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Keeling, Nicholas J.; Dunn, Tyler J.; Bentley, John P.; Ramachandran, Sujith; Hoffman, James M.; Rosenthal, Meagen
doi: 10.1038/s41436-021-01186-xpmid: 33927377
PurposeBarriers to the implementation of pharmacogenomics in clinical practice have been thoroughly discussed over the past decade.MethodsThe objective of this scoping review was to characterize the peer-reviewed literature surrounding the experiences and actions of prescribers, pharmacists, or genetic counselors when using pharmacogenomic information in real-world or hypothetical research settings.ResultsA total of 33 studies were included in the scoping review. The majority of studies were conducted in the United States (70%), used quantitative or mixed methods (79%) with physician or pharmacist respondents (100%). The qualitative content analysis revealed five major methodological approaches: hypothetical clinical case scenarios, real-world studies evaluating prescriber response to recommendations or alerts, cross-sectional quantitative surveys, cross-sectional qualitative surveys/interviews, and a quasi-experimental real-world study.ConclusionThe findings of this scoping review can guide further research on the factors needed to successfully integrate pharmacogenomics into clinical care.
Rossignol, Francis; Duarte Moreno, Marvid S.; Benoist, Jean-François; Boehm, Manfred; Bourrat, Emmanuelle; Cano, Aline; Chabrol, Brigitte; Cosson, Claudine; Díaz, José Luís Dapena; D’Harlingue, Arthur; Dimmock, David; Freeman, Alexandra F.; García, María Tallón;
Wensink, D.; Langendonk, J. G.; Overbey, J. R.; Balwani, M.; Van Broekhoven, E. J. E.; Wagenmakers, M. A. E. M.; Wilson, J. H. P.; Wheeden, K.; Naik, H.; Desnick, R. J.
doi: 10.1038/s41436-021-01176-zpmid:
Schnur, Rhonda E.; Yousaf, Sairah; Liu, James; Chung, Wendy K.; Rhodes, Lindsay; Marble, Michael; Zambrano, Regina M.; Sobreira, Nara; Jayakar, Parul; Pierpont, Mary Ella; Schultz, Matthew J.; Pichurin, Pavel N.; Olson, Rory J.; Graham, Gail E.; Osmond, Matthew;
Polubothu, Satyamaanasa; Zecchin, Davide; Al-Olabi, Lara; Lionarons, Daniël A.; Harland, Mark; Horswell, Stuart; Thomas, Anna C.; Hunt, Lilian; Wlodarchak, Nathan; Aguilera, Paula; Brand, Sarah; Bryant, Dale; Carrera, Cristina; Chen, Hui; Elgar, Greg; Harwood, Catherine A.; Howell, Michael; Larue, Lionel; Loughlin, Sam;
Allen, Emily Graves; Charen, Krista; Hipp, Heather S.; Shubeck, Lisa; Amin, Ashima; He, Weiya; Nolin, Sarah L.; Glicksman, Anne; Tortora, Nicole; McKinnon, Bonnie; Shelly, Katharine E.; Sherman, Stephanie L.
doi: 10.1038/s41436-021-01177-ypmid: 33927378
PurposeApproximately 20–30% of women with an FMR1 premutation experience fragile X–associated primary ovarian insufficiency (FXPOI); however, current risk estimates based on repeat size only identify women with the midrange of repeats to be at the highest risk.MethodsTo better understand the risk by repeat size, we collected self-reported reproductive histories on 1,668 women and divided them into high-resolution repeat size bins of ~5 CGG repeats to determine a more accurate risk for FXPOI in relation to CGG repeat length.ResultsAs previously reported, women with 70–100 CGG repeats were at the highest risk for FXPOI using various statistical models to compare average age at menopause and risk of FXPOI, with women with 85–89 repeats being at the highest risk. Importantly, women with <65 repeats or >120 repeats did not have a significantly increased risk for FXPOI compared to women with <45 repeats.ConclusionUsing a large cross-section study on 1,668 women, we have provided more personalized risk assessment for FXPOI using high-resolution repeat size bins. Understanding the variability in risk has important implications for family planning and overall health among women with a premutation.
