Liewluck T.,Mayo Medical School |
Liewluck T.,University of Colorado at Denver |
Winder T.L.,Prevention Genetics |
Crum B.A.,Mayo Medical School |
And 4 more authors.
European Journal of Neurology | Year: 2013
Background and purpose: Anoctamin 5 (ANO5) is a putative intracellular calcium-activated chloride channel. Recessive mutations in ANO5 cause primary skeletal muscle disorders (limb-girdle muscular dystrophy 2L and distal muscular dystrophy), which are phenotypically similar to dysferlinopathy, a muscular dystrophy due to dysferlin-encoding gene (DYSF) mutations. Methods: This study reports the phenotype and genotype of seven unrelated patients with ANO5-muscular dystrophy. Results: Three patients had amyloid deposition in muscle and two had cardiac involvement. An additional patient without skeletal muscle amyloidosis had cardiac involvement with septal hypokinesis and supraventricular tachycardia requiring ablation. Amyloid subtyping using laser capture microdissection and mass spectrometry-based proteomic analysis did not identify ANO5 or any fragment of ANO5 in the amyloid deposits, but detected other known amyloidogenic proteins. Three patients had myotonic discharges without clinical myotonia. Four ANO5 mutations are novel, including a heterozygous 0.4 Mb deletion involving the entire ANO5 gene. Conclusions: The results of the present study suggest that ANO5 mutations can be associated with amyloid deposition in muscle, but the nature of the amyloid deposits remains indeterminate, as does their relationship with cardiac involvement. ANO5 analysis should be considered in cases of muscle amyloid deposition of indeterminate etiology. Electrical myotonia can accompany ANO5-muscular dystrophy. © 2013 EFNS.
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.
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.
Bharucha-Goebel D.X.,Children's Hospital of Philadelphia |
Santi M.,Children's Hospital of Philadelphia |
Medne L.,Children's 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.
Weisfeld-Adams J.D.,Mount Sinai School of Medicine |
Mehta L.,Mount Sinai School of Medicine |
Rucker J.C.,Mount Sinai School of Medicine |
Dembitzer F.R.,Mount Sinai School of Medicine |
And 6 more authors.
Orphanet Journal of Rare Diseases | Year: 2013
Background: Mutations in LYST, a gene encoding a putative lysosomal trafficking protein, cause Chédiak-Higashi syndrome (CHS), an autosomal recessive disorder typically characterized by infantile-onset hemophagocytic syndrome and immunodeficiency, and oculocutaneous albinism. A small number of reports of rare, attenuated forms of CHS exist, with affected individuals exhibiting progressive neurodegenerative disease beginning in early adulthood with cognitive decline, parkinsonism, features of spinocerebellar degeneration, and peripheral neuropathy, as well as subtle pigmentary abnormalities and subclinical or absent immune dysfunction. Methods. In a consanguineous Pakistani kindred with clinical phenotypes consistent with attenuated CHS, we performed SNP array-based homozygosity mapping and whole gene sequencing of LYST. Results: We identified three individuals homozygous for a novel six base pair in-frame deletion in LYST (c.9827-9832ATACAA), predicting the loss of asparagine and threonine residues from the LYST transcript (p.Asn3276-Thr3277del), and segregating with the phenotype in this family. Conclusions: We further characterize the neurologic features of the attenuated form of CHS, and discuss pathophysiologic mechanisms underlying the neurodegenerative components of CHS. Attenuated CHS is phenotypically heterogenous and should be considered when young adults develop neurodegenerative disease and have pigmentary abnormalities. We briefly discuss surveillance and management of patients with CHS-related neurodegeneration. © 2013 Weisfeld-Adams et al.; licensee BioMed Central Ltd.
Gallione C.J.,Duke University |
Solatycki A.,Prevention Genetics |
Awad I.A.,University of Chicago |
Weber J.L.,Prevention Genetics |
Marchuk D.A.,Duke University
Genetics in Medicine | Year: 2011
Purpose: Cerebral cavernous malformations can occur sporadically or are caused by mutations in one of three identified genes. Cerebral cavernous malformations often remain clinically silent until a mutation carrier suffers a stroke or seizure. Presymptomatic genetic testing has been valuable to follow and manage cerebral cavernous malformation mutation carriers. During routine diagnostic testing, we identified a two base pair change in seven unrelated people of Ashkenazi Jewish heritage. Because of the location of the variant beyond the invariant splice donor sequence, the change was reported as a variant of unknown significance. In this study, we determined whether this change was a disease-causing mutation and whether it represents a founder mutation in the Ashkenazi Jewish population. Methods: Transcripts arising from the normal and mutant alleles were examined by reverse transcription-polymerase chain reaction from affected and unaffected Ashkenazi Jewish cerebral cavernous malformation family members. A synthetic splicing system using a chimeric exon was used to visualize the effects of the change on splice donor site utilization. Results: The two base pair change in CCM2, c.30 + 5-6delinsTT, segregated with affected status in the study families. Reverse transcription-polymerase chain reaction revealed loss of the transcript allele that was in phase with the mutation. The two base pair change, when tested in an in vitro synthetic splicing system, altered splice donor site utilization. Resequencing of the genomic region proximal and distal to the CCM2 gene mutation revealed a common single-nucleotide polymorphism haplotype in affected individuals. Conclusions: The two base pair change in CCM2, c.30 + 5-6delinsTT, disrupted proper splice donor utilization leading to a degraded transcript. Single nucleotide polymorphism haplotype analysis demonstrated that this mutation was due to a founder in the Ashkenazi Jewish population. These data have the potential to simplify genetic testing for cerebral cavernous malformation in the Ashkenazi Jewish population. © 2011 Lippincott Williams & Wilkins.
