Assessing non-Mendelian inheritance in inherited axonopathies

PURPOSE: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot–Marie–Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance. METHODS: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis. RESULTS: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA. CONCLUSION: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders

The Four Ethical Commitments in Educational Administration

This article follows from a previous article where the authors offered that a single school of ethical thought is not sufficient to produce the deep understanding necessary for an administrative decision-maker to arrive at an ethical decision which supports her or his personal and public integrity. In particular, this article applies an interactive ethical matrix composed of four commitments, personal conscience, relational reciprocity, common ethical principles, and professional convictions with constraints. The authors argue that these form a multi-frame analysis, and provide the facts and decision of a Canadian legal case to demonstrate how such an ethical analysis is best suited for the attainment of personal and professional integrity amongst educational decision-makers

Implementing Pediatric Growth Charts into an Electronic Health Record System

Electronic health record (EHR) systems are increasingly being adopted in pediatric practices; however, requirements for integrated growth charts are poorly described and are not standardized in current systems. The authors integrated growth chart functionality into an EHR system being developed and installed in a multispecialty pediatric clinic in an academic medical center. During a three-year observation period, rates of electronically documented values for weight, stature, and head circumference increased from fewer than ten total per weekday, up to 488 weight values, 293 stature values, and 74 head circumference values (p < 0.001 for each measure). By the end of the observation period, users accessed the growth charts an average 175 times per weekday, compared to 127 patient visits per weekday to the sites that most closely monitored pediatric growth. Because EHR systems and integrated growth charts can manipulate data, perform calculations, and adapt to user preferences and patient characteristics, users may expect greater functionality from electronic growth charts than from paper-based growth charts