While autism clearly runs in some families, few inherited genetic causes have been found. A major reason is that these causes are so varied that it's hard to find enough people with a given mutation to establish a clear pattern. Researchers at Boston Children's Hospital have pinpointed several inherited mutations—among the first to be identified—through an unusual approach: using whole-exome sequencing to study large Middle Eastern families with autism.
The study, published in the January 23 issue of the journal Neuron, also found evidence for some of the same mutations in U.S. families. It shows that a number of genes implicated in severe genetic syndromes can have milder mutations that primarily cause autism, and could broaden the number of genetic tests available to families.
Researchers Tim Yu , MD, PhD, Maria Chahrour , PhD, and senior investigator Christopher Walsh , MD, PhD, of Boston Children's Hospital, began with three large Middle Eastern families that had two or more children with autism spectrum disorders (ASDs), looking for recessive mutations—those requiring a "double hit" for the child to have an ASD.
"Families from the U.S. are not ideal for finding inherited genetic mutations, since family sizes are often small," says Walsh, chief of Genetics at Boston Children's and an investigator of the Howard Hughes Medical Institute.
In all three families, the parents were first cousins, a common tradition in the Middle East and one that greatly facilitates the identification of inherited mutations. The researchers first used genetic mapping techniques to narrow their search to specific chromosomal locations, then sequenced the protein-coding genes in those areas (known as whole-exome sequencing).
That turned up recessive mutations in three genes not previously known to be involved in autism, but rather in severe genetic syndromes:
Mutations in AMT, a gene classically associated with a severe metabolic syndrome known as nonketotic hyperglycinemia, marked by severe seizures and death during infancy.
Mutations in PEX7. Typical PEX7 mutations cause rhizomelic chondrodysplasia punctata, a severe syndrome causing metabolic and bone abnormalities, cataracts, severe epilepsy and early death.
Mutations in SYNE1, a gene associated with brain malformation, severe motor and muscle problems, and possibly bipolar psychiatric disease.
The severe syndromes linked to these genes often include autistic behavior or intellectual disability, but not as the primary symptom. Interestingly, the milder mutations discovered in these families seemed to cause disease that is more brain-specific.
"This is the first time these genes have been associated with autism," says Chahrour, who shares first authorship of the study with Yu. "The AMT and PEX7 mutations weren't picked up by standard tests for metabolic disorders, but when you're able to sequence the entire exome, you can find them."
These findings inspired the team to look for other metabolic and other genetic syndromes affecting cognition and behavior with milder forms showing up simply as autism. They screened 163 Middle Eastern families with autism for mutations in 70 genes associated with these syndromes, using a whole-exome approach but analyzing only the 70 genes of interest.
This approach turned up several additional families with ASD mutations, including: