Diagnostic value of exome and whole genome sequencing in craniosynostosis.

BACKGROUND: Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ∼1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. METHODS: We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. RESULTS: We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). CONCLUSIONS: This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Background. Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ~1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. Methods. We utilised exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high priority cases, and in whom prior clinically-driven genetic testing had been negative. Results. We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (2 families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). Conclusions. This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results

Examining the cost effectiveness of interventions to promote the physical health of people with mental health problems: a systematic review

Recently attention has begun to focus not only on assessing the effectiveness of interventions to tackle mental health problems, but also on measures to prevent physical co-morbidity. Individuals with mental health problems are at significantly increased risk of chronic physical health problems, such as cardiovascular disease or diabetes, as well as reduced life expectancy. The excess costs of co-morbid physical and mental health problems are substantial. Potentially, measures to reduce the risk of co-morbid physical health problems may represent excellent value for money

Leading edge chemical crystallography service provision and its impact on crystallographic data science in the twenty-first century

National facilities provide state-of-the-art crystallographic instrumentation and processes and tend to act as an indicator for the direction of a community in the medium term. There has been a significant step up in terms of instrumentation and approach in the last 10 years which has driven data generation. This has had a significant impact on databases – in turn we observe a substantial change in the use of the Cambridge Structural Database (CSD) from relatively basic search/retrieve to gaining deep understanding about factors that govern the solid state. Databases are now able to drive new science in areas such as crystal engineering. Looking forward, we will see more automated pipelining of the data generation process, and this will require better integration with databases. Databases will provide more predictive power – and this will inform the science/crystallography that should be done