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PubMed | Center for Pediatric Genomic Medicine, University of Paris Pantheon Sorbonne, French Atomic Energy Commission, Service de Cardiologie Pediatrique and 5 more.
Type: Journal Article | Journal: Nature genetics | Year: 2015

Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates.


PubMed | Center for Pediatric Genomic Medicine, Rare Disease Unit, Kaiser Permanente, Childrens Hospital of Wisconsin and 8 more.
Type: Clinical Trial | Journal: Molecular genetics and metabolism | Year: 2016

Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427).Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30-60U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty.The study included 24 pediatric patients. Fifteen patients were nave to ERT on entry into the preceding trials TKT032 (12-month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received imiglucerase ERT. Nine patients in the study were previously treated with imiglucerase for >30months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-nave patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients.The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults.


Kamisoglu K.,Rutgers University | Haimovich B.,Rutgers Robert Wood Johnson Medical School | Calvano S.E.,Rutgers Robert Wood Johnson Medical School | Coyle S.M.,Rutgers Robert Wood Johnson Medical School | And 5 more authors.
Critical Care | Year: 2015

Introduction: Two recent, independent, studies conducted novel metabolomics analyses relevant to human sepsis progression; one was a human model of endotoxin (lipopolysaccharide (LPS)) challenge (experimental endotoxemia) and the other was community acquired pneumonia and sepsis outcome diagnostic study (CAPSOD). The purpose of the present study was to assess the concordance of metabolic responses to LPS and community-acquired sepsis. Methods: We tested the hypothesis that the patterns of metabolic response elicited by endotoxin would agree with those in clinical sepsis. Alterations in the plasma metabolome of the subjects challenged with LPS were compared with those of sepsis patients who had been stratified into two groups: sepsis patients with confirmed infection and non-infected patients who exhibited systemic inflammatory response syndrome (SIRS) criteria. Common metabolites between endotoxemia and both these groups were individually identified, together with their direction of change and functional classifications. Results: Response to endotoxemia at the metabolome level elicited characteristics that agree well with those observed in sepsis patients despite the high degree of variability in the response of these patients. Moreover, some distinct features of SIRS have been identified. Upon stratification of sepsis patients based on 28-day survival, the direction of change in 21 of 23 metabolites was the same in endotoxemia and sepsis survival groups. Conclusions: The observed concordance in plasma metabolomes of LPS-treated subjects and sepsis survivors strengthens the relevance of endotoxemia to clinical research as a physiological model of community-acquired sepsis, and gives valuable insights into the metabolic changes that constitute a homeostatic response. Furthermore, recapitulation of metabolic differences between sepsis non-survivors and survivors in LPS-treated subjects can enable further research on the development and assessment of rational clinical therapies to prevent sepsis mortality. Compared with earlier studies which focused exclusively on comparing transcriptional dynamics, the distinct metabolomic responses to systemic inflammation with or without confirmed infection, suggest that the metabolome is much better at differentiating these pathophysiologies. Finally, the metabolic changes in the recovering patients shift towards the LPS-induced response pattern strengthening the notion that the metabolic, as well as transcriptional responses, characteristic to the endotoxemia model represent necessary and "healthy" responses to infectious stimuli. © 2015 Kamisoglu et al.


Makikallio K.,University of Oulu | Kaukola T.,University of Oulu | Tuimala J.,Finnish Red Cross Blood Service | Kingsmore S.F.,Center for Pediatric Genomic Medicine | And 2 more authors.
Cytokine | Year: 2012

