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Timely diagnosis and therapeutic management of rare diseases (RDs) are greatly hampered by limited clinical information and a lack of reliable epidemiological data. RDs constitute a heterogeneous group of disorders, and although they have become major public health issues, there is a paucity of both population- and disease-based data on them, particularly in developing countries. Next-generation sequencing (NGS) has revolutionized the diagnosis of these disorders by allowing fast and cost-effective identification of disease-causing genetic variants, as well as the development of reliable, molecular diagnosis–based registries. Presented here is a 20-year retrospective, single-center study of molecularly confirmed RDs, with causal variants classified as pathogenic or likely pathogenic according to the ACMG criteria. Only disorders with an OMIM disease number or publications regarding them were considered. A total of 605 RDs, classified in 14 different clinical categories, were genetically confirmed. The most common diseases were ocular disorders (34%), neurodevelopmental disorders (23.5%), and neurological disorders (11%). Among the 605 identified disorders, 326 were autosomal dominant, 225 were autosomal recessive, 43 were X-linked, 7 had mitochondrial inheritance, and 4 were caused by somatic mosaicism. A total of 534 genes/genomic regions were demonstrated to carry disease-causing variants. This is the first catalog of genetically confirmed RDs in Mexico, and it can be considered a first step toward a better characterization of the spectrum of such diseases in the country. Patients’ increasing access to diagnostic exome and/or genome sequencing tests has enabled unprecedented success in RD characterization at the genetic level. The vast majority of genetic diagnoses in our series (~ 75%) occurred in the past eight years, which coincides with a wider availability of NGS testing in Mexico. Our catalog is freely accessible through an online database (https://0198bb3b-526c-b682-3f6d-c5894015db9b.share.connect.posit.cloud/), which is intended to be continuously maintained, extended, and updated with contributions from other health professionals in the field of RDs in Mexico. This resource might accelerate the characterization of such diseases in the country, and it may also play a role in the development of a reliable national registry of RD patients.