Table 1.

Global diagnostic programs for rare genetic disease

Program (Clinical site if applicable)	Launch year	Population characteristics	Prior genomic sequencing	Analytic strategies utilized

Undiagnosed Diseases Program ¹	2008	Heterogenous phenotypes	Nil prior genomic sequencing	Traditional genetic and biochemical investigations, ES, GS
Finding Of Rare disease GEnes (FORGE) Canada Project ^55 56	2010	Paediatric, heterogeneous phenotypes	Nil prior genomic sequencing	Traditional genetic and biochemical investigations, ES
Deciphering Developmental Disorders study ^57 58	2011	Paediatric, primarily neurodevelopmental phenotypes	Nil prior genomic sequencing	Traditional genetic and biochemical investigations, ES
Centers for Mendelian Genomics ³	2012	Heterogenous phenotypes	Various genomic sequencing	ES, GS, RNA-seq, methylation, long read sequencing
Undiagnosed Diseases Network ²	2014	Heterogenous phenotypes	Various genomic sequencing (32% ES-negative)	Clinical review, targeted genetic and biochemical investigations, ES, GS
Undiagnosed Diseases Network (Dukes/Columbia Clinical Site) ¹⁶	2014	Heterogenous phenotypes, predominantly paediatric	Various genomic sequencing (60% ES-negative)	Re-phenotyping, targeting genetic and biochemical investigations, and GS.
Undiagnosed Diseases Network (University of California-Los Angeles Clinical Site) ¹⁵	2014	Heterogenous phenotypes, 79% paediatric	Various genomic sequencing	ES, GS, reanalysis of prior genomic sequencing, RNA-seq
Care4Rare Canadian Consortium ^11 59	2014	Heterozygous phenotypes	Nil previous genomic sequencing	ES, GS, reanalysis of sequencing data, multi-omics
SpainUDP ¹²	2015	Heterogenous phenotypes	Nil previous genomic sequencing	Phenotyping, ES
Italian undiagnosed Rare diseases network ⁶⁰	2016	Heterogenous phenotypes	Nil previous genomic sequencing	Phenotyping, ES
Undiagnosed Diseases Program - Western Australia ¹⁴	2016	Heterogenous phenotypes	Nil previous genomic sequencing	Traditional genetic and biochemical investigations, ES, GS
Japan’s initiative on rare and undiagnosed diseases ⁶¹	2017	Heterogenous phenotypes	Undiagnosed post six months of ‘standard’ investigations	NGS technologies
Korean Undiagnosed Diseases Program ¹³	2017	Primarily paediatric, neurological phenotypes	Nil previous genomic testing	Traditional genetic and biochemical investigations, ES

Table 1 highlights other published international undiagnosed disease programs. These are primarily ongoing diagnostic programs, therefore the data summarised in this table reflect the state of the program at the time of publication and do not summarise the true total number of participants or tests in each program. Generally, there are two main study designs. Either the clinical visit/evaluation with genomic analysis is performed involving those doing the clinical evaluation, or the sequencing is completed independently, with phenotype data provided by the referring physician. All programs allow for pathways to functional studies for novel disease-gene discoveries. Entry into each program required an extensive clinical workup, though we have highlighted if the program reports previous genomic sequence before entry, such as ES or GS. The Undiagnosed Diseases Network (UDN) in the United States has multiple clinical sites. We have only included two of these listed in separate rows in the table to underline different methods reported. Abbreviations – ES exome sequencing; GS – genome sequencing; RNA-seq – RNA sequencing