National Human Genome Research Institute
Starts with Acknowledgements.
Goals: help patients get diagnosis… and to discover new diseases.
Anyone can submit an application, and the physician has to send a summary. Then NIH triages the case to decide whether to take it. Reject about 75%. See them for 1 week (free, including travel) as inpatients. Get done about the equivalent of what can be done in 1 year at a regular hospital, with a barrage of tests. Take more children than adults, (40%). Lots of publications!
This program requires good publicity to keep the budget from being cut. Congress has generally been supportive.
Examples: Discovery: 5 adults from Kentucky. Calcification of arteries and joints. Parents were 3rd cousins. (share 1/128th of genes), thus likely homozygous region. Parents were both heterozygous, but homozygous in affected siblings. ROH: 22.4MB. One good candidate gene: NT5E. Details make sense.
70% of patients have skin biopsy, from which fibroblasts were cultured. Could go back and look for others. Could do rescue with vector.
[Into the biochemistry, but too fast to copy down…. Has to do with CD73, AMP-> Adenosine, which signals to inhibit TNAP. If that doesn’t happen, they convert PPi to Pi, which causes mineralization.]
Second example: young girl with dysmorphisms, hypotonia, etc.
Did urine screening, which turned up a tetrasaccharide. Hypothesize deficiency of glucosidase I gene. Compound het turned up in patient in that gene. Story doesn’t end there. Also had low immunoglobulins. Ig was inserted into SCID mouse, and half life was very short – turns out that the sugars are required to protect Igs.
Even more…. did not cause them to have infections. T-Cells found that viral replication was reduced compared to controls. Virus produced was less infective. (Secondary infection reduced). Viruses require glycosylation machinery which wasn’t working!
Third example: parents are first cousins.
Whole exome sequencing: 6 individuals, including 2 parents, 2 unaffected. 1 variant fit: mutation in AFG3L2. Mitochondrial m-AAA protease. There are already neurological diseases associated. Base interacted with both the ability of the protein to homo-dimerise and interact with another protein… so patients had BOTH diseases.
There are Rare diseases, Very rare diseases, and VERY VERY rare diseases that they’ve worked on. [Pages and pages of them…]
Half of diagnostics, half the diagnoses are not made based on NGS… based on doctors and nurses and personal coming together to discuss cases.
Expanded to a Nationwide program. Expanded to 7 sites, with common protocol. Share Identifiable information within sites, and able to share de-identified information publicly.
There is also now a gateway. information is shared through dbGAP, others.
There is a global undiagnosed diseases network…
Phenotype databases (UDPICS), includes exomes and variant analysis. Anyone can get access to this, if requested.
Sharing is important – Example: 22 year old woman with dystonia. By sharing information, they found a physician with 19 other cases with the same gene (in London)… and it made a huge difference in outcome. Patients were eventually diagnosed and 5/19 treated with deep brain simulation, which has worked exceptionally well.