A breakthrough for neurological disorders was reached with innovative genetic technology when two genes were discovered linked to severe forms of childhood epilepsy.
Exome sequencing was used to detect the mutations in DNA sequences that could cause two forms of childhood epilepsy: infantile spasms and Lennox-Gastaut Syndrome—diseases that affect more than two million people in the USA.
A team of scientists led by those at Duke University Medical Center (Durham, NC, USA) screened for de novo mutations in patients with two classical epileptic encephalopathies, 149 who had infantile spasms, and 115 diagnosed with Lennox-Gastaut syndrome. The exome sequences of 264 epileptic children were compared with those of the parents, who did not have the neurological disease. To identify any disease-causing mutations, the investigators analyzed the sequences using various statistical tools.
The results of the study revealed disease-causing mutations in six genes, four of which had been uncovered before in previous studies, but two were discovered for the first time. Among these were the gene encoding for gamma-aminobutyric acid receptor subunit beta-3 (GABRB3), with de novo mutations in four patients, and the gene encoding for the asparagine-linked glycosylation 13 homolog (ALG13), with the same de novo mutation in two patients. Both genes show clear statistical evidence of association with epileptic encephalopathy.
The scientists say that by using novel genetic analysis techniques they also revealed that epilepsy-causing mutations in humans are concentrated in genes that are intolerant or highly sensitive to changes in their DNA sequence. They add that the genes are so sensitive that the smallest change in their DNA sequence means the gene may not work, which could lead to death or severe forms of diseases. Results showed that up to 90 genes could carry epilepsy-causing mutations, and many of these have been previously linked to other neurological disorders, such as autism.
David B. Goldstein, PhD, a study leader, said, “It appears that the time for using this genome approach to understand complex neurological disorders has arrived. One of the most encouraging aspects of this study is that we''re beginning to see how best to interpret and make effective use of exome sequence data. We anticipate that further studies will identify many new disease-causing genes and we intend to develop a watch list of the genes which summarizes their clinical characteristics in way that will be helpful for doctors, patients and other scientists." The study was published on August 11, 2013, in the journal Nature.