U.S. – Russia Scientific Forum
Rare Diseases
Examples from the
Intramural NIH:
Oculocutaneous Albinism
Undiagnosed Diseases Program
David Adams, MD, PhD
National Human Genome Research Institute
National Institutes of Health
The NIH Intramural Program
• The National Institutes of Health
– 90% of resources  Universities, extramural
grants, other initiatives
– 10% of resources  The NIH Intramural Program
• Large research campus near Washington, DC
• The NIH Clinical Center—a hospital dedicated to clinical
research.
• Study participants brought to the NIH to participate in
collaborative research on rare and common illnesses
• Provides a mechanism to see families with rare
conditions who may be spread out over country/world
Two Examples
Oculocutaneous Albinism
The NIH Undiagnosed Diseases Program
• Both studies
– Combine the clinical and research expertise of the
NIH community
– Provide mechanisms for collaborations with
researchers inside and outside the intramural
program
– Focus on rare, ultrarare and/or new diseases
Oculocutaneous Albinism
• Worldwide/pan-ethnic
• ~1:20,000
• An important cause of
inherited visual
impairment
• Primary manifestations
are skin/hair
hypopigmentation and
decreased visual acuity
wikipedia
OCA Genetics and Mechanism
• Syndromic Types
(Hermansky Pudlak Disease,
Chediak Higashi Disease)
• Non-syndromic types
OCA Type 1: Tyrosinase
OCA Type 2: OCA2 protein
OCA Type 3: Tyrosinaserelated protein 1
OCA Type 4: SLC45A2
solute carrier
– Four known genes cause OCA
– One known gene causes OA
In OCA, ~20% of cases will
not have 2 mutations in
any of these genes.
• Defect in melanin
production or melanin
intracellular transport
Tyrosinase Biochemistry
Eye Abnormalities in Albinism
• Foveal
Hypoplasia
• Reduced cone
density
• Reduced visual
acuity
From Wikipedia “fovea”
OCA Natural History Study
Acuity Testing
Recruit OCA
Participants
Basic Science
Investigations
Coherence Tomography
Ophthalmology
Clinical Data
Collection
Evoked Potentials
Retinal Photographs
Audiology
Screening
Spatial Processing
Molecular
Sequencing
Examination/History
Deletion
Adaptation to Low Vision
Confirmation
DNA Variant
Characterization
Bio Materials
Collection
Low Vision OT
Skin Reflectometry
Database
Melanocytes/Fibroblasts
Cell Biology
Plasma/Serum
Immortal line development
Photographs/Family Photographs
In vitro assays
DNA/RNA
Ongoing OCA Projects
Project
Collaborators
Developing clinical trial for a novel therapeutic agent that
increases tyrosinase substrate (tyrosine) and may increase
melanin production in eyes and other tissues.
Brooks
Genotype/phenotype correlations by in silico modeling of
tyrosinase variants.
Sergeev
Understanding the cell biology/functions of OCA2 and OCA4
gene products.
Hearing
Determining causes of OCA when there are no or insufficient
mutations in known OCA genes.
Wang, Gahl
Laboratory
NIH Undiagnosed Disease Program
• Primary Goals
– To provide answers to patients with mysterious
conditions that have long eluded diagnosis
– To advance medical knowledge about rare and
common diseases
• Participants Travel to NIH for Extensive
Diagnostic Evaluation
– Started in 2009
– >5000 inquiries, >400 study participants seen
– Diagnostic and research tools utilized
Records Received
Solved Example: NT5E
NEJM 2011 364:432
Solved Example: Amyloidosis
Unsolved Example: Progressive
Neurological Disorder in a Child
• Normal early
development
• Type I Diabetes
diagnosed at 3 ½ y/o
• Vocal Tremulousness
• Steadily progressive
weakness, dystonia
– Right-sided then
generalized
Unsolved Example: Granulomatous
Skin Disease
Research vs Clinical Approach to
Disease
• Clinical Approach
– Broad range of consultants in one place
– Extensive inpatient evaluation and history taking
– Extensive review of prior records
• Research Approach
– In house and collaborative follow up of diagnostic
leads
– Application of tools for agnostic screening, e.g.
• Metabolic (cell oxidation, microscopy, mass spec.)
• Genetic (whole genome, exome, transcriptome seq.)
Next Generation Sequencing
• Example: Exome Sequencing
– Sequences large subset of all known genes
– Rapid improvements in cost, data quality
– Benefits
• Allows multiple genetic hypotheses to be
explored
– Challenges
• 104 – 105 DNA sequence variants per case
• Many false positives, some false negatives
• Variants must often be verified experimentally
NGS Method Development
• Application to non-optimal cases
– No known consanguinity/regions of homozygosity,
linked regions
– Small families (too small for linkage analysis) or
individuals
• Optimization of strategies to sort/filter
variants
• Low threshold for establishing collaborations
for functional validation of potential diseasecausing variants by subject experts
NGS Example: KCTD7
NGS Example: FA2H
 Combination of SNP array
A
Aa
AA
a
analysis and NGS detects
missense mutation paired with
small deletion
Hardest Problem  Validation
Summary
• The NIH intramural program combines basic
and clinical research
• Two examples of rare-disease research
– Oculocutaneous Albinism
• Studies aimed at understanding clinical, cellular and
genetic aspects of inherited pigmentation disorders
– Undiagnosed Diseases Program
• Study conditions that have long eluded diagnosis
• Aadvance medical knowledge about rare and common
diseases
Summary
“…when there is teamwork and collaboration,
wonderful things can be achieved.”
Mattie Stepanek
Acknowledgements and Contact
Information
• The NIH Undiagnosed Diseases Program
– William A Gahl, MD, PhD, Director
• The NIH National Human Genome Research
Institute
• The many families who partner with us to
advance the cause of rare disease research
• David Adams: david.adams@nih.gov
For an updated copy of these slides, go to:
ftp://ftp.nhgri.nih.gov/pub/NIHUDP/MOSCOW2011/presentation.pdf