The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases

Abstract

Purpose This report describes the NIH Undiagnosed Diseases Program (UDP), details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate over its first two years. Methods Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density SNP arrays and whole exome or genome analysis. Results Of 1191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the NIH Clinical Center on the UDP service. Of those, 47% were children, 55% were females, and 53% had neurological disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathological, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based upon SNP array analysis and three others using WES and filtering of variants. Two new disorders were discovered. Analysis of the SNP-array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls. Conclusions The NIH UDP addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies, and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.

Enhanced utility of family-centered diagnostic exome sequencing with inheritance model–based analysis: results from 500 unselected families with undiagnosed genetic conditions

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The Spectrum of Clinical Utilities in Molecular Pathology Testing Procedures for Inherited Conditions and Cancer

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Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma

“…Nextgeneration sequencing is a very powerful diagnostic tool in exome sequencing and can be used to determine the genetic causes of many rare and complex disorders. 2 Next-generation sequencing also permits to take a step forward in reverse phenotyping. 3 Some examples of reverse phenotyping emerge in the literature.…”