The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.
The CB&M showed excellent reliability in youth. Reliability was comparable for live and videotape rating approaches, meaning that the easier and less expensive live-rating can be recommended. Future work should focus on evaluation of responsiveness to change in rehabilitation centre and community intervention contexts.
A new test of olfactory function, the combined olfactory test, has been designed to assess odours easily recognizable by the test population. The test consists of an odour recognition test of nine odours, where an odour in a bottle is chosen from a list of four possible odours in a forced choice manner. This is followed by a threshold test using a series of three-fold dilutions of 1-butanol. The mean of the two scores is the combined olfactory score. The test was subjected to a validation study. It was performed on 133 participants with a normal sense of smell and a normal rhinological examination and on 94 participants who said that they did not have a sense of smell. There was a highly significant difference between the combined olfactory score in the normal and 'anosmic' groups (P < 0.001). This significant difference was the same between the two groups for the threshold and odour recognition arms of the test. There was a highly significant difference (P < 0.001) between the two subgroups of 'completely anosmic' and 'almost anosmic' participants, indicating that the test could grade the degree of olfactory dysfunction.
Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease.
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