Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature.

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.

A Retrospective Exploration of the Impact of the 'Angelina Jolie Effect' on the Single State-Wide Familial Cancer Program in Perth, Western Australia.

Global media has the power to influence the ways the public engage with health services. On May 14th 2013, Angelina Jolie published an article in the New York Times magazine, outlining her decision to undergo BRCA mutation testing due to a family history of cancer; then proceed with a mastectomy. The article evoked significant interest from the media and the public. During the months that followed, the Familial Cancer Program (FCP) at Genetic Services of Western Australia (GSWA) experienced a significant increase in referrals and enquiries. Resources were overstretched and it became clear we needed to adjust work practices to manage the escalating numbers. New strategies were devised to cope with the influx of enquiries, albeit without the benefit of additional resources. We conducted an audit of referrals to the FCP made between January 2012 and December 2014. This included a comparison of the months prior to and following the New York Times article. The aim of the audit was to quantify the impact of the "Angelina Jolie effect" on referrals to the FCP. Whilst the increased awareness of the role of genetic services in risk assessment and testing for familial breast and ovarian cancer was considered positive, pre-referral risk assessment at the primary health level to evaluate the appropriateness of their patients for referral could have been helpful. Potentially, many inappropriate referrals to FCP may have been avoided with primary health evaluation thus lessening the burden on our service and preventing unnecessary worry in well women who possessed minimal family history or risk factors. It is important to understand the factors driving the uptake of risk reduction activities, particularly if engagement with a genetics service is considered part of that pathway. Continued education about cancer risk due to family history, individual features and awareness surrounding genetic testing criteria, costs and availability is required for both the public and health professionals.

A structural determinant of mycophenolic acid resistance in eukaryotic inosine 5'-monophosphate dehydrogenases.

Mycophenolic acid (MPA) is a potent natural product inhibitor of fungal and other eukaryotic inosine 5'-monophosphate dehydrogenases (IMPDHs) originally isolated from spoiled corn silage. MPA is produced by the filamentous fungi Penicillium brevicompactum, which contains two IMPDHs, PbIMPDHA and PbIMPDHB, both of which are MPA-resistant. The MPA binding sites of these enzymes are identical to MPA-sensitive IMPDHs, so the structural determinants of resistance are unknown. Here we show that a single residue, Ser267, accounts for the MPA resistance of PbIMPDHA. Substitution of Ser267 with Ala, the residue most commonly found in this position in eukaryotic IMPDHs, makes PbIMPDHA sensitive to MPA. Conversely, Aspergillus nidulans IMPDH becomes MPA-resistant when the analogous Ala residue is substituted with Ser. These substitutions have little effect on the catalytic cycles of either enzyme, suggesting the fitness costs are negligible despite the strong conservation of Ala at this position. Intriguingly, while only 1% of fungal IMPDHs contain Ser or Thr at position 267, these residues are found in the IMPDHs from several Aspergillus species that grow at the low temperatures also favored by Penicillium. Perhaps Ser/Thr267 is an evolutionary signature of MPA exposure.

The role of historical intuitions in children's and adults' naming of artifacts.

It is commonly assumed that artifacts are named solely on the basis of properties they currently possess; in particular, their appearance and function. The experiments presented here explore the alternative proposal that the history of an artifact plays some role in how it is named. In three experiments, children between the ages of 4 and 9 years and adults were presented with familiar artifacts whose appearance and function were then radically altered. Participants were tested as to whether they believed that the modified objects were still members of the artifact kind. Results indicate that object history becomes increasingly important over the course of development.

Influence of parental health literacy and dosing responsibility on pediatric glaucoma medication adherence.

OBJECTIVE: To assess glaucoma medication adherence in children, hypothesizing that poor parental health literacy and eye drop instillation by the child are associated with worse adherence. METHODS: This prospective, observational study enrolled pediatric patients with glaucoma who were prescribed eye drops. Parent(s) reported who was responsible for eye drop instillation (parent vs child), took the Rapid Estimate of Adult Literacy in Medicine, and were instructed on the use and purpose of the Medication Event Monitoring System. Calculations included average adherence (proportion of prescribed doses taken), dosing errors (number of overdosing or underdosing events in 24 hours), and proportion of doses taken on schedule (doses taken within 2 hours of prescribed dosing interval). Results are reported as mean (SD) or median. RESULTS: The study included 46 of the 50 enrolled children who used the Medication Event Monitoring System for 30 days or more. Adherence ranged from 43% to 107% (93% [12%]) and was not associated with age (slope, 0.09 [0.52]; P = .86) but decreased with the parent's lower health literacy (slope, 0.62 [0.24]; P = .01).The mean number of dosing errors for medications prescribed daily vs twice daily was similar (3.3 vs 2.9; P = .66). The proportion of doses taken on schedule (within 2 hours of prescribed dosing interval) ranged from 3% to 97% (median, 34%; mean, 41% [24%]) and was better when the parent vs the child instilled eye drops (46% [26%] vs 23% [19%]; P < .001). CONCLUSIONS: Time-dependent glaucoma medication adherence was better when the parent was responsible for eye drop instillation. Overall decreased adherence was associated with decreased parental health literacy. Children of parents with poor health literacy are vulnerable to poor medication adherence; efforts to address poor health literacy may improve outcomes.