11 results on '"Jennifer Heeley"'
Search Results
2. De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy
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Philippe M. Campeau, Gabrielle Lemire, Smrithi Salian, Thomas Garcia, Stylianos E. Antonarakis, Sophie Ehresmann, Seth I. Berger, Justine Rousseau, Sylviane Hanquinet, Armand Bottani, Xiang-Jiao Yang, Jacques Côté, Ann C.M. Smith, Jonathan Humbert, Jennifer Heeley, Rami Alasiri, Erin Beaver, and Periklis Makrythanasis
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Adult ,Male ,Heterozygote ,Adolescent ,DNA Repair ,Mutation, Missense ,ddc:616.0757 ,Lysine Acetyltransferase 5 ,Chromatin remodeling ,Chromodomain ,Histones ,Histone H4 ,03 medical and health sciences ,0302 clinical medicine ,Cerebellar Diseases ,Intellectual Disability ,Report ,Genetics ,Humans ,ddc:576.5 ,Abnormalities, Multiple ,Epigenetics ,KAT5 ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Epilepsy ,biology ,Histone acetyltransferase ,Chromatin Assembly and Disassembly ,Chromatin ,Histone ,Child, Preschool ,biology.protein ,Female ,Cerebellar atrophy ,Atrophy ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery - Abstract
KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.
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- 2020
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3. Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7
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Robert A. Hegele, Maria Iascone, Kevin A. Shapiro, Nicolas Chatron, Marwan Shinawi, Joel Charrow, Jeffrey W. Innis, Luitgard Graul-Neumann, Joanna Goes Castro Meira, Anna Lehman, Dawn L. Earl, Victoria R. Sanders, Shannon Rego, David A. Sweetser, Clémantine Dimartino, Wilhelmina S. Kerstjens-Frederikse, Antonio Vitobello, Davor Lessel, Daniel Grinberg, Laurence Faivre, Ryan Peretz, Katherine M. Christensen, Emma Reesor, Erin Beaver, Elizabeth Wohler, Margot R.F. Reijnders, Deborah Barbouth, Anna Cereda, Kaja Kristine Selmer, Melissa A. Walker, Barbro Stadheim, Alessandro Serretti, Helen Kingston, Jill Clayton-Smith, Raymond Lewandowski, Bernarda Lozić, Robert Stratton, Amelia Kirby, Anne H. O’Donnell-Luria, Sara Gabbiadini, Susanna Balcells, Myriam Oufadem, Christel Thauvin, Maha Aly, Wendy K. Chung, Susan M. White, Lauren C. Briere, Thomas Smol, Stanislas Lyonnet, Roberto Colombo, Catherine E. Keegan, Marie T. McDonald, Melanie Parisot, Tiong Yang Tan, Brian Wong, Christopher T. Gordon, Magnus Dehli Vigeland, Frances A. High, Emily Bryant, Audrey Labalme, Nara Sobreira, Arnold Munnich, Jeanne Amiel, Dayna Morel Swols, Raquel Rabionet, Laura Castilla-Vallmanya, Jennifer Heeley, Gunnar Houge, Michael J. Gambello, Bernardo Blanco-Sánchez, Lynn Pais, Olena M. Vaske, Roser Urreizti, Alison Wray, Veronique Pingault, Damien Sanlaville, John Christodoulou, John Millichap, Valérie Cormier-Daire, Parul Jayakar, Helen Cox, Frédéric Tran Mau-Them, Belinda Chong, Victoria Mok Siu, Anne Slavotinek, Antonie J. van Essen, Ingvild Aukrust, Lorne A. Clarke, Rachel Gannaway, Anne Dieux-Coeslier, Patrick Nitschké, Tony Yao, Simon Sadedin, Danielle Karlowicz, Christelle Rougeot, Christine Bole-Feysot, Sandra Yang, Megan T. Cho, Gaetan Lesca, Christiane Zweier, Castilla-Vallmanya L., Selmer K.K., Dimartino C., Rabionet R., Blanco-Sanchez B., Yang S., Reijnders M.R.F., van Essen A.J., Oufadem M., Vigeland M.D., Stadheim B., Houge G., Cox H., Kingston H., Clayton-Smith J., Innis J.W., Iascone M., Cereda A., Gabbiadini S., Chung W.K., Sanders V., Charrow J., Bryant E., Millichap J., Vitobello A., Thauvin C., Mau-Them F.T., Faivre L., Lesca G., Labalme A., Rougeot C., Chatron N., Sanlaville D., Christensen K.M., Kirby A., Lewandowski R., Gannaway R., Aly M., Lehman A., Clarke L., Graul-Neumann L., Zweier C., Lessel D., Lozic B., Aukrust I., Peretz R., Stratton R., Smol T., Dieux-Coeslier A., Meira J., Wohler E., Sobreira N., Beaver E.M., Heeley J., Briere L.C., High F.A., Sweetser D.A., Walker M.A., Keegan C.E., Jayakar P., Shinawi M., Kerstjens-Frederikse W.S., Earl D.L., Siu V.M., Reesor E., Yao T., Hegele R.A., Vaske O.M., Rego S., Shapiro K.A., Wong B., Gambello M.J., McDonald M., Karlowicz D., Colombo R., Serretti A., Pais L., O'Donnell-Luria A., Wray A., Sadedin S., Chong B., Tan T.Y., Christodoulou J., White S.M., Slavotinek A., Barbouth D., Morel Swols D., Parisot M., Bole-Feysot C., Nitschke P., Pingault V., Munnich A., Cho M.T., Cormier-Daire V., Balcells S., Lyonnet S., Grinberg D., Amiel J., Urreizti R., Gordon C.T., MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
