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Researchers Uncover 17 Novel Genes Related to Developmental Brain Disorders

NEW YORK (GenomeWeb) – Researchers at the Geisinger Health System in Pennsylvania have uncovered 17 novel gene variants that could be related to developmental brain disorders including autism, epilepsy, schizophrenia, and bipolar disorder.

As they reported in JAMA Psychiatry today, the team data mined almost 400 studies from the PubMed database published from Mar. 28, 2003, through May 7, 2015, with large cohorts of individuals with developmental brain disorders. They then conducted a tiered, multilevel data-integration study using whole-genome data from structural and sequence pathogenic loss-of-function (pLOF) variants; phenotype data from six apparently distinct disorders — intellectual disability, autism, attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, and epilepsy; and additional data from large-scale studies, smaller cohorts, and case reports focusing on specific candidate genes.

They then ranked all the candidate genes they found in four tiers: Tier 1 consisted of genes with three or more de novo pLOF variants; tier 2 was made up of genes with two de novo pLOF variants; tier 3 consisted of genes with one de novo pLOF variant; and tier 4 was made up of genes with only inherited pathogenic loss-of-function variants.

Using this approach, the researchers — led by senior author Christa Lese Martin, director of Geisinger's Autism & Developmental Medicine Institute — identified 241 genes that they believe are causative of a brain disorder. Among those, the team found 17 novel genes that have not previously been linked to autism or other brain disorders.

Overall, the team ranked 59 genes in tier 1, 44 in tier 2, 68 in tier 3, and 70 in tier 4. "Of the 241 genes involved in brain disorders, seven were novel high-confidence genes and 10 were novel putative candidate genes," the researchers wrote in their paper. "By transcending clinical diagnostic boundaries, the evidence level for 18 additional genes that were ranked 1 tier higher because of this cross-disorder approach was increased."

"The identification of new genetic causes of brain disorders, such as autism, is increasing our understanding of their underlying biology which will ultimately lead to targeted therapies," Lese Martin said in a statement. "We now know that at least 40 percent to 50 percent of brain disorders are caused by a genetic change in a person's DNA, and studies like ours are adding to this knowledge."

The team has created an online database to make its data easily accessible to researchers and clinicians.