Seemingly diverse autism mutations may share the same underlying mechanism, according to Eric M. Morrow, MD, PhD, Instructor in Psychiatry at Harvard Medical School in Boston, and colleagues.
“The regulation of expression of some autism candidate genes by neuronal membrane depolarization suggests the appealing hypothesis that neural activity–dependent regulation of synapse development may be a mechanism common to several autism mutations,” stated Dr. Morrow and colleagues in the July 11 Science. “Therefore, disruption of activity-regulated synaptic development may be one mechanism common to at least a subset of seemingly heterogeneous autism-associated mutations.”
The researchers studied 88 large families—in which both parents shared recent ancestors—to find inherited causes of autism spectrum disorders. The families, who came from Jordan, Saudi Arabia, Kuwait, Oman, Pakistan, Qatar, Turkey, and the United Arab Emirates, were selected to emphasize the role of inherited genetic mutations.
The investigators gathered data with use of homozygosity mapping and compared the DNA of family members with and without autism to identify recessive mutations. Most individuals exhibited different genetic causes with little overlap between families, but a few exceptions were observed.
“Although the large size of linked loci precluded systemic gene sequencing in most cases, we were surprised to see that several consanguineous pedigrees showed large, rare, inherited homozygous deletions within linked regions, some of which are very likely causative mutations,” Dr. Morrow and colleagues said. Specifically, such deletions linked to autism were found in five families, or 6.4% of the study sample. Family members with one remaining functional copy of their genome segments did not have autism, while those with both copies missing did have autism.
The investigators found six gene disruptions that contributed to autism spectrum disorders. The largest of these gene disruptions involved genes essential for learning in the brain, as they are regulated either directly or indirectly by neuronal activity triggered by experience. Not all the genes were deleted—the remaining genes were simply turned off, leaving room for therapies to possibly turn these genes back on.
“Early brain development is driven largely by intrinsic patterns of gene expression that do not depend on experience-driven synaptic activity,” the investigators stated. “In contrast, postnatal brain development requires input from the environment that triggers the release of neurotransmitter and promotes critical aspects of synaptic maturation.... The connection between experience-dependent neural activity and gene expression in the postnatal period forms the basis of learning and memory, and autism symptoms typically emerge during these later stages of development.”
The researchers’ findings also pointed to potential genetic similarities, such as inherited recessive causes, between autism and other neurologic disorders. Among families in the present study who had one member with autism, there was a relatively equivalent male/female ratio compared with other families with autism, indicating that parents who shared a common recent ancestor was a determining factor. In families with more than one member with autism, the male/female ratio was even more balanced.
“The accumulating number of distinct, individually rare genetic causes in autism suggests that the genetic architecture of autism resembles that of mental retardation and epilepsy, with many syndromes, each individually rare, as well as other cases potentially reflecting complex interactions between inherited changes,” Dr. Morrow and colleagues elaborated. “The relatively reduced male/female ratio of affected children and the reduced rate of linked de novo copy number variants in the consanguineous sample [of the present study] ... both suggest that consanguineous pedigrees with autism are enriched for autosomal recessive causes similar to other congenital neurological disorders in consanguineous populations.”
The research team stated that although their findings support recent studies that suggest autism is highly heterogeneous genetically, homozygosity mapping appears to be an effective way to find underlying shared mechanisms. Understanding these genetic underpinnings could eventually help direct various therapies for the different clinical manifestations of autism.
“Our finding that deletions of genes regulated by neuronal activity or regions potentially involved in regulation of gene expression in autism suggests that defects in activity-dependent gene expression may be a cause of cognitive deficits in patients with autism,” the researchers concluded. In addition, their “data implicating noncoding elements in patients with shared ancestry, as well as the heterozygous nonsense changes in patients without shared ancestry, suggest that loss of proper regulation of gene dosage may be an important genetic mechanism in autism.”
—John Merriman