Since its inception in May 2008, the Undiagnosed Diseases Program at the National Institutes of Health has received more than 4,000 physician inquiries and in excess of 1,250 patients' medical records. Investigators involved in this trans-NIH initiative — led by William Gahl, clinical director of the National Human Genome Research Institute — have tackled more than 200 cases of rare diseases to date.
Speaking to an audience of intramural investigators at the NIH Research Festival last month, Gahl outlined his team's use of million-SNP arrays and whole-exome sequencing in its efforts to characterize cryptic genetic diseases. Aside from providing patients and their families with — albeit somewhat indeterminate — diagnoses and treatment options, Gahl said that his team aims to assess the utility of genomic techniques in perplexing clinical scenarios.
"Our goal is to really use this type of next-generation genetics and our ... patients to model how whole-exome sequencing and how SNP-array analysis can be used to discover new diseases," Gahl said.
Nearly half of all cases that filter through the program's screening process are neurological in nature, and a substantial portion of cases are pediatric.
Gahl's team has found that, on average, program patients do not have more copy-number variants than healthy individuals. "The number of SNPs … is virtually the same for the controls and the patients," he said. Notably, many of the disease-causing mutations they have detected occur in runs of homozygosity — that is, genomic regions ranging from 200 kilobases to 15 megabases in length in which heterozygosity is markedly absent.
In this way, investigators have determined the degree of consanguinity among some patients' ancestors. Gahl said that one patient showed "three percent homozygosity in his genome," which is consistent with a second-cousin relationship between his parents. "This is important because in regions of homozygosity, [within] the model of an autosomal recessive disease, all you need is one mutation in an ancestor. … The amount of homozygosity is a real indication of, and can be correlated with, the disease state," he added.
In a case involving five blood-related patients who all showed painful ectopic calcifications in their vasculature, Gahl's group identified runs of homozygosity in the genomic region in which the gene that encodes the CD73 enzyme resides. In their subsequent pathway analyses, Gahl's team determined that adenosine is critical for calcium phosphatase inhibition, which represents a "disease function that was not known before" and postulated a potential therapy involving lentiviral transduction of CD73, as the resumption of adenosine production might inhibit calcification.
Investigations such as these have "revealed not only a new disease, but a new mechanism and possible therapeutics," Gahl said. "We learn a lot from rare diseases which may be applicable to common diseases."