Zhou, Amy; Rand, Casey M.; Hockney, Sara M.; Niewijk, Grace; Reineke, Patrick; Speare, Virginia; Berry-Kravis, Elizabeth M.; Zhou, Lili; Jennings, Lawrence J.; Yu, Min; Ceccherini, Isabella; Bachetti, Tiziana; Pennock, Melanie; Yap, Kai Lee;
Eddiry, Sanaa; Diene, Gwenaelle; Molinas, Catherine; Salles, Juliette; Auriol, Françoise Conte; Gennero, Isabelle; Bieth, Eric; Skryabin, Boris V.; Rozhdestvensky, Timofey S.; Burnett, Lisa C.; Leibel, Rudolph L.; Tauber, Maithé; Salles, Jean Pierre
doi: 10.1038/s41436-021-01185-ypmid: 34040195
PurposePrader–Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction due to deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene appears critical for the expression of the PWS phenotype. We aimed to clarify the role of SNORD116 in cellular and animal models with regard to growth hormone therapy (GHT), the main approved treatment for PWS.MethodsWe collected serum and induced pluripotent stem cells (iPSCs) from GH-treated PWS patients to differentiate into dopaminergic neurons, and in parallel used a Snord116 knockout mouse model. We analyzed the expression of factors potentially linked to GH responsiveness.ResultsWe found elevated levels of circulating IGFBP7 in naive PWS patients, with IGFBP7 levels normalizing under GHT. We found elevated IGFBP7 levels in the brains of Snord116 knockout mice and in iPSC-derived neurons from a SNORD116-deleted PWS patient. High circulating levels of IGFBP7 in PWS patients may result from both increased IGFBP7 expression and decreased IGFBP7 cleavage, by downregulation of the proconvertase PC1.ConclusionSNORD116 deletion affects IGFBP7 levels, while IGFBP7 decreases under GHT in PWS patients. Modulation of the IGFBP7 level, which interacts with IGF1, has implications in the pathophysiology and management of PWS under GHT.Graphical Abstract[graphic not available: see fulltext]
Showing 1 to 10 of 25 Articles
doi: 10.1038/s41436-021-01200-2pmid: 34040193
PurposeProlidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature.MethodsNineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival.ResultsOur cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old.ConclusionProlidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH.
PurposePatients with erythropoietic protoporphyria (EPP), a severe painful photodermatosis, experience prodromal sensations when exposed to sunlight, which are the “warning signals” to exit the sun, as prolonged exposure causes an excruciatingly painful phototoxic attack. The unique prodromal cutaneous sensations are reversible and differ from the severe burning pain attack lasting 2–7 days. Previously, afamelanotide treatment was studied using time to pain or time outside as primary outcome measures. Since patients have an ingrained fear of sunlight, these measures did not capture the full treatment effect. We retrospectively characterized and evaluated time to prodrome (TTP) as a safer, patient-reported outcome (PRO) measure in afamelanotide-treated patients.MethodsStructured interviews recorded TTP before and during afamelanotide treatment in retrospective US and Dutch cohort studies.ResultsThirty-one US and 58 Dutch EPP patients participated. Before afamelanotide treatment, 54.8% US and 39.7% Dutch patients reported TTP onset <10 minutes in direct sunlight. In both studies, patients’ TTP’s were significantly longer during afamelanotide treatment (p < 0.0001). All US patients’ TTP increased; no TTP was <10 minutes. Among Dutch patients 81% improved; only 10.3% reported TTPs < 10 minutes.ConclusionEPP patients reported substantial improvements in TTP during afamelanotide treatment. TTP could provide a safer, PRO-based efficacy endpoint for assessing future EPP treatments.
