A whole-exome capture and next-generation sequencing was applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, and severe cognitive deficit, and without any identifiable Syndromic pattern, and to her parents, we disclosed a de novo heterozygous pathogenic mutation, c.697_699del p.Phe233del (rs786204835)(ACMG classification PS2, PM1, PM2, PP5), harbored in the PURA gene (MIM*600473) (5q31.3), associated with Autosomal Dominant Mental Retardation 31 (MIM # 616158). We used the significant improvement in the accuracy of protein structure prediction recently implemented in AlphaFold that incorporates novel neural network architectures and training procedures based on the evolutionary, physical, and geometric constraints of protein structures. The wild-type (WT) sequence and the mutated sequence, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURAwt and the PURA–Phe233del showed that the occurrence of the Phe233del affects between 220–320 amino acids. The distortion in the PURA structural conformation in the ~5 Å surrounding area after the p.Phe233del produces a conspicuous disruption of the repeat III, where the DNA and RNA helix unwinding capability occurs. PURA Protein–DNA docking corroborated these results in an in silico analysis that showed a loss of the contact of the PURA–Phe233del III repeat domain model with the DNA. Together, (i) the energetic and stereochemical, (ii) the hydropathic indexes and polarity surfaces, and (iii) the hybrid Quantum Mechanics–Molecular Mechanics (QM–MM) analyses of the PURA molecular models demarcate, at the atomic resolution, the specific surrounding region affected by these mutations and pave the way for future cell-based functional analysis. To the best of our knowledge, this is the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects in protein structure using artificial intelligence algorithms and molecular and atomic resolution stereochemical analyses.

Background and Objectives: Neurodevelopmental disorders (NDDs), including developmental delay (DD), autism spectrum disorder (ASD), intellectual disability (ID), attention-deficit/hyperactivity disorder (ADHD), and specific learning disorders, affect 15% of children and adolescents worldwide. Advances in next-generation sequencing, particularly whole exome sequencing (WES), have improved the understanding of NDD genetics. Methodology: This study analyzed 3244 patients undergoing WES (single, duo, trio analyses), with 1028 meeting inclusion criteria (67% male; aged 0–50 years). Results: Pathogenic (P) or likely pathogenic (LP) variants were identified in 190 patients, achieving a diagnostic yield of 13.4% (singleton), 14% (duo), and 21.2% (trio). A total of 207 P/LP variants were identified in NDD-associated genes: 38% were missense (48 de novo), 29% frameshift (26 de novo), 21% nonsense (14 de novo), 11% splicing site (14 de novo), and 1% inframe (1 de novo). De novo variants accounted for 49.8% of cases, with 86 novels de novo variants and 27 novel non de novo variants unreported in databases like ClinVar or scientific literature. Conclusions: This is the largest study on WES in Colombian children with NDDs and one of the largest in Latino populations. It highlights WES as a cost-effective first-tier diagnostic tool in low-income settings, reducing diagnostic timelines and improving clinical care. These findings underscore the feasibility of implementing WES in underserved populations and contribute significantly to understanding NDD genetics, identifying novel variants with potential for further research and clinical applications.

