In a study published Thursday in the American Journal of Human Genetics, the international team of researchers looked at blood samples from two patients with a rare disorder called Potocki-Shaffer syndrome, said Hyung-Goo Kim, the lead author and a research fellow in Dr. Lawrence Layman’s OB/GYN genetics lab at GHSU.
The syndrome can cause intellectual disability, craniofacial abnormalities such as a misshapen or small skull, enlarged openings between bones in the skull and bony outgrowths.
Specific genetic defects have been identified for the bony growths and skull opening problems but not for the other features. Using genetic analysis of the two patients and a third patient identified from the literature, the researchers were able to focus in on a large “breakpoint,” or disruption in the chromosomes of the patients. Within that area, they were able to zero in on a single disrupted gene called PHF21A.
To test whether it really was the gene, the researchers suppressed the equivalent gene in zebrafish to create the skull formation problems and then could “rescue” or reverse the syndrome by giving the protein from the gene.
Though the specific syndrome is rare, intellectual disability and craniofacial problems are not, and the discovery could lend insights into other more common disorders, said Layman, a co-author of the paper and the chief of the Section of Reproductive Endocrinology, Infertility and Genetics at GHSU.
“We usually start with a really severe phenotype. Then you start going back and looking at less severe (cases),” he said. “That kind of step could be done in the future where you look at people with milder craniofacial abnormalities. Even the intellectual disability could be very subtle. It might even be some kind of antisocial behavior or autism even, not as severe as a severe intellectual deficiency. There might be milder variants of both parts of that phenotype.”
With such a syndrome, looking at the patient’s chromosomes would tell generally where the problem is, “because the shape of the chromosome and length of the chromosome are different than normal chromosomes,” Kim said. That is like having a map of Georgia and trying to use it to find a specific car on a specific street, he said.
GHSU now has the Developmental Gene Discovery Project, in which samples taken from patients with developmental problems allow scientists to look for genes that might be the cause, Kim said.
“We are working to find the disease genes,” he said. “We are gene hunters. We want to know which gene is responsible for what kind of development in our bodies. And if it goes awry, what kind of (problem) does it cause?”
The Human Genome Project, completed nearly a decade ago, identified the 20,000 to 25,000 genes in the body.
“But that doesn’t mean we know all of the function of the genes,” Kim said. Being able to pair a gene with a specific function opens the door to the possibility of preventing or fixing the problem, he said. Likening it to an auto mechanic finding a faulty part, “then you have the possibility to replace, like a new part, (through) gene therapy or you can repair the broken part somehow.”