Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

Background Skeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a heterogeneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies. Developments in genetic and treatment technologies are leading to unparalleled therapeutic advances; thus, it is more important than ever to molecularly confirm SD conditions. Data on ‘rates-of-molecular yields’ in SD conditions, through exome sequencing approaches, is limited. Figures of 39% and 52.5% have been reported in the USA (n = 54) and South Korea (n = 185) respectively. Methods We discuss a single-centre (in the UK) experience of whole-exome sequencing (WES) in a cohort of 15 paediatric patients (aged 5 months to 12 years) with SD disorders previously molecularly unconfirmed. Our cohort included patients with known clinical diagnoses and undiagnosed skeletal syndromes. Extensive phenotyping and expert radiological review by a panel of international SD radiology experts, coupled with a complex bioinformatics pipeline, allowed for both gene-targeted and gene-agnostic approaches. Results Significant variants leading to a likely or confirmed diagnosis were identified in 53.3% (n = 8/15) of patients; 46.7% (n = 7/15) having a definite molecular diagnosis and 6.7% (n = 1/15) having a likely molecular diagnosis. We discuss this in the context of a rare disease in general and specifically SD presentations. Of patients with known diagnoses pre-WES (n = 10), molecular confirmation occurred in 7/10 cases, as opposed to 1/5 where a diagnosis was unknown pre-test. Thus, diagnostic return is greatest where the diagnosis is known pre-test. For WGS (whole genome sequencing, the next iteration of WES), careful case selection (ideally of known diagnoses pre-test) will yield highest returns. Conclusions Our results highlight the cost-effective use of WES-targeted bioinformatic analysis as a diagnostic tool for SD, particularly patients with presumed SD, where detailed phenotyping is essential. Thorough co-ordinated clinical evaluation between clinical, radiological, and molecular teams is essential for improved yield and clinical care. WES (and WGS) yields will increase with time, allowing faster diagnoses, avoiding needless investigations, ensuring individualised patient care and patient reassurance. Further diagnoses will lead to increased information on natural history/mechanistic details, and likely increased therapies and clinical trials

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3(-/-) mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.Genetics of disease, diagnosis and treatmen

Temperature-based prediction and validation of pink bollworm, Pectinophora gossypiella infestation on cotton crop

Pink bollworm Pectinophora gossypiella infestation on cotton now a days found to be a major alarm to cotton crop in Pakistan. The effect of past and future temperatures climatic factors on the infestation rate of pink bollworm needs to be extensively studied. Field visits were organized in different areas across 17 main districts of Punjab, Pakistan, for eight consecutive years from 2012 to 2019. Based on past data, the pink bollworm infestation rate for the year 2040 was estimated. Our results showed an extensive infestation of pink bollworm on cotton throughout the visited locations between 0.1 and 35.7 % range above the economic threshold level, that cause reasonable cotton productivity losses. Based on the results of historical data of infestation rate, the nine of the 17 districts (53 %), Bahawalnagar, Bahawalpur, Faisalabad, Jahang, Mianwali, Multan, Muzaffargarh, Rahimyar Khan, and Lodhran, showed significantly (p < 0.05) higher pink bollworm infestation rate than the other cotton-growing areas. Moreover, the systematic increase level of pink bollworm infestation was predicted in 2040, especially in the five districts, Bhakar, Jahang, Khanewal, Faisalabad, and Vehari. Considering the importance of biological parameters, different temperature regimes (21 °C, 28 °C, and 35 °C) were tested for the validity of temperature-based prediction. Our results showed that growth capacity of P. gossypiella were increased at 28 °C. It revealed that, variation in weather due to current climatic condition with decreases of temperature increases P. gossypiella infestation on cotton crop. In this investigation, the effects of a severe outbreak of pink bollworm infections in Punjab's cotton-growing regions are discussed

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3−/− mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling

Global Asthma Network survey suggests more national asthma strategies could reduce burden of asthma

Background Several countries or regions within countries have an effective national asthma strategy resulting in a reduction of the large burden of asthma to individuals and society. There has been no systematic appraisal of the extent of national asthma strategies in the world. Methods The Global Asthma Network (GAN) undertook an email survey of 276 Principal Investigators of GAN centres in 120 countries, in 2013–2014. One of the questions was: “Has a national asthma strategy been developed in your country for the next five years? For children? For adults?”. Results Investigators in 112 (93.3%) countries answered this question. Of these, 26 (23.2%) reported having a national asthma strategy for children and 24 (21.4%) for adults; 22 (19.6%) countries had a strategy for both children and adults; 28 (25%) had a strategy for at least one age group. In countries with a high prevalence of current wheeze, strategies were significantly more common than in low prevalence countries (11/13 (85%) and 7/31 (22.6%) respectively, p &lt; 0.001). Interpretation In 25% countries a national asthma strategy was reported. A large reduction in the global burden of asthma could be potentially achieved if more countries had an effective asthma strategy. © 2017 SEICA