doi: 10.1038/s41436-021-01182-1pmid: 34040189
PurposeThe human chromosome 19q13.11 deletion syndrome is associated with a variable phenotype that includes aplasia cutis congenita (ACC) and ectrodactyly as specific features. UBA2 (ubiquitin-like modifier-activating enzyme 2) lies adjacent to the minimal deletion overlap region. We aimed to define the UBA2-related phenotypic spectrum in humans and zebrafish due to sequence variants and to establish the mechanism of disease.MethodsExome sequencing was used to detect UBA2 sequence variants in 16 subjects in 7 unrelated families. uba2 loss of function was modeled in zebrafish. Effects of human missense variants were assessed in zebrafish rescue experiments.ResultsSeven human UBA2 loss-of-function and missense sequence variants were detected. UBA2-phenotypes included ACC, ectrodactyly, neurodevelopmental abnormalities, ectodermal, skeletal, craniofacial, cardiac, renal, and genital anomalies. uba2 was expressed in zebrafish eye, brain, and pectoral fins; uba2-null fish showed deficient growth, microcephaly, microphthalmia, mandibular hypoplasia, and abnormal fins. uba2-mRNAs with human missense variants failed to rescue nullizygous zebrafish phenotypes.ConclusionUBA2 variants cause a recognizable syndrome with a wide phenotypic spectrum. Our data suggest that loss of UBA2 function underlies the human UBA2 monogenic disorder and highlights the importance of SUMOylation in the development of affected tissues.
doi: 10.1038/s41436-021-01204-ypmid: 34145395
PurposeMuch of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach.MethodsWhole-genome copy-number findings in patients with melanoma predisposition syndrome congenital melanocytic nevus were extrapolated to a sporadic melanoma cohort. Functional effects of duplications in PPP2R3B were investigated using immunohistochemistry, transcriptomics, and stable inducible cellular models, themselves characterized using RNAseq, quantitative real-time polymerase chain reaction (qRT-PCR), reverse phase protein arrays, immunoblotting, RNA interference, immunocytochemistry, proliferation, and migration assays.ResultsWe identify here a previously unreported genetic susceptibility to melanoma and melanocytic nevi, familial duplications of gene PPP2R3B. This encodes PR70, a regulatory unit of critical phosphatase PP2A. Duplications increase expression of PR70 in human nevus, and increased expression in melanoma tissue correlates with survival via a nonimmunological mechanism. PPP2R3B overexpression induces pigment cell switching toward proliferation and away from migration. Importantly, this is independent of the known microphthalmia-associated transcription factor (MITF)-controlled switch, instead driven by C21orf91. Finally, C21orf91 is demonstrated to be downstream of MITF as well as PR70.ConclusionThis work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching.
doi: 10.1038/s41436-021-01178-xpmid: 33958749
PurposeCCHS is an extremely rare congenital disorder requiring artificial ventilation as life support. Typically caused by heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene, identification of a relationship between PARM length and phenotype severity has enabled anticipatory management. However, for patients with non-PARMs in PHOX2B (NPARMs, ~10% of CCHS patients), a genotype–phenotype correlation has not been established. This comprehensive report of PHOX2B NPARMs and associated phenotypes, aims at elucidating potential genotype–phenotype correlations that will guide anticipatory management.MethodsAn international collaboration (clinical, commercial, and research laboratories) was established to collect/share information on novel and previously published PHOX2B NPARM cases. Variants were categorized by type and gene location. Categorical data were analyzed with chi-square and Fisher’s exact test; further pairwise comparisons were made on significant results.ResultsThree hundred two individuals with PHOX2B NPARMs were identified, including 139 previously unreported cases. Findings demonstrate significant associations between key phenotypic manifestations of CCHS and variant type, location, and predicted effect on protein function.ConclusionThis study presents the largest cohort of PHOX2B NPARMs and associated phenotype data to date, enabling genotype–phenotype studies that will advance personalized, anticipatory management and help elucidate pathological mechanisms. Further characterization of PHOX2B NPARMs demands longitudinal clinical follow-up through international registries.