Background: Cytokines and growth factors synthesized by placental trophoblasts are suggested to induce endothelial and vascular smooth muscle cell apoptosis and affect angiogenesis. Objective: To investigate cord blood and placental immunoproteins in order to find new clues on pathogenetic factors of preterm preeclampsia. Methods: Cord blood samples were collected on 163 consecutive preterm deliveries prior to 32 gestational weeks. Placental function, clinical risk factors and 107 umbilical artery immunoproteins were analyzed. Classification and regression trees analysis was used to detect associations between the immunoproteins, clinical parameters and preterm preeclampsia. Placental expression of the immunoproteins and their receptors were subsequently investigated. Results: Preeclampsia complicated 34% of the pregnancies in this preterm cohort. Umbilical artery CCL16, CCL24, and CCL23 were associated with preeclampsia, CCL16 showing the strongest relationship with an OR (95% CI) of 24.5 (5.4-112.0). High umbilical artery CCL16 was also characteristic to fetuses with severe growth restriction (<3rd percentile). CCL16, CCL24 and their receptors, CCR1 and CCR3 were expressed in preeclamptic placentas. Conclusions: High umbilical artery CCL16 is prominently detected in preterm preeclamptic pregnancies with severe growth restriction. A link to compensatory proangiogenic mechanisms has to be considered. © 2012 Elsevier Ltd.


Soden S.E.,Center for Pediatric Genomic Medicine | Soden S.E.,University of Missouri - Kansas City | Saunders C.J.,Center for Pediatric Genomic Medicine | Saunders C.J.,University of Missouri - Kansas City | And 37 more authors.
Science Translational Medicine | Year: 2014

Neurodevelopmental disorders (NDDs) affect more than 3% of children and are attributable to single-gene mutations at more than 1000 loci. Traditional methods yield molecular diagnoses in less than one-half of children with NDD. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) can enable diagnosis of NDD, but their clinical and cost-effectiveness are unknown. One hundred families with 119 children affected by NDD received diagnostic WGS and/or WES of parent-child trios, wherein the sequencing approach was guided by acuity of illness. Forty-five percent received molecular diagnoses. An accelerated sequencing modality, rapid WGS, yielded diagnoses in 73% of families with acutely ill children (11 of 15). Forty percent of families with children with nonacute NDD, followed in ambulatory care clinics (34 of 85), received diagnoses: 33 by WES and 1 by staged WES then WGS. The cost of prior negative tests in the nonacute patients was $19,100 per family, suggesting sequencing to be cost-effective at up to $7640 per family. A change in clinical care or impression of the pathophysiology was reported in 49% of newly diagnosed families. If WES or WGS had been performed at symptom onset, genomic diagnoses may have been made 77 months earlier than occurred in this study. It is suggested that initial diagnostic evaluation of children with NDD should include trio WGS or WES, with extension of accelerated sequencing modalities to high-acuity patients. © 2014, American Association for the Advancement of Science. All rights reserved.


Kingsmore S.F.,Center for Pediatric Genomic Medicine | Kingsmore S.F.,University of Missouri - Kansas City | Petrikin J.,Center for Pediatric Genomic Medicine | Petrikin J.,University of Missouri - Kansas City | And 4 more authors.
Genome Medicine | Year: 2015

Today there exist two medical applications where relatively strong evidence exists to support the broad adoption of genome-informed precision medicine. These are the differential diagnosis of single gene diseases and genotype-based selection of patients for targeted cancer therapies. However, despite the availability of the $1000 genome and $700 exome for research, there is as yet little broad uptake of genomic medicine, even in these applications. Significant impediments to mainstream adoption exist, including unavailability in many institutions, lack of scalability in others, a dearth of physician understanding of interpreted genome or exome results or knowledge of how to translate consequent precision medicine care plans, and a lack of test reimbursement. In short, genomic medicine lacks a breakthrough application. Rapid genome sequencing of acutely ill infants with suspected genetic diseases (STATseq) may become that application when scaled to dozens of trios per day without loss of timeliness or accuracy. Also critical for broad adoption is embedding STATseq in software for timely patient ascertainment, augmented intelligence for interpretation, explanation of results for generalist physicians, and dynamic precision medicine decision support. © 2015 Kingsmore et al.


Smith L.D.,University of Missouri - Kansas City | Smith L.D.,Center for Pediatric Genomic Medicine | Willig L.K.,University of Missouri - Kansas City | Willig L.K.,Center for Pediatric Genomic Medicine | And 2 more authors.
Cold Spring Harbor Perspectives in Medicine | Year: 2016

As the ability to identify the contribution of genetic background to human disease continues to advance, there is no discipline of medicine in which this may have a larger impact than in the care of the ill neonate. Newborns with congenital malformations, syndromic conditions, and inherited disorders often undergo an extensive, expensive, and long diagnostic process, often without a final diagnosis resulting in significant health care, societal, and personal costs. Although ethical concerns have been raised about the use of whole-genome sequencing in medical practice, its role in the diagnosis of rare disorders in ill neonates in tertiary care neonatal intensive care units has the potential to augment or modify the care of this vulnerable population of patients. © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.


