The Patient in Precision Medicine: A Systematic Review Examining Evaluations of Patient-Facing Materials.

Precision medicine (PM) has the potential to tailor healthcare to the individual patient by using their genetic information to guide treatment choices. However, this process is complex and difficult to understand for patients and providers alike. With a recent push in the healthcare community to understand the patient experience and engage patients in their care, it is important to give patients the opportunity to learn about PM. We performed a systematic review to identify previous work assessing the quality of patient-facing PM materials from 2008 to July 2018. Ten studies were identified, which used varying methods and measures. A qualitative assessment was conducted to compare key elements of the studies, including study design, characteristics of the participant population, what measurements were used to assess the PM materials, understandability, preference, psychological reactions, and the type of PM materials being assessed. The studies identified provide important groundwork by highlighting consistent aspects of design that aid in comprehension. Eight of the ten studies focused on the content and organization of genomic test results, while the remaining two assessed educational tools. Two main design elements that appeared across the studies were appropriately designed visual aids and simplified language. The studies identified were limited by the participant populations that were used, which were primarily white and well educated. Only one study attempted to oversample patient populations typically underrepresented in this type of research. Through our systematic review, it is evident that the breadth of knowledge in this field is limited in scope and that more work must be done to ensure that patients can engage in their care when faced with PM.

VRK2A is an A-type lamin-dependent nuclear envelope kinase that phosphorylates BAF.

The nuclear envelope (NE) is critical for numerous fundamental cellular functions, and mutations in several NE constituents can lead to a heterogeneous spectrum of diseases. We used proximity biotinylation to uncover new constituents of the inner nuclear membrane (INM) by comparative BioID analysis of lamin A, Sun2 and a minimal INM-targeting motif. These studies identify vaccinia-related kinase-2 (VRK2) as a candidate constituent of the INM. The transmembrane VRK2A isoform is retained at the NE by association with A-type lamins. Furthermore, VRK2A physically interacts with A-type, but not B-type, lamins. Finally, we show that VRK2 phosphorylates barrier to autointegration factor (BAF), a small and highly dynamic chromatin-binding protein, which has roles including NE reassembly, cell cycle, and chromatin organization in cells, and subtly alters its nuclear mobility. Together these findings support the value of using BioID to identify unrecognized constituents of distinct subcellular compartments refractory to biochemical isolation and reveal VRK2A as a transmembrane kinase in the NE that regulates BAF.

Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome.

Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs.