RESUMEN
Non-invasive prenatal testing (NIPT) for fetal aneuploidy detection is increasingly being offered in the clinical setting. Whereas the majority of tests only report fetal trisomies 21, 18 and 13, genome-wide analyses have the potential to detect other fetal, as well as maternal, aneuploidies. In this review, we discuss the technical and clinical advantages and challenges associated with genome-wide cell-free fetal DNA profiling.
Asunto(s)
Aneuploidia , ADN/genética , Enfermedades Fetales/diagnóstico , Diagnóstico Prenatal/métodos , Femenino , Enfermedades Fetales/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Embarazo , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Clinical otosclerosis (OMIM 166800/605727) has a prevalence of 0.2-1% among white adults, making it the single most common cause of hearing impairment in this group. It is caused by abnormal bone homeostasis of the otic capsule with the consequent development of sclerotic foci that invade the stapedio-vestibular joint (oval window) interfering with free motion of the stapes. Impaired ossicular chain mobility results in a conductive hearing loss. We identified the first locus for otosclerosis (OTSC1) on chromosome 15 in 1998 and reported a second locus (OTSC2) on chromosome 7 last year. Here we present results of a genome wide linkage study on a large Cypriot family segregating otosclerosis. Results of this study exclude linkage to OTSC1 and OTSC2 and identify a third locus, OTSC3, on chromosome 6p. The defined OTSC3 interval covers the HLA region, consistent with reported associations between HLA-A/HLA-B antigens and otosclerosis.
Asunto(s)
Cromosomas Humanos Par 6/genética , Ligamiento Genético/genética , Marcadores Genéticos/genética , Otosclerosis/genética , Mapeo Cromosómico/métodos , Femenino , Pruebas Genéticas , Humanos , Escala de Lod , Masculino , LinajeRESUMEN
Otosclerosis is caused by abnormal bone homeostasis of the otic capsule, resulting in hearing impairment in 0.3%-0.4% of the white population. The etiology of the disease remains unclear and environmental as well as genetic factors have been implicated. We localized the first autosomal-dominant locus to chromosome 15 in 1998 (OTSC1) in an Indian family and, recently, we reported the localization of a second gene for otosclerosis to a 16 cM interval on chromosome 7q (OTSC2). In this study, we recruited and analyzed nine additional families (seven Belgian and two Dutch families with 53 affected and 20 unaffected subjects) to investigate the importance of these loci in autosomal-dominant otosclerosis. We completed linkage analysis with three microsatellite markers of chromosome 15 (D15S652, D15S1004, D15S657) and five microsatellite markers of chromosome 7 (D7S495, D7S2560, D7S684, D7S2513, D7S2426). In two families, results compatible with linkage to OTSC2 were found, but in the seven remaining families OTSC1 and OTSC2 were excluded. Heterogeneity testing provided significant evidence for genetic heterogeneity, with an estimated 25% of families linked to OTSC2. These results indicate that, besides OTSC1 and OTSC2, there must be at least one additional otosclerosis locus.
Asunto(s)
Cromosomas Humanos Par 15 , Cromosomas Humanos Par 7 , Heterogeneidad Genética , Otosclerosis/genética , Salud de la Familia , Femenino , Genes Dominantes , Ligamiento Genético , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite , LinajeAsunto(s)
Cromosomas Humanos Par 3/genética , Predisposición Genética a la Enfermedad/genética , Otosclerosis/genética , Adulto , Anciano , Mapeo Cromosómico , Salud de la Familia , Femenino , Genotipo , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Países Bajos , LinajeRESUMEN
Otosclerosis due to abnormal bone homeostasis of the otic capsule is a frequent cause of hearing loss in adults. Usually, the hearing loss is conductive, resulting from fixation of the stapedial footplate, which prevents normal ossicular vibration in response to sound. An additional type of sensorineural hearing loss may be caused by otosclerotic damage to the cochlea. The etiology of the disease is unknown, and both environmental and genetic factors have been implicated. Autosomal dominant inheritance with reduced penetrance has been proposed, but large families are extremely rare. To elucidate the pathogenesis of the disease, identification of the responsible genes is essential. In this study, we completed linkage analysis in a Belgian family in which otosclerosis segregates as an autosomal dominant disease. After excluding linkage to a known locus on chromosome 15 (OTSC1), we found linkage on chromosome 7q, with a multipoint LOD score of 3.54. Analysis of key recombinant individuals maps this otosclerosis locus (OTSC2) to a 16-cM interval on chromosome 7q34-36 between markers D7S495 and D7S2426.