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Rare Truncating Mutations Play Role in Neurodevelopmental Disease

NEW YORK (GenomeWeb) – An international team led by investigators in the US and Sweden has investigated the disease and phenotypic impact of rare truncating mutations in a large cohort of individuals profiled by exome sequencing.

Using data from 100,296 individuals, the researchers looked at potential ties between rare or ultra-rare protein-truncating variants (PTVs) and dozens of traits or diseases. The findings, appearing online today in the American Journal of Human Genetics, highlighted PTV-intolerant (PI) gene mutations coinciding with conditions such as autism spectrum disorder (ASD), bipolar disorder, schizophrenia, intellectual disability, or ADHD.

"[I]n this large [whole-exome sequencing] study, we showed that PI genes are well suited to capture the impact of rare to ultra-rare PTVs on the cognitive, behavioral, and developmental spectra," senior and co-corresponding author Benjamin Neale, a genetics and psychiatric researcher at the Massachusetts General Hospital and the Broad Institute, and his colleagues wrote. "This is less the case for major later-onset complex traits with modest effect on reproductive fitness."

The team saw other associations in PTV-prone individuals as well, including reduced stature, lower educational attainment, and an uptick in prior hospitalizations. On the other hand, the analysis did not unearth extensive PTVs in genes implicated in prior genome-wide association studies focused on common trait- or disease-associated variants.

For their analyses, the researchers looked at exome sequence data from several case-control and cohort studies, searching for possible associations between 10 diseases, 13 quantitative traits, and rare or ultra-rare truncating changes affecting 3,172 genes that are intolerant to such PTVs.

Through a series of phenotype- and ethnicity-specific analyses, they saw a significant association between PTV enrichment and the psychiatric or neurodevelopmental conditions considered, but they did not detect an over-representation of PTVs in the PI genes when focusing on later onset conditions or conditions such as type 2 diabetes or inflammatory bowel disease that do not directly affect the brain.

The team saw similar associations when it focused on a class of less severe damaging missense variants. Those variants tended to be more prevalent in the PI genes and conditions implicated in the PTV-centered analyses.

The authors' subsequent analyses hinted that ultra-rare PI-PTVs implicated in ASD, ADHD, bipolar disorder, and schizophrenia "are likely to be pleitropic, influencing some core intermediate phenotypes that relate to risk across many psychiatric disorders." 

Still, they noted that "strong enrichment of PI-PTVs in individuals with neurodevelopmental/psychiatric disorders does not exclude the existence of non-PI genes involved in the etiology of these disorders. These genes, however, are more likely to have weaker and, possibly, trait-specific effect."