De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.

We examined national trends and socioeconomic inequalities in cancer survival in England and Wales during the 1990s, using population-based data on 2.2 million patients who were diagnosed with one of the 20 most common cancers between 1986 and 1999 and followed up to 2001. Patients were assigned to one of five deprivation categories (from 'affluent' to 'deprived') using characteristics of their electoral ward of residence at diagnosis. We estimated relative survival up to 5 years after diagnosis, adjusting separately in each deprivation category for background mortality by age, sex and calendar period. We estimated trends in survival and in the difference in survival between deprivation categories ('deprivation gap') over the periods 1986 -90, 1991 -95 and 1996 -99. We used period analysis to examine likely survival rates in the near future. Survival improved for most cancers in both sexes during the 1990s, and appears likely to continue improving for most cancers in the near future. The deprivation gap in survival between rich and poor was wider for patients diagnosed in the late 1990s than in the late 1980s. Increases in cancer survival in England and Wales during the 1990s are shown to be significantly associated with a widening deprivation gap in survival.

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Primary malignant bone sarcomas (MBS) are rare and there are few studies examining their incidence and outcome. Here, the incidence and survival of all subtypes of MBS registered in England between 1979 and 2007 were analysed from patient registry data held by the National Cancer Intelligence Network (NCIN). Over 11,002 new cases of MBS were registered, an average of 379 per year. There was no change in incidence demonstrated over the study period (p 5 0.08). Although a peak incidence is observed in adolescence, approximately half of MBS are diagnosed in patients over 50 years. An improvement in outcome of MBS was observed between those patients registered from 1979 to 1983 and 1983 to 1987 (p < 0.0001), but there has been no improvement since. In the most recent period studied (patients diagnosed 1998-2002) 5-year survival was 55% in Ewing sarcoma, 70% in chondrosarcoma, 56% in chordoma and 43% in osteosarcoma. Patients diagnosed with osteosarcoma over the age of 40 years or with a non-extremity tumour have a significantly inferior outcome; 22% 5-year survival >40 years compared with 53% <40 years (p < 0.0001) and 16% non-extremity tumour compared to 48% extremity tumour (p < 0.0001). This population-based study has allowed us to confidently define the English incidence and survival rates of both the commoner bone tumours such as osteosarcoma, and rarer entities such as chordoma as well as groups with inferior outcome. The lack of significant improvement over recent decades for these diseases is cause for concern and further research.Malignant tumours arising in bone (MBS) are uncommon. The majority are sarcomas, or primary mesenchymal tumours. Bone sarcomas are much less common than those arising in soft tissue but even together, they account for less than 1% of cancers. 1 Although rare, MBS are important as they include two major cancers of children and young people, osteosarcoma and Ewing sarcoma. A proportion of people with these illnesses may be cured but often with complex multi-modality therapies. 2 In comparison with other cancers, knowledge of epidemiology, aetiology and biology of bone tumours has been insufficient to lead to any recent improvements in identification, prevention or treatment.There are important aetiological associations with genetic conditions such as retinoblastoma and some skeletal dysplasias. 3,4 There is a well-recognised association with prior exposure to ionising radiation, particularly for osteosarcoma. 5,6 The age distribution of osteosarcoma also gives some aetiological clues, with incidence being greatest during the skeletal growth period of adolescence but also occurring in later life, classically thought to be in association with Paget's disease. 7 A recent review of aetiological factors in bone tumours demonstrated some putative associations but further research is clearly required. 8 There are a number of studies that have examined the incidence and outcome of patients with MBS using data from registries and databases, or examining specific tumour types or age groups. [9...

BackgroundCornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.MethodsWe screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.ResultsPathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.ConclusionsFuture diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.