The discovery provides answers to children and families affected by neurological symptoms with no known cause.
The National Institutes of Health's Undiagnosed Disease Network estimates that 25-30 million Americans, or 1 in 10 of the population, lives with a rare disease. Many of these individuals lack an official diagnosis, even if their underlying disorder has already been discovered. Programs like Cleveland Clinic's Rare Disease Center focus on meeting the needs of people with rare diseases through innovative research and clinical care.
Recent findings published in Human Molecular Genetics detail a new neurodevelopmental disorder discovered by a multidisciplinary team lead by Cleveland Clinic researcher Bin Zhang, PhD, Genomic Medicine, and Northeast Ohio physician Heng Wang, MD.
The disorder, characterized by autism-like symptoms, motor issues and seizures, is linked to a gene called PPP1R3F, which the researchers discovered helps the brain store and process the sugar glycogen for energy.
As Medical Director of the Das Deutsch Center in Middlefield, Ohio, Dr. Wang sees many children with rare genetic disorders - primarily from Northeast Ohio's Amish community.
When one patient presented with symptoms characteristic of a neurodevelopmental disorder, but one that he had not seen before, Dr. Wang ordered whole exon sequencing to read and look for abnormalities in genes across the child's entire DNA sequence.
The results showed a variant in the PPP1R3F gene, which he then entered in GeneMatcher – an international, deidentified gene-matching database. The database revealed 12 other patients worldwide with variants of the same gene. The patients shared similar symptoms.
Dr. Wang sought out the expertise of Dr. Zhang, who studies similar genes in his lab, to confirm whether a variant in the PPP1R3F gene was responsible for this previously uncharacterized neurodevelopmental disorder.
"It's rare for a clinician to order whole exon sequencing for a patient who presents with autism spectrum disorder or with seizures," Dr. Zhang says. "Most tests look for specific genes that we already know cause symptoms. In this case, the next-generation sequencing helped us find a new potential disease-causing candidate that would have been overlooked."
The lab results confirmed that variations in the PPP1R3F gene affect the ability of brain cells to maintain glycogen levels, suggesting that these variants may affect glycogen metabolism in the brain of patients with this newly identified disorder. This is significant because it points to a little-understood link between glycogen metabolism deficiencies in the brain and developmental and cognitive problems.
Dr. Zhang says that the next steps of understanding this disorder will require additional collaboration.
"We believe even more patients could be affected by this disorder," says Dr. Zhang, referencing that other variations in PPP1R3F could also be linked to autism or epilepsy. "We believe that someday soon, our work will lead us to being able to make clinical recommendations for these patients to help improve their quality of life."
With their awards, Drs. Srivastava and Zhang will study the blood-clotting protein factor VIII.