Centromere protein A (Cenpa for mouse, CENP-A for other species) is a histone H3-like protein that is thought to be involved in the nucleosomal packaging of centromeric DNA. Using gene targeting, we have disrupted the mouse Cenpa gene and demonstrated that the gene is essential. Heterozygous mice are healthy and fertile whereas null mutants fail to survive beyond 6.5 days postconception. Affected embryos show severe mitotic problems, including micronuclei and macronuclei formation, nuclear bridging and blebbing, and chromatin fragmentation and hypercondensation. Immunofluorescence analysis of interphase cells at day 5.5 reveals complete Cenpa depletion, diffuse Cenpb foci, absence of discrete Cenpc signal on centromeres, and dispersion of Cenpb and Cenpc throughout the nucleus. These results suggest that Cenpa is essential for kinetochore targeting of Cenpc and plays an early role in organizing centromeric chromatin at interphase. The evidence is consistent with the proposal of a critical epigenetic function for CENP-A in marking a chromosomal region for centromere formation.

BackgroundGenomic testing has reached the point where, technically at least, it can be cheaper to undertake panel-, exome- or whole genome testing than it is to sequence a single gene. An attribute of these approaches is that information gleaned will often have uncertain significance. In addition to the challenges this presents for pre-test counseling and informed consent, a further consideration emerges over how - ethically - we should conceive of and respond to this uncertainty. To date, the ethical aspects of uncertainty in genomics have remained under-explored.DiscussionIn this paper, we draft a conceptual and ethical response to the question of how to conceive of and respond to uncertainty in genomic medicine. After introducing the problem, we articulate a concept of ‘genomic uncertainty’. Drawing on this, together with exemplar clinical cases and related empirical literature, we then critique the presumption that uncertainty is always problematic and something to be avoided, or eradicated. We conclude by outlining an ‘ethics of genomic uncertainty’; describing how we might handle uncertainty in genomic medicine. This involves fostering resilience, welfare, autonomy and solidarity.ConclusionsUncertainty will be an inherent aspect of clinical practice in genomics for some time to come. Genomic testing should not be offered with the explicit aim to reduce uncertainty. Rather, uncertainty should be appraised, adapted to and communicated about as part of the process of offering and providing genomic information.

Cascade testing or screening provides an important mechanism for identifying people at risk of a genetic condition. For some autosomal dominant conditions, such as Familial Hpercholesterolaemia (FH), identifying relatives allows for significant health-affecting interventions to be administered, which can extend a person's life expectancy significantly. However, cascade screening is not without ethical implications. In this paper, we examine one ethically contentious aspect of cascade screening programmes, namely the alternative methods by which relatives of a proband can be contacted. Should the proband be responsible for contacting his or her family members, or should the screening programme contact family members directly? We argue that direct contact is an ethically justifiable method of contact tracing in cascade screening for FH. Not only has this method of contact already been utilised without adverse effects, an examination of the ethical arguments against it shows these are unsubstantiated. We describe several criteria which, if met, will allow an appropriate balance to be struck between maximising the efficiency of family tracing and respecting the interests of probands and their relatives.