RESUMEN
OBJECTIVES: To develop a comprehensive mutation analysis system with a high rate of detection, to develop a tool to predict the chance of detecting a mutation in the L1CAM gene, and to look for genotype-phenotype correlations in the X-linked recessive disorder, L1 syndrome. METHODS: DNA from 367 referred patients was analysed for mutations in the coding sequences of the gene. A subgroup of 100 patients was also investigated for mutations in regulatory sequences and for large duplications. Clinical data for 106 patients were collected and used for statistical analysis. RESULTS: 68 different mutations were detected in 73 patients. In patients with three or more clinical characteristics of L1 syndrome, the mutation detection rate was 66% compared with 16% in patients with fewer characteristics. The detection rate was 51% in families with more than one affected relative, and 18% in families with one affected male. A combination of these two factors resulted in an 85% detection rate (OR 10.4, 95% CI 3.6 to 30.1). The type of mutation affects the severity of L1 syndrome. Children with a truncating mutation were more likely to die before the age of 3 than those with a missense mutation (52% vs 8%; p=0.02). CONCLUSIONS: We developed a comprehensive mutation detection system with a detection rate of almost 20% in unselected patients and up to 85% in a selected group. Using the patients' clinical characteristics and family history, clinicians can accurately predict the chance of finding a mutation. A genotype-phenotype correlation was confirmed. The occurrence of (maternal) germline mosaicism was proven.
Asunto(s)
Análisis Mutacional de ADN/métodos , Estudios de Asociación Genética , Asesoramiento Genético/métodos , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Molécula L1 de Adhesión de Célula Nerviosa/genética , Secuencia de Bases , Niño , Preescolar , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Mutación de Línea Germinal , Humanos , Lactante , Recién Nacido , Masculino , Mosaicismo , Molécula L1 de Adhesión de Célula Nerviosa/análisis , Guías de Práctica Clínica como Asunto , SíndromeRESUMEN
The most frequent monogenic predisposition to CRC is hereditary non-polyposis colorectal cancer (HNPCC). Less frequent are syndromes with polyposis. In some families the occurrence of CRC indicates a familial risk of CRC without the diagnostic criteria for the above syndromes being fulfilled. In families where causative mutations are identified, predictive genetic testing is offered. When no mutation is identified in a family, the risk of individual members of the family is evaluated according to the family history. Individuals with a high risk of CRC are offered surveillance.