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Butterfield R.J.,University of Utah | Foley A.R.,University College London | Dastgir J.,U.S. National Institutes of Health | Asman S.,University of Utah | And 9 more authors.
Human Mutation | Year: 2013

Glycine substitutions in the conserved Gly-X-Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly-X-Y triplets 10-15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N-terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix. Glycine substitutions in the Gly-X-Y motif in the triple helical domain of COL6A1, COL6A2, or COL6A3 are the most commonly identified mutations in Ullrich congenital muscular dystrophy and Bethlem myopathy. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in this region including clustering of these mutations in a short segment N-terminal to the 17th Gly-X-Y triplet which is associated with increased severity. We hypothesize that this region may represent a functional domain within the triple helix. Published 2013. Wiley Periodicals, Inc. *This article is a U.S. Government work and is in the public domain in the USA. Source


Kim R.H.,Hospital for Sick Children | Kim R.H.,University of Toronto | Hall D.A.,St. Michaels Hospital | Hall D.A.,University of Toronto | And 7 more authors.
Annals of the American Thoracic Society | Year: 2014

Rationale: Primary ciliary dyskinesia (PCD) is an autosomal recessive genetic disorder of motile cilia. The diagnosis of PCD has previously relied on ciliary analysis with transmission electron microscopy or video microscopy. However, patients with PCD may have normal ultrastructural appearance, and ciliary analysis has limited accessibility. Alternatively, PCD can be diagnosed by demonstrating biallelic mutations in known PCD genes. Genetic testing is emerging as a diagnostic tool to complement ciliary analysis where interpretation and access may delay diagnosis. Objectives: To determine the diagnostic yield of genetic testing of patients with a confirmed or suspected diagnosis of PCD in a multiethnic urban center. Methods: Twenty-eight individuals with confirmed PCD on transmission electron microscopy of ciliary ultrastructure and 24 individuals with a probable diagnosis of PCD based on a classical PCD phenotype and low nasal nitric oxide had molecular analysis of 12 genes associated with PCD. Results: Of 49 subjects who underwent ciliary biopsy, 28 (57%) were diagnosed with PCD through an ultrastructural defect. Of the 52 individuals who underwent molecular genetic analysis, 22 (42%) individuals had two mutations in known PCD genes. Twenty-four previously unreported mutations in known PCD genes were observed. Combining both diagnostic modalities of biopsy and molecular genetics, the diagnostic yield increased to 69% compared with 57% based on biopsy alone. Conclusions: The diagnosis of PCD is challenging and has traditionally relied on ciliary biopsy, which is unreliable as the sole criterion for a definitive diagnosis. Molecular genetic analysis can be used as a complementary test to increase the diagnostic yield. Copyright © 2014 by the American Thoracic Society. Source


McIver B.,University of South Florida | Castro M.R.,Mayo Medical School | Morris J.C.,Mayo Medical School | Henry M.,Mayo Medical School | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Molecular markers hold the promise of improved diagnostic yield in thyroid fine-needle biopsy. The Afirma gene expression classifier (GEC), available commercially, reports a negative predictive value of94%in the diagnosis of benign nodules after indeterminate cytology. However, there are currently no independent studies of the performance of this assay.Objective: The aim was to assess the performance of the Afirma GEC in an academic medical center. Copyright © 2014 by the Endocrine Society.Design: Samples for the GEC were collected according to the manufacturer's recommended protocol from patients undergoing thyroid fine-needle aspiration. We requested GEC analysis on nodules reported cytologically as follicular neoplasm or atypia or follicular lesion of undetermined significance from patients willing to defer surgery.Patients: All patients undergoing thyroid fine-needle aspiration during the study period, whose cytology was reported as follicular neoplasm or atypia of undetermined significance/follicular lesion of undetermined significance, were offered access to the test and recruited to this study.Intervention: Patients whose GEC was "benign" were offered ultrasound follow-up in lieu of surgery. Those with a "suspicious" GEC were advised to undergo diagnostic lobectomy.Setting: The study was conducted at a large academic medical center.Main Outcome Measure: Wemeasured the rate of benign and suspicious calls from the Afirma GEC and histological diagnosis after surgery.Results: A total of 72 nucleic acid samples were sent for GEC analysis. In 12 (17%) of these samples, there was insufficientmRNA, leaving 60 Afirma results for analysis. Of these, 16 (27%) were benign, whereas 44 (73%) were suspicious. The rate of confirmed malignancy in GEC-suspicious nodules was only 17%.Conclusion: The Afirma GEC demonstrates a lower than expected rate of benign reports in follicular or Hürthle cell neoplasm and a lower than anticipated malignancy rate within GEC-suspicious nodules. These data suggest that the positive predictive value of the GEC is lower than previously reported and call into question the performance of the test when applied in the context of specialized academic cytopathology. Source


