterious). Autistic children also showed enrichment for inherited CNVs compared to their siblings. These CNVs were more often inherited from the mother and tended to be smaller (less than 100 kilobases), suggesting a role for a Female Protective Effect in the mothers. In support of this notion, they also found that when studying single nucleotide variant (SNV) LGDs, male autistics were more likely to have inherited potentially deleterious mutations from the mother, whereas female autistics had a stronger enrichment in de novo mutations, once again suggesting that females on average require a heavier genetic burden in order to compare symptomologically to their male counterparts.

Associated with the de novo CNV events, Krumm et al. also found that the autism-risk genes, FMR1, associated with Fragile X Syndrome, and CHD8, associated with a currently unnamed autism-related syndrome, were overrepresented in these mutation events. Interestingly, small maternally-inherited duplication events were enriched as CHD8 target genes, though the same was not true for the fragile X protein, FMRP. They went on to study macrocephaly in those families with gene mutations potentially downstream of CHD8 activity, finding that both macrocephaly and microcephaly were overrepresented in this subset.


Individuals with CHD8 mutations. So far, almost all cases of CHD8 mutation studied have autism, indicating that CHD8 mutations are highly penetrant for the condition. A handful of other genes, including ADNP, show similar trends in penetrance.

This finding may agree well with recent work by Hormozdiari et al. (2015) that identified two large, non-overlapping functional networks linking autism candidate genes. One network focused around long-term potentiation and calcium signaling pathways, meanwhile the other is involved in histone modification, transcriptional regulation, and cell growth and differentiation. CHD8 is a primary player in the latter module, integral especially in regulating activity of the Wnt pathway.


While this newest study doesn’t provide any particularly miraculous leaps and bounds to the state of knowledge of autism genetics, it does offer a few new interesting tidbits as well as continue to reinforce blossoming concepts in the current literature, primarily involving the nature of genetic risk of autism, the differences in those risk factors between simplex and multiplex families and between high-, moderate-, and lower-functioning individuals, and between the sexes. In particular, once again, it supports the idea that rarer gene-disrupting mutations, be they CNVs or SNVs, may be more common to severe simplex cases of autism, meanwhile higher-functioning multiplex families could be characterized by more common variants that are comparatively less penetrant and confer lower, though still significant, risk for autism and may be more polygenic or even multifactorial, including environmental agencies. Time will tell.

#canonicalWntpathway #Aspergerssyndrome #simplexautism #autismspectrum #SimonsSimplexCollection #Wntpathway #copynumbervariant #singlenucleotidevariant #CHD8 #autisticspectrumdisorder #singlenucleotidepolymorphism #CNV #femaleprotectiveeffect #SNP #likelygenedisruptingmutations #ASD #ADNP #microcephaly #autism #FMR1 #multiplexautism #SNV #socialresponsivenessscore #macrocephaly #LGD #FMRP #femaleprotectivemodel

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