BackgroundHeterogeneity in clinical bleeding phenotype has been observed in hemophilia patients with similar FVIII or FIX activity levels. Thrombin generation and plasmin generation, as a global he...Show moreBackgroundHeterogeneity in clinical bleeding phenotype has been observed in hemophilia patients with similar FVIII or FIX activity levels. Thrombin generation and plasmin generation, as a global hemostasis assay, may contribute to a better prediction of which patients are at an increased risk of bleeding.ObjectivesThe objective of this study was to describe the association between clinical bleeding phenotype and thrombin generation and plasmin generation profiles in patients with hemophilia.MethodsThe Nijmegen Hemostasis Assay, which simultaneously measures thrombin and plasmin generation, was performed in plasma samples of patients with hemophilia participating in the sixth Hemophilia in the Netherlands study (HiN6). Patients receiving prophylaxis underwent a washout period. A severe clinical bleeding phenotype was defined as a self-reported annual bleeding rate of ≥5, a self-reported annual joint bleeding rate of ≥3, or the use of secondary/tertiary prophylaxis.ResultsIn total, 446 patients, with a median age of 44 years, were included in this substudy. Thrombin generation and plasmin generation parameters differed between patients with hemophilia and healthy individuals. The median thrombin peak height was 1.0 nM, 25.9 nM, 47.1 nM, and 143.9 nM in patients with severe, moderate, and mild hemophilia and healthy individuals, respectively. A severe bleeding phenotype was observed in patients with a thrombin peak height of <49% and a thrombin potential of <72% compared to healthy individuals, and was independent of the hemophilia severity. The median thrombin peak height was 0.70% in patients with a severe clinical bleeding phenotype and 30.3% in patients with a mild clinical bleeding phenotype. The median thrombin potentials for these patients were 0.06% and 59.3%, respectively.ConclusionA decreased thrombin generation profile is associated with a severe clinical bleeding phenotype in patients with hemophilia. Thrombin generation in combination with bleeding severity may be a better tool to personalize prophylactic replacement therapy irrespective of hemophilia severity. Show less
Background: X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency disease caused by XIAP gene mutations. A broad range of phenotype, severity, and age at onset... Show moreBackground: X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency disease caused by XIAP gene mutations. A broad range of phenotype, severity, and age at onset present challenges for patient management. Objective: We sought to characterize the phenotype, treatment, and survival outcomes of XIAP deficiency and to assess parameters influencing prognosis. Methods: Data published from 2006 to 2020 were retrospectively analyzed. Results: A total of 167 patients from 117 families with XIAP deficiency were reported with 90 different mutations. A wide spectrum of clinical features were seen, of which hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease were the most common. Patients frequently developed multiple features with no clear genotype-phenotype correlation. A total of 117 patients were managed conservatively and 50 underwent hematopoietic stem-cell transplantation (HSCT), with respective overall survival probabilities of 90% and 53% at age 16 years. The predominant indication for HSCT was early-onset HLH. Active HLH and myeloablative conditioning regimens increased HSCT-related mortality, although HSCT outcome was much better after 2015 than before. For conservatively managed patients reaching adulthood, survival probabilities were 86% at age 30 years and 37% by age 52 years, with worse outcomes for patients developing the disease before the age of 5 years or with new disease features in adulthood. Nine asymptomatic mutation carriers with a median age of 13.5 years were identified. Conclusions: Our study demonstrates the variable nature of XIAP deficiency, which evolves over life for individual patients. Better therapeutic strategies and prospective studies are required to reduce morbidity and mortality and improve decision making and long-term outcomes for patients with XIAP deficiency. (J Allergy Clin Immunol 2022;150:456-66.) Show less
BACKGROUND: Up to one-half of childhood sarcomeric hypertrophic cardiomyopathy (HCM) presents before the age of 12 years, but this patient group has not been systematically characterized.OBJECTIVES... Show moreBACKGROUND: Up to one-half of childhood sarcomeric hypertrophic cardiomyopathy (HCM) presents before the age of 12 years, but this patient group has not been systematically characterized.OBJECTIVES: The aim of this study was to describe the clinical presentation and natural history of patients presenting with nonsyndromic HCM before the age of 12 years. METHODS: Data from the International Paediatric Hypertrophic Cardiomyopathy Consortium on 639 children diagnosed with HCM younger than 12 years were collected and compared with those from 568 children diagnosed between 12 and 16 years. RESULTS: At baseline, 339 patients (53.6%) had family