Mcpherson E.,Marshfield Clinic | Johnson P.,Marshfield Clinic | Schema L.,Marshfield Clinic | Zaleski C.,Prevention Genetics
American Journal of Medical Genetics, Part A | Year: 2015

Although tumors are an occasional cause of neonatal death and have been reported in stillbirths, there are no studies specifically evaluating the frequency or types of tumors in stillborn infants. We observed metastatic neuroblastoma in a fetus miscarried at 17 weeks of gestational age. Fetal death was attributed to endocrine effects of the tumor causing fetal hypertension, arrhythmia, and/or placental dysfunction. This case, which is the earliest report of a pathologically confirmed neuroblastoma, prompted review of all tumors in the Wisconsin Stillbirth Service Program database. There were 10 lethal and two incidental tumors among the 2,786 stillbirths and second trimester miscarriages in the database for an overall incidence of 1/232, which is about 50 times the incidence of clinically recognized tumors in liveborn infants. The most frequent tumors were teratoma and hemangioma that, while benign, caused death due to high output cardiac failure, hemorrhage into the tumor, or obstruction of vital organs. Only three tumors were malignant, and except for the index case, mechanisms of death were similar to those of the benign tumors. Except for the index case, all were found in the third trimester, suggesting that congenital tumors rarely become lethal until the third trimester. However, it is also possible that tumors may be missed in younger fetuses. The possibility of detecting an unsuspected tumor is yet another reason for autopsy in stillbirths and late miscarriages. © 2014 Wiley Periodicals, Inc. Source


Bharucha-Goebel D.X.,Childrens Hospital of Philadelphia | Santi M.,Childrens Hospital of Philadelphia | Medne L.,Childrens Hospital of Philadelphia | Zukosky K.,U.S. National Institutes of Health | And 8 more authors.
Neurology | Year: 2013

Objective: To report a series of 11 patients on the severe end of the spectrum of ryanodine receptor 1 (RYR1) gene-related myopathy, in order to expand the clinical, histologic, and genetic heterogeneity associated with this group of patients. Methods: Eleven patients evaluated in the neonatal period with severe neonatal-onset RYR 1-associated myopathy confirmed by genetic testing were ascertained. Clinical features, molecular testing results, muscle imaging, and muscle histology are reviewed. Results: Clinical features associated with the severe neonatal presentation of RYRl-associated myopathy included decreased fetal movement, hypotonia, poor feeding, respiratory involvement, arthrogryposis, and ophthalmoplegia in 3 patients, and femur fractures or hip dislocation at birth. Four patients had dominant RYR 1 mutations, and 7 had recessive RYR 1 mutations. One patient had a cleft palate, and another a congenital rigid spine phenotype-findings not previously described in the literature in patients with early-onset RYR 1 mutations. Six patients who underwent muscle ultrasound showed relative sparing of the rectus femoris muscle. Histologically, all patients with dominant mutations had classic central cores on muscle biopsy. Patients with recessive mutations showed great histologic heterogeneity, including fibrosis, variation in fiber size, skewed fiber typing, very small fibers, and nuclear internalization with or without ill-defined cores. Conclusions: This series confirms and expands the clinical and histologic variability associated with severe congenital RYR1-associated myopathy. Both dominant and recessive mutations of the RYR 1 gene can result in a severe neonatal-onset phenotype, but more clinical and histologic heterogeneity has been seen in those with recessive RYR1 gene mutations. Central cores are not obligatory histologic features in recessive RYR1 mutations. Sparing of the rectus femoris muscle on imaging should prompt evaluation for RYR1-associated myopathy in the appropriate clinical context. © 2013 American Academy of Neurology. Source

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