Scientists from Seattle Children's Research Institute and the University of Washington, in collaboration with the Genomic Disorders Group Nijmegen in the Netherlands, have identified two new genes that cause Baraitser-Winter syndrome, a rare brain malformation characterized by droopy eyelids, intellectual disabilities, and hearing loss that can be progressive (Nature Genetics, online, Feb. 26, 2012).

"This discovery brings the total number of genes identified with this type of brain defect to eight," said William Dobyns, MD, a geneticist at Seattle Children's Research Institute.

Identification of the additional genes associated with the syndrome makes it possible for researchers to learn more about brain development.

The brain defect found in Baraitser-Winter syndrome is a smooth brain malformation, or lissencephaly, as whole or parts of the surface of the brain appear smooth in scans of patients. Previous studies by Dr. Dobyns and other scientists identified six genes that cause the smooth brain malformation, accounting for approximately 80 percent of affected children. To date, physicians and researchers worldwide have identified approximately 20 individuals with the syndrome.

Although the condition is rare, the new findings have broad scientific implications, Dr. Dobyns said. "Actins, or the proteins encoded by the ACTB and ACTG1 genes, are among the most important proteins in the function of individual cells. They are critical for cell division, cell movement, internal movement of cellular components, cell-to-cell contact, signaling and cell shape."

The defects that were discovered occur in the only two actin genes expressed in most cells. The correct combination of genes must be expressed at the right time to allow proper development.

"Birth defects associated with these two genes seem to be quite severe," said Dr. Dobyns. "Children and people with these genes have short stature, an atypical facial appearance, birth defects of the eye, and the smooth brain malformation, along with moderate mental retardation and epilepsy. Hearing loss occurs and can be progressive."

Co-authors of the study were Jean-Baptiste Riviere, PhD, Christopher Sullivan, Susan Christian, Brian O'Roak, PhD, Jay Shendure, MD, PhD, and many other physicians and scientists from North America and Europe.