Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease

Abstract

Background: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added.

Methods: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care.

Results: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes.

Conclusions: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).

Figure 1.. Drosophila Study of NR5A1 p.R92W Variant.

Panels A through I show preparations of cuticles from first-instar drosophila larvae. The first column (Panels A, D, and G) shows cuticles from wild-type controls, in which green fluorescent protein was expressed during egg maturation. Eight prominent abdominal denticle belts and three faint thoracic denticle belts are visible in each panel. The second column shows cuticles from embryos with expression of human NR5A1 at six times the baseline level (Panel B), three times the baseline level (Panel E), and the baseline level (Panel H). Only four or five abdominal denticle belts are present in each panel; overexpression of NR5A1 very severely affects development and causes a phenotype that is very similar to the phenotype observed with the wild-type fly homologue (not shown). The third column shows cuticles from embryos with expression of mutant NR5A1 (NR5A1 p.R92W variant) at six times the baseline level (Panel C), three times the baseline level (Panel F), and the baseline level (Panel I). When mutant NR5A1 is expressed at the baseline level and three times the baseline level, there is no loss of denticle belts, a finding suggestive of a loss-of-function mutation. However, when mutant NR5A1 is expressed at six times the baseline level, it causes loss of some segments, a finding suggestive of a severe loss-of-function mutation but not of a complete null allele. In the first row (Panels A, B, and C), virgin maternal triple driver (MTD) GAL4 females were crossed with UAS males, contributing six doses of GAL4 to the embryo. In the second row (Panels D, E, and F), virgin MTD GAL4/+, UAS/+ females were crossed with male siblings of the same genotype, contributing three doses of GAL4. In the third row (Panels G, H, and I), virgin NGT40 GAL4/+, UAS/+ females were crossed with male siblings of the same genotype, contributing just one dose of GAL4.