histories of HCM, 132 (20.9%) had heart failure symptoms, and 250 (39.2%) were prescribed cardiac medications. The median maximal left ventricular wall thickness z-score was 8.7 (IQR: 5.3-14.4), and 145 patients (27.2%) had left ventricular outflow tract obstruction. Over a median follow-up period of 5.6 years (IQR: 2.3-10.0 years), 42 patients (6.6%) died, 21 (3.3%) underwent cardiac transplantation, and 69 (10.8%) had life-threatening arrhythmic events. Compared with those presenting after 12 years, a higher proportion of younger patients underwent myectomy (10.5% vs 7.2%; P = 0.045), but fewer received primary prevention implantable cardioverter-defibrillators (18.9% vs 30.1%; P = 0.041). The incidence of mortality or life-threatening arrhythmic events did not differ, but events occurred at a younger age. CONCLUSIONS: Early-onset childhood HCM is associated with a comparable symptom burden and cardiac phenotype as in patients presenting later in childhood. Long-term outcomes including mortality did not differ by age of presentation, but patients presenting at younger than 12 years experienced adverse events at younger ages. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. Show less
Haimel, M.; Pazmandi, J.; Heredia, R.J.; Dmytrus, J.; Bal, S.K.; Zoghi, S.; ... ; Boztug, K. 2022
Background: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype... Show moreBackground: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. Objectives: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. Methods: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. Results: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. Conclusions: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities. Show less
Bayley, J.P.; Bausch, B.; Jansen, J.C.; Hensen, E.F.; Tuin, K. van der; Corssmit, E.P.M.; ... ; Neumann, H.P.H. 2021
Background Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD... Show moreBackground Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for SDHD variants. In the present study we zoom in on the genotype-phenotype associations of SDHB gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy. Methods We analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating SDHB variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis. Results Compared with missense variants, truncating SDHB variants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant. Conclusion SDHB truncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function. Show less
Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non... Show morePersonalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs-primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes-and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response. Show less
Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non... Show morePersonalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs-primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes-and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response. Show less
Lee, M. van der; Kriek, M.; Guchelaar, H.J.; Swen, J.J. 2020
The continuous development of new genotyping technologies requires awareness of their potential advantages and limitations concerning utility for pharmacogenomics (PGx). In this review, we provide... Show moreThe continuous development of new genotyping technologies requires awareness of their potential advantages and limitations concerning utility for pharmacogenomics (PGx). In this review, we provide an overview of technologies that can be applied in PGx research and clinical practice. Most commonly used are single nucleotide variant (SNV) panels which contain a pre-selected panel of genetic variants. SNV panels offer a short turnaround time and straightforward interpretation, making them suitable for clinical practice. However, they are limited in their ability to assess rare and structural variants. Next-generation sequencing (NGS) and long-read sequencing are promising technologies for the field of PGx research. Both NGS and long-read sequencing often provide more data and more options with regard to deciphering structural and rare variants compared to SNV panels-in particular, in regard to the number of variants that can be identified, as well as the option for haplotype phasing. Nonetheless, while useful for research, not all sequencing data can be applied to clinical practice yet. Ultimately, selecting the right technology is not a matter of fact but a matter of choosing the right technique for the right problem. Show less
Hack, R.J.; Rutten, J.W.; Person, T.N.; Li, J.; Khan, A.; Griessenauer, C.J.; ... ; Zand, R. 2020
