RESUMEN
Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Fenotipo , Humanos , Femenino , Masculino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Niño , Alemania , Secuenciación del Exoma/métodos , Adolescente , Estudios de Asociación Genética/métodos , Pruebas Genéticas/métodos , Preescolar , Estudios Prospectivos , Adulto , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/diagnóstico , Lactante , Adulto JovenRESUMEN
In the era of high throughput sequencing, special software is required for the clinical evaluation of genetic variants. We developed REEV (Review, Evaluate and Explain Variants), a user-friendly platform for clinicians and researchers in the field of rare disease genetics. Supporting data was aggregated from public data sources. We compared REEV with seven other tools for clinical variant evaluation. REEV (semi-)automatically fills individual ACMG criteria facilitating variant interpretation. REEV can store disease and phenotype data related to a case to use these for phenotype similarity measures. Users can create public permanent links for individual variants that can be saved as browser bookmarks and shared. REEV may help in the fast diagnostic assessment of genetic variants in a clinical as well as in a research context. REEV (https://reev.bihealth.org/) is free and open to all users and there is no login requirement.
Asunto(s)
Variación Genética , Programas Informáticos , Humanos , Fenotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Enfermedades Raras/genética , Enfermedades Raras/diagnóstico , Bases de Datos GenéticasRESUMEN
Generalized lipodystrophy is a feature of various hereditary disorders, often leading to a progeroid appearance. In the present study we identified a missense and a frameshift variant in a compound heterozygous state in SUPT7L in a boy with intrauterine growth retardation, generalized lipodystrophy, and additional progeroid features. SUPT7L encodes a component of the transcriptional coactivator complex STAGA. By transcriptome sequencing, we showed the predicted missense variant to cause aberrant splicing, leading to exon truncation and thereby to a complete absence of SUPT7L in dermal fibroblasts. In addition, we found altered expression of genes encoding DNA repair pathway components. This pathway was further investigated and an increased rate of DNA damage was detected in proband-derived fibroblasts and genome-edited HeLa cells. Finally, we performed transient overexpression of wildtype SUPT7L in both cellular systems, which normalizes the number of DNA damage events. Our findings suggest SUPT7L as a novel disease gene and underline the link between genome instability and progeroid phenotypes.
Asunto(s)
Retardo del Crecimiento Fetal , Lipodistrofia Generalizada Congénita , Factores de Transcripción , Humanos , Masculino , Daño del ADN , Reparación del ADN/genética , Retardo del Crecimiento Fetal/genética , Fibroblastos/metabolismo , Células HeLa , Lipodistrofia/genética , Lipodistrofia Generalizada Congénita/genética , Mutación con Pérdida de Función , Mutación Missense , Factores de Transcripción/genéticaRESUMEN
Genomic variant prioritization is crucial for identifying disease-associated genetic variations. Integrating facial and clinical feature analyses into this process enhances performance. This study demonstrates the integration of facial analysis (GestaltMatcher) and Human Phenotype Ontology analysis (CADA) within VarFish, an open-source variant analysis framework. Challenges related to non-open-source components were addressed by providing an open-source version of GestaltMatcher, facilitating on-premise facial analysis to address data privacy concerns. Performance evaluation on 163 patients recruited from a German multi-center study of rare diseases showed PEDIA's superior accuracy in variant prioritization compared to individual scores. This study highlights the importance of further benchmarking and future integration of advanced facial analysis approaches aligned with ACMG guidelines to enhance variant classification.