NEW YORK – By analyzing numerous types of genetic and health-related data, researchers have uncovered a previously unrecognized subtype of autism spectrum disorder.
In a new study, researchers from the US and Israel examined whether a precision medicine approach that relies on various streams of data could help unearth distinct subtypes of autism spectrum disorder. ASD, which affects 1 in 54 children in the US, is both clinically and genetically heterogeneous.
As they reported in Nature Medicine on Monday, the researchers combed through whole-exome sequencing, brain gene expression, and health record and healthcare claims data to uncover an autism subtype marked by dyslipidemia. According to the researchers, these different disease subtypes could help lead to more targeted ASD treatments.
"Previously, autism subtypes have been defined based on symptoms only — autistic disorder, Asperger syndrome, etc. — and they can be hard to differentiate as it is really a spectrum of symptoms," co-first author Yuan Luo, associate professor of preventive medicine at Northwestern University Feinberg School of Medicine, said in a statement. "The autism subtype characterized by abnormal [lipid] levels identified in this study is the first multidimensional evidenced-based subtype that has distinct molecular features and an underlying cause."
As ASD is thought to develop prenatally, the researchers first gathered gene expression data from typically developing human brains from the BrainSpan Atlas of the Developing Brain. Within this set of 524 samples from 26 brain regions from 42 individuals, they searched for clusters of exons that are co-expressed during early development and, as more boys than girls are affected by autism, are differentially expressed between males and females.
At the same time, they sifted through whole-exome sequencing data from 3,531 individuals, some with autism and some without, from simplex and multiplex autism families. In this way, they teased out variants discordant between affected and unaffected siblings that were likely gene disrupting.
After mapping these variants back to the developmentally expressed exon clusters, the researchers identified 33 neurodevelopmentally co-regulated exon clusters that were differentially expressed by sex and clustered with deleterious variants associated with ASD.
Functional analysis of these clusters linked them to a number of biological processes, including expected functions like chromatin and transcriptional regulation, as well as immune and synaptic function, but the analysis also highlighted lipid regulation. This suggested to the researchers that dyslipidemia might occur among individuals with ASD.
Using medical record data from more than 2.7 million people seen at Boston Children's Hospital, they then compared blood lipid levels of individuals with ASD, their unaffected family members, and unrelated matched controls. Overall, they found that children with ASD had blood lipid profiles that fell outside typical ranges, even after accounting for age, sex, and metabolic state. Similarly, based on healthcare claims data from 34 million individuals, dyslipidemia diagnoses were more common among people who also had ASD.
The researchers further sifted through their data to see if there were other clinical features shared among individuals with dyslipidemia-linked ASD. They found epilepsy, sleep disorders, and attention deficit hyperactivity disorder were more common among individuals with dyslipidemia-linked ASD, indicating that dyslipidemia might broadly contribute to altered neurodevelopment. They estimated that this dyslipidemia-linked subtype affects almost 7 percent of people with ASD.
The identification of an ASD subtype from a broad dataset could lead to better definitions of ASD subgroups and could uncover tailored targets for intervention and prevention to better personalize ASD treatments, the researchers noted.
"Today, autism is diagnosed based only on symptoms, and the reality is, when a physician identifies it, it's often when early and critical brain developmental windows have passed without appropriate intervention," Luo added. "This discovery could shift that paradigm."