Background and Purpose:Cysteine altering NOTCH3 variants, which have previously been exclusively associated with the rare hereditary small vessel disease cerebral autosomal dominant arteriopathy... Show moreBackground and Purpose:Cysteine altering NOTCH3 variants, which have previously been exclusively associated with the rare hereditary small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, have a population frequency of 1:300 worldwide. Using a large population database, and taking genotype as a starting point, we aimed to determine whether individuals harboring a NOTCH3 cysteine altering variant have a higher load of small vessel disease markers on brain magnetic resonance imaging than controls, as well as a higher risk of stroke and cognitive impairment.Methods:A cross-sectional study using integrated clinical, neuroimaging, and whole-exome sequencing data of 92 456 participants from the Geisinger DiscovEHR initiative cohort. The case group consisted of individuals harboring a NOTCH3 cysteine altering variant (n=118). The control group consisted of randomly selected age- and sex-matched individuals who did not have any nonsynonymous variants in NOTCH3 (n=184). Medical records including brain magnetic resonance imagings were evaluated for clinical and neuroimaging findings associated with small vessel disease. Group comparisons were done using Fisher exact test and ordinal logistic regression models. Risk of stroke was assessed using Cox regression.Results:Of the 118 cases, 39.0% were men, mean age 58.1 +/- 16.9 years; 12.6% had a history of stroke, compared with 4.9% of controls. The risk of stroke was significantly increased after age 65 years (hazard ratio, 6.0 [95% CI, 1.4-26.3]). Dementia, mild cognitive impairment, migraine with aura and depression were equally prevalent in cases and controls. Twenty-nine cases (25%) and 45 controls (24%) had an available brain magnetic resonance imaging. After age 65 years, cases had a higher white matter lesion burden and more lacunes. A severe small vessel disease phenotype compatible with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy was rarely seen.Conclusions:Cysteine altering NOTCH3 variants are an important contributor to the risk of stroke, lacunes, and white matter hyperintensities in the elderly population. Show less
Variants in the Melanocortin 1 Receptor (MC1R) gene have been associated with an increased risk of melanoma, but the role in nevus count is unclear. We investigated if specificMC1Rgene variants or... Show moreVariants in the Melanocortin 1 Receptor (MC1R) gene have been associated with an increased risk of melanoma, but the role in nevus count is unclear. We investigated if specificMC1Rgene variants or the number ofMC1Rgene variants and phenotypical features were associated with nevus count. A total of 494 participants of the 'Leiden skin cancer study' were included and the MC1R gene coding sequence was analysed by single-strand conformation polymorphism analysis followed by sequencing of unknown variants. The association betweenMC1Rgene variants and nevus count and the association between age, gender and phenotypical features and nevus count were studied using the Chi-square test. Study of nine frequently occurringMC1Rgene variants in participants without skin cancer (n = 203) showed that the 'r' Val60Leu variant was significantly associated with high nevus count (>50 nevi) (P = 0.017). This association was very strong among women (P < 0.001), but not present among men. Having one or twoMC1Rvariants in general did not show a significant difference in the nevus count. Hair colour, skin type, eye colour and age were not significantly associated with nevus count, whereas gender showed a significant association (P = 0.008), with the highest nevus counts in female. The Val60Leu variant of the MC1R gene could be a promising candidate as an independent predictor of high nevus count, particularly in women. This information about the genetic makeup could promote personalized follow-up strategies and might help to prevent skin cancer in the future. Show less
Hemophilia A and B are inherited X-linked disorders of hemostasis, associated with an increased bleeding tendency. Patients with severe hemophilia have undetectable clotting factor levels and... Show moreHemophilia A and B are inherited X-linked disorders of hemostasis, associated with an increased bleeding tendency. Patients with severe hemophilia have undetectable clotting factor levels and experience spontaneous bleeds. In patients with nonsevere hemophilia, the clotting factor levels are 2% to 40% of normal and bleeds predominantly occur after provocative events such as trauma and surgery. Despite this milder phenotype, patients with nonsevere hemophilia may suffer from considerable morbidity and have an increased mortality risk. However, many aspects of the course of disease and treatment remain unclear. Information on the factors influencing interindividual differences in bleeding phenotype is lacking, and misdiagnosis may occur due to assay discrepancies in the diagnostic workup. Desmopressin is the preferred treatment modality, but some patients and indications require treatment with clotting factor concentrates. This may elicit inhibitor formation, which is associated with an increased burden of disease and a higher mortality rate. It has been found that patients with nonsevere hemophilia A carry a lifelong risk for this serious complication. In this review, we provide an overview of the current knowledge of the diagnosis and management of nonsevere hemophilia. A report of science presented at the International Society on Thrombosis and Haemostasis 2019 Annual Congress is also provided. Show less
Talib, M.; Schooneveld, M.J. van; Thiadens, A.A.; Fiocco, M.; Wijnholds, J.; Florijn, R.J.; ... ; Boon, C.J.F. 2019
