Model organisms contribute to diagnosis and discovery in the undiagnosed diseases network: current state and a future vision

Abstract

Decreased sequencing costs have led to an explosion of genetic and genomic data. These data have revealed thousands of candidate human disease variants. Establishing which variants cause phenotypes and diseases, however, has remained challenging. Significant progress has been made, including advances by the National Institutes of Health (NIH)-funded Undiagnosed Diseases Network (UDN). However, 6000-13,000 additional disease genes remain to be identified. The continued discovery of rare diseases and their genetic underpinnings provides benefits to affected patients, of whom there are more than 400 million worldwide, and also advances understanding the mechanisms of more common diseases. Platforms employing model organisms enable discovery of novel gene-disease relationships, help establish variant pathogenicity, and often lead to the exploration of underlying mechanisms of pathophysiology that suggest new therapies. The Model Organism Screening Center (MOSC) of the UDN is a unique resource dedicated to utilizing informatics and functional studies in model organisms, including worm (Caenorhabditis elegans), fly (Drosophila melanogaster), and zebrafish (Danio rerio), to aid in diagnosis. The MOSC has directly contributed to the diagnosis of challenging cases, including multiple patients with complex, multi-organ phenotypes. In addition, the MOSC provides a framework for how basic scientists and clinicians can collaborate to drive diagnoses. Customized experimental plans take into account patient presentations, specific genes and variant(s), and appropriateness of each model organism for analysis. The MOSC also generates bioinformatic and experimental tools and reagents for the wider scientific community. Two elements of the MOSC that have been instrumental in its success are (1) multidisciplinary teams with expertise in variant bioinformatics and in human and model organism genetics, and (2) mechanisms for ongoing communication with clinical teams. Here we provide a position statement regarding the central role of model organisms for continued discovery of disease genes, and we advocate for the continuation and expansion of MOSC-type research entities as a Model Organisms Network (MON) to be funded through grant applications submitted to the NIH, family groups focused on specific rare diseases, other philanthropic organizations, industry partnerships, and other sources of support.

Keywords: C. elegans; Drosophila melanogaster; Model organisms; Undiagnosed diseases; Zebrafish.

Fig. 1

Overview of Phase I activity of the Model Organism Screening Center (MOSC) of the Undiagnosed Diseases Network (UDN). A total of 239 variants were submitted for consideration from the 907 cases evaluated at Phase I UDN Clinical Sites. States with Phase I Clinical Sites are marked in red. After bioinformatic analysis on all submissions, 59 genes were selected for study by the Fly Core and 16 genes by the Zebrafish Core. Gene names in red indicate novel disease gene candidates, whereas those in black represent proposed phenotypic expansions, according to the assessment by the clinical sites at the time of submission to the MOSC. Gene names that are in bold and underlined indicate cases where data from the MOSC directly led to a diagnosis (see Table 1 for details)

Fig. 2

Schematic of the relationships among teams that make up the Model Organism Screening Center (MOSC). Functions of the MOSC and Clinical Sites are noted in blue. Arrows symbolize the collaborative communication among teams

Fig. 3

Overview of information flow and activities, including original evaluation of the patient and candidate variant identification to model organism (MO) studies. Outputs include pathogenicity assessment and, in some cases, a “deeper dive” into the underlying mechanism. Proposed Model Organism Network (MON) activities include identifying disease mechanisms for additional genes through collaborations with other model organism experts. The red box indicates potential interactions with ongoing gene discovery programs such as the Centers for Mendelian Genomics (CMG) or its future equivalents