spontaneous mutations bigger role than thought

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Joined: 25 Aug 2013
Age: 64
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Location: Long Island, New York

27 Sep 2021, 8:17 am

Analysis ups estimate of spontaneous mutations’ role in autism

Spontaneous genetic mutations contribute to autism in 30 to 39 percent of all people with the condition, an increase over previous estimates, according to a new study. The rate is even higher — 52 to 67 percent — among autistic children whose siblings do not also have the condition.

These spontaneous, or ‘de novo,’ mutations are not found in either of an autistic person’s parents and occur more often in autistic people than in non-autistic people. They may also contribute primarily to autism in so-called ‘simplex’ families, which have one autistic child, the researchers conducting the new study say. Inherited mutations, by contrast, explain most cases in ‘multiplex’ families, which have more than one autistic child, they say.

“This study confirms our observation clearly that de novo is not very important in multiplex,” says lead investigator Ivan Iossifov, associate professor of genetics at Cold Spring Harbor Laboratory in New York. “It sounds like an obvious thing, and we certainly took it for granted, but there was no clear observation.”

Some analyses of multiplex families have relied on cell lines that can accumulate de novo mutations as they grow in culture dishes — a problem known as ‘genetic drift’ — and thus skew results. The new work screens samples for those stray mutations, making it possible to distinguish the de novo mutations that contribute to autism.

The researchers analyzed the whole-genome sequences of 1,869 autistic children and 1,874 of their non-autistic siblings from the Simons Simplex Collection (SSC), which collects data on simplex families, and 1,107 autistic children in multiplex families from the Autism Genetic Resource Exchange (AGRE). The Simons Simplex Collection is funded by the Simons Foundation, Spectrum’s parent organization.

The sequences in SSC come from blood samples, whereas some of those in the AGRE database come from lymphoblastoids, continuously replicating cell lines derived from blood cells. Because these cell lines are susceptible to genetic drift, the researchers devised a technique to screen the samples and remove participants with an unusually high number of de novo mutations.

Next they looked for three types of de novo mutations — single nucleotide swaps, short insertions and deletions of DNA called ‘indels’ and larger ones called copy number variations — and focused on those most likely to disrupt a gene’s function. About 9.8 percent of autistic children from simplex families have disruptive de novo mutations, the researchers found, compared with 2.2 percent of the children in multiplex families.

The team then probed the portion of the genome that does not code for proteins, only in the simplex families. About 13 percent of the children from simplex families had noncoding mutations that likely contribute to autism; 6 percent had mutations in sequences between the coding portions of genes, known as introns, which often help to regulate gene expression.

Professionally Identified and joined WP August 26, 2013
DSM 5: Autism Spectrum Disorder, DSM IV: Aspergers Moderate Severity.

“My autism is not a superpower. It also isn’t some kind of god-forsaken, endless fountain of suffering inflicted on my family. It’s just part of who I am as a person”. - Sara Luterman


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Joined: 4 Feb 2014
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27 Sep 2021, 8:22 am

I'm not surprised by this finding.


Joined: 5 Mar 2018
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27 Sep 2021, 2:46 pm

Given the huge range of severity between siblings and the fact that most parents & some siblings are NT, its rather obvious that most cases of autism are not completely hereditary.

"The reasonable man adapts himself to the world; the unreasonable one persists in trying to adapt the world to himself. Therefore all progress depends upon the unreasonable man."

- George Bernie Shaw