@article {818, title = {A genomic strategy for precision medicine in rare diseases: integrating customized algorithms into clinical practice.}, journal = {J Transl Med}, volume = {23}, year = {2025}, month = {2025 Jan 20}, pages = {86}, abstract = {

BACKGROUND: Despite the use of Next-Generation Sequencing (NGS) as the gold standard for the diagnosis of rare diseases, its clinical implementation has been challenging, limiting the cost-effectiveness of NGS and the understanding, control and safety essential for decision-making in clinical applications. Here, we describe a personalized NGS-based strategy integrating precision medicine into a public healthcare system and its implementation in the routine diagnosis process during a five-year pilot program.

METHODS: Our approach involved customized probe designs, the generation of virtual panels and the development of a personalized medicine module (PMM) for variant prioritization. This strategy was applied to 6500 individuals including 6267 index patients and 233 NGS-based carrier screenings.

RESULTS: Causative variants were identified in 2061 index patients (average 32.9\%, ranging from 12 to 62\% by condition). Also, 131 autosomal-recessive cases could be partially genetically diagnosed. These results led to over 5000 additional studies including carrier, prenatal and preimplantational tests or pharmacological and gene therapy treatments.

CONCLUSION: This strategy has shown promising improvements in the diagnostic rate, facilitating timely diagnosis and gradually expanding our services portfolio for rare diseases. The steps taken towards the integration of clinical and genomic data are opening new possibilities for conducting both retrospective and prospective healthcare studies. Overall, this study represents a major milestone in the ongoing efforts to improve our understanding and clinical management of rare diseases, a crucial area of medical research and care.

}, keywords = {Algorithms, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Precision Medicine, rare diseases}, issn = {1479-5876}, doi = {10.1186/s12967-025-06069-2}, author = {M{\'e}ndez-Vidal, Cristina and Bravo-Gil, Nereida and Perez-Florido, Javier and Marcos-Luque, Irene and Fern{\'a}ndez, Raquel M and Fernandez-Rueda, Jose Luis and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Mart{\'\i}n-S{\'a}nchez, Marta and Fern{\'a}ndez-Su{\'a}rez, Elena and Mena, Marcela and Carmona, Rosario and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {1182, title = {Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy.}, journal = {The Journal of molecular diagnostics : JMD}, year = {2016}, month = {2016 Jan 2}, abstract = {Charcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1\%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies.}, keywords = {Charcot-Marie-Tooth, CMT, Diagnostic, NGS, Panels, rare diseases, Targeted resequencing}, issn = {1943-7811}, doi = {10.1016/j.jmoldx.2015.10.005}, url = {http://www.sciencedirect.com/science/article/pii/S1525157815002615}, author = {Lupo, Vincenzo and Garcia-Garcia, Francisco and Sancho, Paula and Tello, Cristina and Garc{\'\i}a-Romero, Mar and Villarreal, Liliana and Alberti, Antonia and Sivera, Rafael and Joaqu{\'\i}n Dopazo and Pascual-Pascual, Samuel I and M{\'a}rquez-Infante, Celedonio and Casasnovas, Carlos and Sevilla, Teresa and Espin{\'o}s, Carmen} }