BACKGROUND
Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level.
METHODS
To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient’s clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes.
RESULTS
We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%).
CONCLUSIONS
Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children’s Hospital Foundation and others.)
Metabolomics of EVLP perfusate revealed a small panel of metabolites highly correlated with early LTx outcomes, and may be potential biomarkers that can improve selection of marginal lungs on EVLP. Further validation studies are needed to confirm these findings.
In Canada, there is a recent trend toward non-categorization of services of students with emotional and behavioural disabilities (EBD). Yet in Alberta, the coding of students with EBD provides opportunities to diagnose students' learning difficulties but is hindered in this process, in large part, by being tied into special needs funding. Current coding and subsequent funding practices favour a medical model approach that provides opportunity to over-and misidentify students for higher funding levels. Though this is likely done with good intentions to get services otherwise denied, it may have led to a perverse situation of the practice of 'coding for dollars' for these students. In this article we discuss the Alberta EBD coding and funding model using administrative data as well as conclusion remarks from a seminar participated in by different stakeholders. Recommendations for policy changes will be addressed.
Literature aimed at addressing ways to meet learning needs of disenfranchised students can be enhanced through the addition of case studies. International comparative approaches looking at the specifics of cases can also add to the literature on schooling for disenfranchised students. The purpose of our research was to elicit the perceptions of humanities educators in Spain and in Canada regarding enhancing opportunities to retain disenfranchised students in secondary schools. Our analysis was based on case studies and document analysis. For the purpose of this research, disenfranchised is defined as at-risk of leaving school prior to high school completion due to personal difficulties resulting from environmental conditions (such as poverty, family difficulties, drug addiction, and violent communities).
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