Thiffault I.,Center for Pediatric Genomic Medicine | Thiffault I.,University of Missouri - Kansas City | Bernard G.,McGill University
European Journal of Medical Genetics | Year: 2016

We comment on the recent publication by Khalifa and Naffa who are reporting a young girl with variants in both WDR45 and POLR3A, which they state contribute to her clinical manifestations. We are arguing in this letter that the clinical, MRI, and genetics findings are not compatible with 4H leukodystrophy and that this patient is not affected by this condition. © 2016 Elsevier Masson SAS


PubMed | Center for Pediatric Genomic Medicine, Edico Genome and University of New Mexico
Type: | Journal: Genome medicine | Year: 2015

While the cost of whole genome sequencing (WGS) is approaching the realm of routine medical tests, it remains too tardy to help guide the management of many acute medical conditions. Rapid WGS is imperative in light of growing evidence of its utility in acute care, such as in diagnosis of genetic diseases in very ill infants, and genotype-guided choice of chemotherapy at cancer relapse. In such situations, delayed, empiric, or phenotype-based clinical decisions may meet with substantial morbidity or mortality. We previously described a rapid WGS method, STATseq, with a sensitivity of >96% for nucleotide variants that allowed a provisional diagnosis of a genetic disease in 50h. Here improvements in sequencing run time, read alignment, and variant calling are described that enable 26-h time to provisional molecular diagnosis with >99.5% sensitivity and specificity of genotypes. STATseq appears to be an appropriate strategy for acutely ill patients with potentially actionable genetic diseases.


PubMed | Center for Pediatric Genomic Medicine, Lovelace Respiratory Research Institute, Rutgers University and Rutgers Robert Wood Johnson Medical School
Type: | Journal: Critical care (London, England) | Year: 2015

Two recent, independent, studies conducted novel metabolomics analyses relevant to human sepsis progression; one was a human model of endotoxin (lipopolysaccharide (LPS)) challenge (experimental endotoxemia) and the other was community acquired pneumonia and sepsis outcome diagnostic study (CAPSOD). The purpose of the present study was to assess the concordance of metabolic responses to LPS and community-acquired sepsis.We tested the hypothesis that the patterns of metabolic response elicited by endotoxin would agree with those in clinical sepsis. Alterations in the plasma metabolome of the subjects challenged with LPS were compared with those of sepsis patients who had been stratified into two groups: sepsis patients with confirmed infection and non-infected patients who exhibited systemic inflammatory response syndrome (SIRS) criteria. Common metabolites between endotoxemia and both these groups were individually identified, together with their direction of change and functional classifications.Response to endotoxemia at the metabolome level elicited characteristics that agree well with those observed in sepsis patients despite the high degree of variability in the response of these patients. Moreover, some distinct features of SIRS have been identified. Upon stratification of sepsis patients based on 28-day survival, the direction of change in 21 of 23 metabolites was the same in endotoxemia and sepsis survival groups.The observed concordance in plasma metabolomes of LPS-treated subjects and sepsis survivors strengthens the relevance of endotoxemia to clinical research as a physiological model of community-acquired sepsis, and gives valuable insights into the metabolic changes that constitute a homeostatic response. Furthermore, recapitulation of metabolic differences between sepsis non-survivors and survivors in LPS-treated subjects can enable further research on the development and assessment of rational clinical therapies to prevent sepsis mortality. Compared with earlier studies which focused exclusively on comparing transcriptional dynamics, the distinct metabolomic responses to systemic inflammation with or without confirmed infection, suggest that the metabolome is much better at differentiating these pathophysiologies. Finally, the metabolic changes in the recovering patients shift towards the LPS-induced response pattern strengthening the notion that the metabolic, as well as transcriptional responses, characteristic to the endotoxemia model represent necessary and healthy responses to infectious stimuli.

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