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0301 basic medicine ,NF-KAPPA-B ,PROTEIN ,030105 genetics & heredity ,medicine.disease_cause ,Germline ,Transcriptome ,ACTIVATION ,POLYUBIQUITINATION ,Missense mutation ,Exome ,Genetics (clinical) ,Genetics ,Sanger sequencing ,Mutation ,leads ,Necrosi ,craniofacial development ,Phenotype ,Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,intellectual disability ,patent ductus arteriosu ,symbols ,Mutation, Missense ,Biology ,traf7 ,Article ,akt1 ,target ,03 medical and health sciences ,symbols.namesake ,Necrosis ,patent ductus arteriosus ,medicine ,Humans ,blepharophimosi ,Tumors ,MUTATIONS ,Fibroblasts ,medicine.disease ,Blepharophimosis ,TRAF7 ,blepharophimosis ,GENOMIC ANALYSIS ,Germ Cells ,030104 developmental biology ,MENINGIOMAS - Abstract
PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.
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- 2020
4. Best Practices for Virtual Care: A Consensus Statement From the Canadian Rheumatology Association
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Claire E.H. Barber, Deborah M. Levy, Vandana Ahluwalia, Arielle Mendel, Regina Taylor-Gjevre, Tommy Gerschman, Sahil Koppikar, Konstantin Jilkine, Elizabeth Stringer, Cheryl Barnabe, Sibel Zehra Aydin, Nadia Luca, Roberta Berard, Keith Tam, Jennifer Burt, Jocelyne C. Murdoch, Graeme Zinck, Therese Lane, Jennifer Heeley, Megan Mannerow, Renee Mills, Linda Wilhelm, Nicole M.S. Hartfeld, and Brent Ohata
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Canada ,Consensus ,Delphi Technique ,Rheumatology ,virtual care ,Immunology ,education ,rheumatology ,Immunology and Allergy ,Humans - Abstract
ObjectiveTo develop best practice statements for the provision of virtual care in adult and pediatric rheumatology for the Canadian Rheumatology Association’s (CRA) Telehealth Working Group (TWG).MethodsFour members of the TWG representing adult, pediatric, university-based, and community rheumatology practices defined the scope of the project. A rapid literature review of existing systematic reviews, policy documents, and published literature and abstracts on the topic was conducted between April and May 2021. The review informed a candidate set of 7 statements and a supporting document. The statements were submitted to a 3-round (R) modified Delphi process with 22 panelists recruited through the CRA and patient advocacy organizations. Panelists rated the importance and feasibility of the statements on a Likert scale of 1–9. Statements with final median ratings between 7–9 with no disagreement were retained in the final set.ResultsTwenty-one (95%) panelists participated in R1, 15 (71%) in R2, and 18 (82%) in R3. All but 1 statement met inclusion criteria during R1. Revisions were made to 5/7 statements following R2 and an additional statement was added. All statements met inclusion criteria following R3. The statements addressed the following themes in the provision of virtual care: adherence to existing standards and regulations, appropriateness, consent, physical examination, patient-reported outcomes, use in addition to in-person visits, and complex comanagement of disease.ConclusionThe best practice statements represent a starting point for advancing virtual care in rheumatology. Future educational efforts to help implement these best practices and research to address identified knowledge gaps are planned.
