Rhys Dore

The concentration of proteins containing intrinsically disordered regions must be tightly controlled to maintain cellular homeostasis ^1,2 . However, mechanisms for collective control of these proteins, which tend to localize to membraneless condensates, are less understood than pathways mediated by membrane-bound organelles ^3,4 . Here we report ‘interstasis’, a homeostatic mechanism in which increased concentration of proteins within RNA–protein condensates induces the sequestration of their own mRNAs. The selectivity of interstatic mRNA capture relies on the structure of the genetic code and conserved codon biases, which ensure that similar multivalent RNA regions encode similar low-complexity domains. For example, arginine-enriched mixed charge domains (R-MCDs) tend to be encoded by repetitive purine-rich sequences in mRNAs. Accumulation of proteins containing R-MCDs increases the cohesion of nuclear speckles, which induces selective capture of purine-rich multivalent mRNAs. The multivalent regions are bound by specific RNA-binding proteins, including TRA2 proteins, which relocalize to speckles upon interstasis to promote selective mRNA capture. CLK-mediated phosphorylation of TRA2 proteins counters their localization to speckles, thereby modulating interstasis. Thus, the condensation properties of nuclear speckles act as a sensor for interstasis, a collective negative-feedback loop that co-regulates mRNAs of highly dosage-sensitive genes, which primarily encode nuclear condensation-prone proteins.

Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson’s disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1 . We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1 . Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1 . We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1 . These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function—yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.

Primary ciliary dyskinesia (PCD) is a rare, chronic genetic condition with variable features arising from motile cilia dysfunction, including recurrent respiratory infections, sinonasal disease, reduced hearing, infertility and situs inversus. The aim of the study was to understand the experiences of young people with PCD as they transition into adulthood and adult healthcare services. An interpretative phenomenological analytical method was applied. Semi-structured interviews were conducted with three participants aged 18–24 years. Four interconnected group experiential themes were identified: (1) reconceptualising a stigmatised identity, (2) sharing the journey to independence, (3) entering adulthood with newfound autonomy, (4) anticipating an uncertain future. Overall, we found that transition for young people with PCD presents as a complex period marked by identity-formation, creating systems of support and becoming an autonomous adult. Facilitation of personalised and integrated approaches to care should be prioritised. Our findings are important to help health professionals provide appropriate, anticipatory support.

The COVID-19 pandemic changed the delivery of healthcare within the United Kingdom. A virtual model of care, utilising telephone and video consultations, was rapidly imposed upon cancer genetics teams. This large-scale change in service delivery has led to new opportunities that can be harnessed to improve patient care. There is a clear potential to mitigate geographical barriers, meet increasing patient expectations of implementing virtual consultations, reduce hospital carbon footprints, and decrease hospital costs while increasing efficiency. However, there are also significant challenges introduced by this model of care. Virtual healthcare consultations introduce another new level of digital exclusion for patients and clinicians. There are also potential challenges for maintaining patient confidentiality, and limited utility in circumstances where a physical exam may be warranted. For clinicians, there may be impacts on empathetic responses delivered and challenges in workflow and workload. Virtual consultations are likely to continue being a feature of cancer genetics services. A flexible approach is needed to allow for virtual and traditional models of care to work together and best meet patients’ needs. Cancer genetics services should harness the opportunities provided by virtual processes to improve patient care, whilst collaborating with patient groups and other stakeholders to carefully examine and address the challenges that virtual consultations introduce.

The European Society of Human Genetics—Young Committee (ESHG-Y) aims to support young human geneticists by developing strategies and programs for better education and creating a strong network in all European countries. In this report, we present the ESHG-Y projects conducted since its conception. We organized the educational sessions at the ESHG Annual Conference, the European Dysmorphology Meetings, and a virtual session in collaboration with the European Board of Medical Genetics (EBMG). Also, the ESHG-Y regularly promotes relevant activities and succeeded in creating an active network of young geneticists. Our representatives have a supportive role in well-known organizations such as: ESHG Board, ESHG Scientific Program Committee, ESHG Education Committee, EBMG, ERN-Ithaca, Unique - Rare Chromosome Disorder Support group, Orphanet, EuroGEMS, MOOC BIG and more. Taking into consideration all activities and ongoing projects, we can state that the ESHG-Y successfully achieves its objectives and brings young professionals together.

The human genome contains numerous duplicated regions, such as parent-pseudogene pairs, causing sequencing reads to align equally well to either gene. The extent to which this ambiguity complicates transcriptomic analyses is currently unknown. This is concerning as many parent genes have been linked to disease, including GBA1, causally linked to both Parkinson’s and Gaucher disease. We find that most of the short sequencing reads that map to GBA1 , also map to its pseudogene, GBAP1 . Using long-read RNA-sequencing in human brain, where all reads mapped uniquely, we demonstrate significant differences in expression compared to short-read data. We identify novel transcripts from both GBA1 and GBAP1 , including protein-coding transcripts that are translated in vitro and detected in proteomic data, but that lack GCase activity. By combining long-read with single-nuclear RNA-sequencing to analyse brain-relevant cell types we demonstrate that transcript expression varies by brain region with cell-type-selectivity. Taken together, these results suggest a non-lysosomal function for both GBA1 and GBAP1 in brain. Finally, we demonstrate that inaccuracies in annotation are widespread among parent genes, with implications for many human diseases.

BACKGROUND Ethnic diversity in dermatology has previously been neglected within educational curricula. This has previously been demonstrated within many established dermatology textbooks. Many urban populations find their communities becoming increasingly diverse and medical education must match these changes. The increasing use and modernisation of mobile technology in health education may represent an avenue to provide increasingly diverse knowledge related to dermatology in dark skin populations. OBJECTIVE To review the representation of dark skin photography and diseases in dermatological educational resources provided via mobile application technology. METHODS Mobile applications related to ‘dermatology’ were reviewed within the Google Play Store. Only original mobile applications made for education of medical students or health professionals were analysed. Photographic depictions of dermatological conditions were categorised according to Fitzpatrick type 1-4, Fitzpatrick type 5-6, or uncertain. Additionally, mobile applications were reviewed for information regarding four conditions more common in people with darker skin: central centrifugal cicatricial alopecia, melasma, acral lentiginous melanoma, and keloid scarring. RESULTS Of 200 mobile applications reviewed, 12 were included within the analysis. In total 3755 in-app photographs were categorised into Fitzpatrick type 1-4 (3398 photographs, 90.5%), Fitzpatrick type 5-6 (245 photographs, 6.5%), or uncertain (112 photographs, 3.0%). The degree of photographs showing Fitzpatrick 5-6 ranged from 0.7% to 17.6% between the different mobile applications. This was not significantly different from results previously gained from photographic depictions in dermatology textbooks. Furthermore, the number of mobile applications presenting overt educational information regarding the four conditions reviewed varied considerably; central centrifugal cicatricial alopecia (1 application, 8.3%), melasma (5 applications, 41.7%), acral lentiginous melanoma (4 applications, 33.3%), and keloid scarring (6 applications, 50%). No mobile applications contained information for all four conditions. CONCLUSIONS There is limited depiction of dermatological conditions in darker skin tones within mobile applications aimed at educational students and professionals in dermatology.