Whole exome sequencing uncovers defective gene linked to severe growth and metabolic disorders
An emerging technology called whole exome sequencing – which enables researchers to sequence all 20,000 of the body’s genomes at once rather than one gene at a time – has helped identify a defective gene that causes a rare condition marked by a spectrum of growth and metabolic disorders in children.
The defective XRCC4 gene, identified by Andrew Dauber, MD, MMSc, co-leader of the newly formed Cincinnati Center for Growth Disorders, includes a splice mutation that deletes 23 amino acids from the gene, interfering with the body’s ability to repair DNA damage.
XRCC4 was discovered by examining DNA from a Chilean brother and sister, both of whom were diagnosed with severe short statue, gonadal failure and early-onset metabolic syndromes that resulted in a gastrointestinal tumor in the sister, diabetes and other multi-system complications. The 39-year-old brother is still alive; the sister died at 36. Findings based on their tissues were published online March 5, 2015 in The Journal of Clinical Endocrinology & Metabolism.
“The body is constantly repairing damage that occurs to DNA, and this gene is part of the DNA damage repair process,” says Dauber. “We were able to show in skin cells from one of the patients that the cells were not able to execute the DNA damage repair process correctly.”
The finding creates deeper understanding of a spectrum of complications associated with the defective gene, and creates direct links among patient genome sequencing, translational biology in the lab, patient diagnosis and genetic counseling, he says.
“Our patients are among the oldest in the world to be identified, and because of this new understanding, the hope is that we’ll be better able to counsel them and their families about a variety of other issues that they might face, including predisposition to tumors, insulin resistance and other complications.”
