RESUMEN
The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
Asunto(s)
Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Genómica/métodos , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Genotipo , Humanos , Mutación/genética , FenotipoRESUMEN
Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Eliminación de Gen , Proteínas del Tejido Nervioso/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Adolescente , Adulto , Trastorno Autístico/genética , Proteínas de Unión al Calcio , Niño , Preescolar , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Exones , Facies , Femenino , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , Moléculas de Adhesión de Célula Nerviosa , Penetrancia , Fenotipo , Esquizofrenia/genética , Adulto JovenRESUMEN
Direct-to-consumer genetic testing came on the scene 2 decades ago as a means for allowing consumers to access their genetic information without the involvement of a physician or genetic counselor. Results are delivered directly to the consumer, often leading to misinterpretation and needless medical interventions or false reassurance. Increasingly, we are seeing these patients in our genetics clinics for test interpretation, management guidance and confirmatory genetic testing.