RESUMEN
BACKGROUND: High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID). RESULTS: We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed. CONCLUSIONS: Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.
Asunto(s)
Discapacidad Intelectual/genética , Aberraciones Cromosómicas , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN/genética , Femenino , Estudios de Asociación Genética , Genómica , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Masculino , Linaje , FenotipoRESUMEN
Glycosuria as an accidental finding implies a diagnostic workout. We present the cases of two asymptomatic female teenagers referred to a hospital outpatient clinic due to isolated glycosuria detected in a routine analysis. The diagnostic workout revealed isolated glycosuria in the absence of other abnormalities. The genetic study confirmed the diagnosis of renal glycosuria, by revealing SCL5A2 gene mutations. Renal glycosuria is characterized by persistent glycosuria in the absence of hyperglycaemia or generalized renal tubular dysfunction. It's usually asymptomatic and has good prognosis. The authors call the attention to this rare entity, since it can be the reason for reference to a hospital outpatient clinic, underlining the importance of a differential diagnosis with more serious diseases that require proper treatment.
Asunto(s)
Glucosuria Renal/diagnóstico , Adolescente , Femenino , HumanosRESUMEN
A glicosúria como achado acidental implica um estudo etiológico. Apresentam-se os casos de duas adolescentes do sexo feminino, assintomáticas, referenciadas por glicosúria detectada em análise de rotina. Negavam infecções, traumatismos e ingestão de fármacos ou tóxicos. O estudo efetuado confirmou glicosúria na ausência de outras alterações. O estudo genético revelou a presença de mutações do gene SCL5A2, confirmando o diagnóstico de glicosúria renal. A glicosúria renal familiar caracteriza-se por glicosúria isolada persistente na ausência de hiperglicemia e de disfunção tubular renal generalizada. É, geralmente, assintomática e o prognóstico é favorável. Alerta-se para esta rara entidade, pois pode ser motivo de referenciação para consulta de pediatria, salientando-se a importância do diagnóstico diferencial com afecções mais graves que necessitam de tratamento adequado.
Glycosuria as an accidental finding implies a diagnostic workout. We present the cases of two asymptomatic female teenagers referred to a hospital outpatient clinic due to isolated glycosuria detected in a routine analysis. The diagnostic workout revealed isolated glycosuria in the absence of other abnormalities. The genetic study confirmed the diagnosis of renal glycosuria, by revealing SCL5A2 gene mutations. Renal glycosuria is characterized by persistent glycosuria in the absence of hyperglycaemia or generalized renal tubular dysfunction. It's usually asymptomatic and has good prognosis. The authors call the attention to this rare entity, since it can be the reason for reference to a hospital outpatient clinic, underlining the importance of a differential diagnosis with more serious diseases that require proper treatment.
Asunto(s)
Adolescente , Femenino , Humanos , Glucosuria Renal/diagnósticoRESUMEN
The Kallmann syndrome is characterised by the association of hypogonadotropic hypogonadism and hypo/anosmia. It represents a phenotypically and genotypically heterogeneous clinical entity, with six genes identified so far in the literature-KAL1, FGFR1, PROKR2, PROK2, CHD7 and FGF8. Mutations in the FGFR1 gene can be found in approximately 10% of the patients. The authors present the case of a female adolescent with hypogonadotropic hypogonadism and impaired olfactory acuity in the presence of hypoplasia of the nasal sulcus and agenesis of the olfactory bulbs. The molecular analysis of the fibroblast growth factor receptor 1 identified a heterozygous mutation c.1377_78insA (p.V460SfsX3) in exon 10 of FGFR1 gene. This mutation has not yet been reported in the literature. A theoretical review of clinical features and therapeutic approach of this syndrome is also presented.