Considerable fraction of global cancer cases stem from hereditary cancer predisposition syndromes (HCSs). The identification of genetic variants linked to HCSs is crucial for prompt treatment of both patients and their families. This study aimed to assess the diagnostic performance of multigene panels in detecting variants linked to hereditary cancer predisposition in a cohort of 8165 individuals from Colombia. We analyzed 8165 individuals in Colombia (2018–2024), with and without personal or family cancer history, using NGS hereditary cancer panels. Variant interpretation (P, LP, VUS) was performed with SOPHiA DDM and Varsome Clinical, following ACMG guidelines and ClinGen Hereditary Cancer Group criteria. 61.8% (n = 5049) of patients were referred from Bogotá and 38.10% (n = 3116) from other cities in Colombia. It was not possible to distinguish between ethnic groups. The age range of patients was 0–97 (mean = 55 years; SD = 12.1), 86% (n = 7024) were female and 14% (n = 1142) male. 409 P/LP variants were identified in high-penetrance genes such as BRCA1/2, in 946 individuals, resulting in an overall diagnostic yield of 9.82%. Among the most important findings were increased diagnostic yields in ovarian and colorectal cancer, as well as in unaffected individuals with a family history of cancer. Finally, 38 novel variants and recurrent alterations in 27 HCS-related genes reinforce the need to prioritize these biomarkers in diagnostic evaluations. This study provides insights into the performance of genetic panels for detecting HCS-associated variants in the largest Latin American cohort evaluated to date. These findings demonstrate that robust panel-based testing strategies enable the systematic detection of clinically relevant signs that would not be captured through phenotype-driven approaches alone. BRCA1 and BRCA2 were the most frequently altered high-penetrance genes, with higher diagnostic yields in breast, ovarian, and colorectal cancers, as well as in unaffected individuals with a family history. Fundación Universitaria Sanitas.

Background: Comprehensive genomic profiling (CGP) identifies genetic alterations and patterns that are crucial for therapy selection and precise treatment development. In Colombia, limited access to CGP tests underscores the necessity of documenting the prevalence of treatable genetic alterations. This study aimed to describe the somatic genetic profile of specific cancer types in Colombian patients and assess its impact on treatment selection. Methods: A retrospective cohort study was conducted at Clínica Colsanitas S.A. from March 2023 to June 2024. Sequencing was performed on the NextSeq2000 platform with the TruSight Oncology 500 (TSO500) assay, which simultaneously evaluates 523 genes for DNA analysis and 55 for RNA; additionally, analyses were performed with the SOPHiA DDM software. The tumor mutational burden (TMB), microsatellite instability (MSI), and programmed cell death ligand 1 (PDL1) were assessed. Results: Among 111 patients, 103 were evaluated, with gastrointestinal (27.93%), respiratory (13.51%), and central nervous system cancers (10.81%) being the most prevalent. TP53 (37%), KMT2C (28%), and KRAS (21%) were frequent mutations. Actionable findings were detected in 76.7% of cases, notably in digestive (20 patients) and lung cancers (8 patients). MSI was stable at 82.52% and high at 2.91%, whilst TMB was predominantly low (91.26%). Conclusions: The test has facilitated access to targeted therapies, improving clinical outcomes in Colombian patients. This profiling test is expected to increase opportunities for personalized medicine in Colombia.

Introduction: The integration of genetic testing in pediatrics has advanced significantly in recent years. The incorporation of technologies such as Next Generation Sequencing (NGS) and array-based Comparative Genomic Hybridization (aCGH) in increasingly younger patients has accelerated the transition toward precision medicine.Methods: This retrospective cross-sectional study (January 2021–June 2024) included 187 neonates (≤90 days old) from the NICUs of the Clínica Colsanitas network in Bogotá, Colombia and evaluate the diagnostic yield for genomic testing comprising 82 Whole Exome Sequencing (WES) and 125 aCGH tests, with 18 patients undergoing both. This study also examined the phenotypic traits of patients to investigate potential associations with a higher diagnostic yield. Symptoms were characterized using Human Phenotype Ontology (HPO) terms and analyzed with a propagation algorithm for improved accuracy.Results: The diagnostic yield was 30.5% for WES and 8% for aCGH. Noteworthy, we identify four novel SNVs with potential pathogenicity and report a rare case of co-occurring deletion and duplication, both previously unreported in the literature. Phenotypic analysis revealed a strong association between what were considered “growth abnormalities” related to intrauterine growth restriction, low birth weight, and/or growth retardation, with “head or neck abnormalities” related to specific malformations of the face or head and/or dysmorphic facial phenotypes.Discussion: These findings highlight the importance of applying, in particular, WES as a first-level clinical diagnostic test in patients with suspected genetic or complex diseases who are hospitalized in the NICU. Consequently, it is hoped that these results will support the development of clinical guidelines for the integration of molecular genetic testing into neonatal care in Colombia.