Publication Date
10-1-2024
Journal
European Journal of Human Genetics
DOI
10.1038/s41431-023-01523-5
PMID
38177409
PMCID
PMC11499817
PubMedCentral® Posted Date
1-4-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, Chile, Rare Diseases, Phenotype, Male, Female, Child, Undiagnosed Diseases, Exome Sequencing, Child, Preschool, Genetic Testing, Adolescent
Abstract
Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the "diagnostic odyssey" for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.
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Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Diseases Commons, Genetics Commons, Genomics Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons
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