Findings indicate that inherited and new mutations act together, according to paper in PloS Genetics.

Scientists have identified 27 different genetic regions where rare copy number variations were found in the genes of children with autism spectrum disorders (ASDs) but not in healthy controls. They note that these findings reinforce the view that multiple gene variants, both common and rare, may be interacting to cause the heterogeneous group of disorders included under autism spectrum disorders.

“We identified additional autism susceptibility genes, many of which, as we previously found, belong to the neuronal cell adhesion molecule family involved in the development of brain circuitry in early childhood,” says study leader, Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia and associate professor of pediatrics at the University of Pennsylvania School of Medicine.

A paper called “Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes” appears in the June 26 edition of PloS Genetics detailing these findings.

The researchers compared genetic samples of 3,832 individuals from 912 families with multiple children with ASDs against genetic samples of 1,070 disease-free children from The Children’s Hospital of Philadelphia. “We focused on changes in the exons of DNA protein-coding areas in which deletions or duplications are more likely to directly disrupt biological functions,” explains Dr. Hakonarson.

The investigators identified more than 150 loci harboring rare variants in multiple unrelated probands but not in controls. They were able to confirm 27 of these on examination of an independent replication cohort comprising 859 cases and an additional 1,051 controls.

Rare variants at known loci including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A as well as several other genes in the 15q11–q13 region were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with deletions or duplications observed in 12 unrelated cases but no controls. Less is known about MDGA2, key to neurological development, likewise observed to be case-specific.

The team also discovered many private gene mutations, those found only in one or a few individuals, Dr. Hakonarson adds. Additionally, the investigators note, the fact that hundreds of distinct rare variants were each seen only once highlights the complexity in ASDs and points to the continued need for larger cohorts.

“We are finding that both inherited and new, or de novo, genetic mutations are scattered throughout the genome, and we suspect that different combinations of these variations contribute to autism susceptibility,” remarks Maja Bucan, Ph.D., professor of genetics at the University of Pennsylvania School of Medicine.

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Nerve Cell Defects in Autism Spectrum Disorder Discovered (Oct. 19, 2006)

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