Suarez-Cedeno G.,Mayo Medical School |
Suarez-Cedeno G.,University of Antioquia |
Winder T.,Prevention Genetics |
Milone M.,Mayo Medical School
Muscle and Nerve | Year: 2014
Introduction: DNAJB6 mutations cause an autosomal dominant myopathy that can manifest as limb-girdle muscular dystrophy (LGMD1D/1E) or distal-predominant myopathy. In the majority of patients this myopathy manifests in adulthood and shows vacuolar changes on muscle biopsy. Methods: Clinical, electrophysiological, pathological, and molecular findings are reported. Results: We report a 56-year-old woman, who, like 3 other family members, became symptomatic in childhood with slowly progressive limb-girdle muscle weakness, normal serum creatine kinase (CK) values, and myopathic electromyographic findings. Muscle biopsy showed vacuolar changes and congophilic inclusions, and molecular analysis revealed a pathogenic mutation in the DNAJB6 gene. Differences and similarities with previously described cases are assessed. Conclusions: Childhood-onset of DNAJB6 myopathy is more frequent than previously believed; congophilic inclusions may be present in the muscle of these patients. © 2013 Wiley Periodicals, Inc.
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.
Borovik L.,University of Wisconsin - Madison |
Modaff P.,University of Wisconsin - Madison |
Waterham H.R.,University of Amsterdam |
Krentz A.D.,Prevention Genetics |
Pauli R.M.,University of Wisconsin - Madison
American Journal of Medical Genetics, Part A | Year: 2013
The Lamin B receptor (LBR) gene has been described to encode a bifunctional protein. Mutations in the LBR gene can affect neutrophil segmentation and sterol reductase activity and have been associated with two different recognized clinical conditions, Pelger-Huet anomaly (PHA) and Greenberg skeletal dysplasia. PHA is a benign autosomal co-dominant laminopathy resulting in bilobed neutrophil nuclei in heterozygotes, and unsegmented (ovoid) neutrophil nuclei in homozygotes. Some putative PHA homozygotes have been reported with minor skeletal malformations. Greenberg skeletal dysplasia is a severe autosomal recessive, perinatal lethal dwarfing disorder in which heterozygous carriers are usually without clinical manifestations. We here report a girl who has bilobed neutrophil nuclei and a mild skeletal dysplasia. Mutation analysis showed two novel mutations in the LBR gene: c.651_653 delinsTGATGAGAAA (p.Ile218Aspfs*19) and c.1757G>A (p.Arg586His). These mutations were found to be in trans, and, thus, she is a compound heterozygote. Sterol analysis found trace amounts of cholesta-8,14-dien-3beta-ol, which is normally undetected in healthy individuals. This and previously reported cases suggest that mutations in LBR can result in a continuum of phenotypic manifestations. © 2013 Wiley Periodicals, Inc.
Hughes S.S.,The Childrens Mercy Hospitals and Clinics |
Welsh H.I.,The Childrens Mercy Hospitals and Clinics |
Safina N.P.,The Childrens Mercy Hospitals and Clinics |
Bejaoui K.,Prevention Genetics |
Ardinger H.H.,The Childrens Mercy Hospitals and Clinics
American Journal of Medical Genetics, Part A | Year: 2014
CHARGE syndrome is an autosomal dominant malformation syndrome associated with mutations in CHD7. The condition is typically sporadic with few familial cases reported. The diagnosis of CHARGE syndrome is based on a combination of major and minor criteria comprised of structural and functional abnormalities, most of which are part of the original CHARGE acronym, although additional anomalies have been added. To date, family history has not been considered in the diagnostic criteria. Here we report a family with a previously unreported missense mutation in exon 31 of CHD7, in which family history played a role in the diagnosis of CHARGE syndrome. Given the tremendous phenotypic variability and the dominant nature of CHARGE syndrome, we propose that family history be included as a major diagnostic criterion. A positive family history would include any individual with an apparently isolated unilateral major CHARGE anomaly or someone with a few of the minor features. Our cases support this proposal; had family history not been considered in this case, CHD7 testing might not have been pursued, leading to incomplete medical follow-up and erroneous genetic counseling. Additionally, with the increased incidence of orofacial clefting in this family, as well as in the literature, we suggest that cleft lip and/or palate be added to the major diagnostic criteria for CHARGE syndrome. © 2013 Wiley Periodicals, Inc.