RESUMEN
Copy number variants and indels in 251 families with evidence of X-linked intellectual disability (XLID) were investigated by array comparative genomic hybridization on a high-density oligonucleotide X chromosome array platform. We identified pathogenic copy number variants in 10% of families, with mutations ranging from 2 kb to 11 Mb in size. The challenge of assessing causality was facilitated by prior knowledge of XLID-associated genes and the ability to test for cosegregation of variants with disease through extended pedigrees. Fine-scale analysis of rare variants in XLID families leads us to propose four additional genes, PTCHD1, WDR13, FAAH2, and GSPT2, as candidates for XLID causation and the identification of further deletions and duplications affecting X chromosome genes but without apparent disease consequences. Breakpoints of pathogenic variants were characterized to provide insight into the underlying mutational mechanisms and indicated a predominance of mitotic rather than meiotic events. By effectively bridging the gap between karyotype-level investigations and X chromosome exon resequencing, this study informs discussion of alternative mutational mechanisms, such as noncoding variants and non-X-linked disease, which might explain the shortfall of mutation yield in the well-characterized International Genetics of Learning Disability (IGOLD) cohort, where currently disease remains unexplained in two-thirds of families.
Asunto(s)
Cromosomas Humanos X/genética , Variaciones en el Número de Copia de ADN/genética , Mutación INDEL/genética , Discapacidad Intelectual/genética , Rotura Cromosómica , Segregación Cromosómica/genética , Estudios de Cohortes , Enfermedad/genética , Femenino , Reordenamiento Génico/genética , Genes Ligados a X/genética , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Reproducibilidad de los Resultados , Retroelementos/genética , Eliminación de Secuencia/genéticaRESUMEN
OBJECTIVE: Use of the bacteriology laboratory to guide antibiotic prescribing in primary care is often considered inappropriate due to difficulties of access in a relevant time scale. The overnight analysis offered to general practitioners in the Grampian area of Scotland for the past 6 years (ABLE), and which had previously been shown to reduce antibiotic prescribing by two-thirds in a randomized controlled trial, was audited to see if it was being used correctly in general practice, that is to reduce unnecessary antibiotic prescribing. METHODS: 699 consultations were audited. Of these, 357 were ABLE patients. The other 342 were chosen because an antibiotic had been prescribed. RESULTS: Only 36.7% (140) of the ABLE patients were prescribed an antibiotic, 65.7% being given a delayed action script. All but 10 were culture positive. ABLE patients had a greater proportion of urinary tract infections than the non-ABLE patients, but less lower-respiratory and skin or soft-tissue infection. The antibiotics prescribed reflected the differences in infection type. The repeat visit rate and repeat antibiotic prescription rate were almost identical between the two groups. CONCLUSION: While the overall use of ABLE in Grampian is low, its use seems to be appropriate in that it is successfully being used to identify bacterial infection and reduce unnecessary antibiotic prescribing.