#AGBTPH – William Gahl, The NIH Undiagnosed Diseases Program: Expansion to a national and international network

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.

Investigative studies.

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…]

More examples..

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.

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