Objective This study aimed to evaluate the clinical and functional impact of a novel apolipoprotein A5 (ApoA5) variant by assessing lipoprotein lipase (LPL) activity. Subjects and methods Demographic and clinical data, including blood lipid levels and body mass index, were retrospectively collected from an endocrinology clinic registry. Ten individuals with familial chylomicronemia syndrome (FCS) carrying a novel APOA5 variant were included. Whole-exome sequencing was performed using the latest generation DNB-SEQ400 platform. LPL activity was measured in post-heparin plasma using a radiometric assay. Statistical analysis: Categorical variables were summarized as frequencies and percentages, and continuous variables as mean ± standard deviation or median (range), as appropriate. Group comparisons were performed using the Mann-Whitney U test or chi-square test. Analyses were conducted using the Statistical Package for the Social Sciences software (v. 25.0). A p-value < 0.05 was considered statistically significant. Results We report ten cases of FCS with a homozygous missense variant of uncertain significance in APOA5: c.694T>C; p.(Ser232Pro), located in exon 3. In six patients assessed for LPL activity, levels remained consistently below 20% compared to normotriglyceridemic controls. The addition of exogenous serum containing APOA5 restored LPL activity to above 20% in all cases, indicating functional rescue. Conclusion Measurement of LPL activity demonstrated the functional impact of the APOA5 c.694T>C; p.(Ser232Pro) variant. These findings support reclassification of the variant as likely pathogenic and enable differentiation from multifactorial chylomicronemia syndrome.
Johnayro Gutiérrez, P. Castaño, Claudia Monsalve et al.· Archives of Endocrinology an...· 0 citations
RASopathies are a group of genetic disorders caused by germline variants affecting the RAS/MAPK pathway. Their shared phenotypic features—craniofacial anomalies, cardiac defects, cutaneous findings, neurodevelopmental issues, and cancer predisposition—make diagnosis challenging, especially since most lack standardized clinical criteria. This study aimed to develop a practical diagnostic algorithm based on high-frequency Human Phenotype Ontology (HPO) features. Key clinical variables for each RASopathy were identified through HPO, PubMed, and GeneReviews. Only findings present in 80–99% of cases or supported by expert consensus were included. A decision-tree algorithm was constructed and preliminarily evaluated using a blinded cohort of 50 individuals with confirmed molecular diagnoses. Patients were eligible for inclusion if they met the following criteria: (1) molecularly confirmed diagnosis of a RASopathy by next-generation sequencing identifying a pathogenic or likely pathogenic variant; (2) availability of complete phenotypic records in the institutional clinical database; and (3) age at evaluation between 0 and 18 years. Patients were excluded if phenotypic data were incomplete or if molecular confirmation was absent. The algorithm integrates phenotypic patterns and genotype–phenotype correlations. Validation showed 78% accuracy (95% CI: 64.0–88.4%) for clinical diagnosis and 66% accuracy (95% CI: 51.2–78.8%) for molecular prediction. To our knowledge, this is the first HPO-based diagnostic algorithm for the clinical and molecular approach to RASopathies. It provides a structured, accessible tool to improve early recognition and guide molecular testing, particularly for the RASopathy subtypes represented in the validation cohort. Further external validation including underrepresented subtypes is required.
Fernanda Meneses, C. Quintero, J. Lores et al.· International Journal of Mol...· 0 citations
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