Working as true detectives, a team of scientists at Baylor College of Medicine discovered a genetic cause of a newly recognized syndrome that presents with developmental delay, hypotonia, dysmorphic features, and sleep apnea. The vehicle for discovery was a patient from Australia who had these symptoms but could not be diagnosed with a disease after undergoing multiple diagnostic tests. When the Baylor researchers ran a DNA sequence analysis on the patient and her parents, they found five genes differential between the patient and her parents.
One of the mutations was in the gene “AT-Hook binding DNA motif Containing gene” (AHDC1). Similar mutations have never been found in healthy control individuals. “This led us to ask if there were any other undiagnosed disease cases that had similar mutations in this gene,” said Dr. Fan Xia from the Whole Genome Laboratory at BCM in a press release. Consequently, the team examined DNA sequences from 2,000 other unsolved disease cases at the Laboratory and found three candidates who were candidates for the same mutation.
“We found that these patients also had damaging mutations that had newly arisen in the same gene AHDC1,” said Dr. Xia, who is the lead author for the study published in American Journal of Human Genetics. “The independent occurrence of new mutations in each of these families is extremely strong evidence that this gene is the cause of this syndrome.” All four patients studied had similar symptoms, despite their different locations in the world: two were from Texas, one was from Pennsylvania, and the first from Austrália, as mentioned. “We have simultaneously provided answers for the affected families and advanced an important basic research question,” commented Dr. Richard Gibbs, corresponding author of the study.
The frequency of the syndrome is unknown. In fact, “little is known about this gene and the discovery of its link to this syndrome is an important advance towards analyzing its function,” said Dr. Gibbs. Human AHDC1 codes a protein that is 1,603 amino acids long and has two functional units. The mutations were found only in region 2 and preserved region 1. Since the mutations were in a single coding exon, the protein produced may be a dominant-negative protein, which might allow researchers to find a solution to the symptoms.
Other authors on the study include Matthew N. Bainbridge, Michael F. Wangler, Reid Sutton, Roopa L. Nalam, Wenmiao Zhu, Jill V. Hunter, Samantha J. Penney, Arthur L. Beaudet, Sharon E. Plon, Eric A. Boerwinkle, James R. Lupski, Christine M. Eng, Donna M. Muzny and Yaping Yang, all of Baylor; Tiong Yang Tan Margot Nash, Monique M. Ryan, Joy Yaplito-Lee, of the Murdoch Children’s Research Institute of Royal Children’s Hospital in Australia; Elaine H. Zackai, Margaret H. Harr, and Matthew A. Deardorff of The Children’s Hospital of Philadelphia in Pennsylvania and Angela E. Scheuerle of Tesserae Genetics in Dallas, Texas.