Colleen Wahl

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

Purpose:This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program’s application of genomic technology to establish diagnoses, and details the Program’s success rate during its first 2 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 single-nucleotide polymorphism arrays and whole exome or genome analysis.Results:Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls.Conclusion:The National Institutes of Health Undiagnosed Diseases Program 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.Genet Med 2012:14(1):51–59

The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience.

Purpose:Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants.Methods:Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reportable incidental findings for each participant. We also defined variant status as inherited or de novo for those with available parental sequence data.Results:We identified 14 independent reportable variants in 159 (8.8%) families. For nine families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (nine minor children and four adult children). The remaining five variants occurred in adults for whom parental sequences were unavailable.Conclusion:Our results are consistent with the expectation that a small percentage of exomes will result in identification of an incidental finding under the American College of Medical Genetics and Genomics recommendations. Additionally, our analysis of family sequence data highlights that genome and exome sequencing of families has unavoidable implications for immediate family members and therefore requires appropriate counseling for the family.Genet Med 16 10, 741–750.

Computational evaluation of exome sequence data using human and model organism phenotypes improves diagnostic efficiency.

Purpose:Medical diagnosis and molecular or biochemical confirmation typically rely on the knowledge of the clinician. Although this is very difficult in extremely rare diseases, we hypothesized that the recording of patient phenotypes in Human Phenotype Ontology (HPO) terms and computationally ranking putative disease-associated sequence variants improves diagnosis, particularly for patients with atypical clinical profiles.Methods:Using simulated exomes and the National Institutes of Health Undiagnosed Diseases Program (UDP) patient cohort and associated exome sequence, we tested our hypothesis using Exomiser. Exomiser ranks candidate variants based on patient phenotype similarity to (i) known disease–gene phenotypes, (ii) model organism phenotypes of candidate orthologs, and (iii) phenotypes of protein–protein association neighbors.Results:Benchmarking showed Exomiser ranked the causal variant as the top hit in 97% of known disease–gene associations and ranked the correct seeded variant in up to 87% when detectable disease–gene associations were unavailable. Using UDP data, Exomiser ranked the causative variant(s) within the top 10 variants for 11 previously diagnosed variants and achieved a diagnosis for 4 of 23 cases undiagnosed by clinical evaluation.Conclusion:Structured phenotyping of patients and computational analysis are effective adjuncts for diagnosing patients with genetic disorders.Genet Med 18 6, 608–617.

IgG4-related disease presenting as recurrent mastoiditis

IgG4-related disease (IgG4-RD) is a recently recognized disorder characterized by an overabundance of IgG4-positive plasma cells in affected tissues and, frequently, elevated serum IgG4 levels. First recognized in the context of autoimmune pancreatitisi, IgG4-RD presents as either a localized area of involvement within a single organ or as a multicentric disease, affecting several organs. Those organs include the pancreas, gallbladder, salivary glands, retroperitoneum, kidneys, lungs, prostate, ocular adnexaii, maxillary sinus, ethmoid sinusiii, lacrimal glands, breast, liver, large blood vessels, mediastinum, lymph nodesiv, pituitaryv, esophagusvi, and dura matervii. The histopathology of IgG4-RD involves a lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. The disease process generally destroys the normal tissue architecture and replaces it with fibrotic tissue, creating a variety of histologic patterns. The appearance can be pseudolymphomatous (characterized by a dense infiltrate of small lymphocytes), sclerosing (characterized by fibrosis with some areas of lymphocyte aggregates), or mixed (characterized by fibrosis, plasma cells, and lymphocytic infiltrates)viii. IgG4-RD lesions can progress by infiltrating the surrounding tissues or by expanding as a space-occupying mass. The lesions are often exquisitely sensitive to glucocorticoids, but long-term, prospective therapeutic trials are lacking. We hereby describe a patient with IgG4-RD manifesting as recurrent inflammatory disease of the middle ear and mastoid, complicated by bone erosion.

Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience

Traditionally, the use of genomic information for personalized medical decisions relies on prior discovery and validation of genotype–phenotype associations. This approach constrains care for patients presenting with undescribed problems. The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) hypothesized that defining disease as maladaptation to an ecological niche allows delineation of a logical framework to diagnose and evaluate such patients. Herein, we present the philosophical bases, methodologies, and processes implemented by the NIH UDP. The NIH UDP incorporated use of the Human Phenotype Ontology, developed a genomic alignment strategy cognizant of parental genotypes, pursued agnostic biochemical analyses, implemented functional validation, and established virtual villages of global experts. This systematic approach provided a foundation for the diagnostic or non-diagnostic answers provided to patients and serves as a paradigm for scalable translational research.

Late diagnosis and atypical brain imaging of Aicardi-Goutières syndrome: are we failing to diagnose Aicardi-Goutières syndrome-2?

Aicardi–Goutières syndrome (AGS) is a rare disorder with in utero or postnatal onset of encephalopathy and progressive neurological deterioration. The seven genetic subtypes of AGS are associated with abnormal type I interferon‐mediated innate immune response. Most patients with AGS present with progressive microcephaly, spasticity, and cognitive impairment. Some, especially those with type 2 (AGS2), manifest milder phenotypes, reduced childhood mortality, and relative preservation of physical and cognitive abilities. In this report, we describe two siblings (sister and brother) diagnosed with AGS2 in their second decade, who exhibited static encephalopathy since 1 year of age with spastic quadriplegia and anarthria but preserved intellect. Both were homozygous for the common pathogenic RNASEH2B allele (c.529G>A, p.Ala177Thr). Rather than manifesting calcifications and leukoencephalopathy, both had increased iron signal in the basal ganglia. Our report broadens the clinical and imaging spectrum of AGS2 and emphasizes the importance of including AGS2 in the differential diagnosis of idiopathic spastic cerebral palsy.