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- 2022
5. Mobile element insertion detection in 89,874 clinical exomes
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Kyle Retterer, Carlos Borroto, Erin Beaver, Jane Juusola, Lorne A. Clarke, Kevin Galens, Zhancheng Zhang, Shuxi Liu, Jennifer Heeley, Kevin J. Arvai, Rebecca I. Torene, Jagdeep S. Walia, Julie Scuffins, Danna Hull, Bethany Friedman, Hana Sroka, and Sarah Neil
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0301 basic medicine ,mobile elements ,rare disease ,Binomial test ,Computational biology ,030105 genetics & heredity ,Brief Communication ,DNA sequencing ,03 medical and health sciences ,Exome Sequencing ,medicine ,diagnostics ,Humans ,Exome ,Genetic Testing ,Genetics (clinical) ,Exome sequencing ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Sequence Analysis, DNA ,Confidence interval ,030104 developmental biology ,Mobile genetic elements ,Mendelian disease ,business ,Founder effect - Abstract
Purpose Exome sequencing (ES) is increasingly used for the diagnosis of rare genetic disease. However, some pathogenic sequence variants within the exome go undetected due to the technical difficulty of identifying them. Mobile element insertions (MEIs) are a known cause of genetic disease in humans but have been historically difficult to detect via ES and similar targeted sequencing methods. Methods We developed and applied a novel MEI detection method prospectively to samples received for clinical ES beginning in November 2017. Positive MEI findings were confirmed by an orthogonal method and reported back to the ordering provider. In this study, we examined 89,874 samples from 38,871 cases. Results Diagnostic MEIs were present in 0.03% (95% binomial test confidence interval: 0.02–0.06%) of all cases and account for 0.15% (95% binomial test confidence interval: 0.08–0.25%) of cases with a molecular diagnosis. One diagnostic MEI was a novel founder event. Most patients with pathogenic MEIs had prior genetic testing, three of whom had previous negative DNA sequencing analysis of the diagnostic gene. Conclusion MEI detection from ES is a valuable diagnostic tool, reveals molecular findings that may be undetected by other sequencing assays, and increases diagnostic yield by 0.15%.
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- 2020
6. The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results
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Beth A. Kozel, Jennifer Heeley, Charles W. Goss, Tomi L. Toler, Sarah K. Brown, Emily Fassi, Dustin Baldridge, Marcia C. Willing, Marisa Vineyard, Linda Manwaring, Marwan Shinawi, Elise Fiala, and Dorothy K. Grange
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Adult ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Genetic syndromes ,Genetics, Medical ,Genetic counseling ,Genetic Counseling ,Bioinformatics ,Article ,Diagnostic modalities ,Young Adult ,03 medical and health sciences ,Physicians ,Exome Sequencing ,medicine ,Humans ,Exome ,Genetic Testing ,Child ,Expert Testimony ,Genetics (clinical) ,Exome sequencing ,Retrospective Studies ,Medical Geneticist ,Exome Clinic ,business.industry ,Genetic Diseases, Inborn ,Infant, Newborn ,Infant ,Geneticist ,3. Good health ,030104 developmental biology ,Child, Preschool ,Cohort ,Diagnostic Yield ,Medical genetics ,Female ,business - Abstract
Evaluation of the clinician’s role in the optimal interpretation of clinical exome sequencing (ES) results. Retrospective chart review of the first 155 patients who underwent clinical ES in our Exome Clinic and direct interaction with the ordering geneticist to evaluate the process of interpretation of results. The most common primary indication was neurodevelopmental problems (~66%), followed by multiple congenital anomalies (~10%). Based on sequencing data, the overall diagnostic yield was 36%. After assessment by the medical geneticist, incorporation of detailed phenotypic and molecular data, and utilization of additional diagnostic modalities, the final diagnostic yield increased to 43%. Seven patients in our cohort were included in initial case series that described novel genetic syndromes, and 23% of patients were involved in subsequent research studies directly related to their results or involved in efforts to move beyond clinical ES for diagnosis. Clinical management was directly altered due to the ES findings in 12% of definitively diagnosed cases. Our results emphasize the usefulness of ES, demonstrate the significant role of the medical geneticist in the diagnostic process of patients undergoing ES, and illustrate the benefits of postanalytical diagnostic work-up in solving the “diagnostic odyssey.” Genet Med advance online publication 02 March 2017
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- 2017
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7. Clinical and genetic characterization of individuals with predicted deleterious PHIP variants
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Ashley Wilson, Jane Juusola, Keri Ramsey, Antonio Vitobello, Wendy K. Chung, Marie-Noelle Bonnet Dupeyron, Kirsten E. Craddock, Volkan Okur, Jennifer Heeley, Laurence Faivre, and Erica H. Gerkes
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Genetics ,0303 health sciences ,Mutation ,IDENTIFICATION ,business.industry ,media_common.quotation_subject ,Nonsense ,General Medicine ,medicine.disease ,medicine.disease_cause ,Hypotonia ,Frameshift mutation ,03 medical and health sciences ,0302 clinical medicine ,Intellectual disability ,Missense mutation ,Medicine ,Attention deficit hyperactivity disorder ,Autism ,medicine.symptom ,business ,030217 neurology & neurosurgery ,030304 developmental biology ,media_common - Abstract
Heterozygous deleterious variants in PHIP have been associated with behavioral problems, intellectual disability/developmental delay, obesity/overweight, and dysmorphic features (BIDOD syndrome). We report an additional 10 individuals with pleckstrin homology domain-interacting protein (PHIP)-predicted deleterious variants (four frameshift, three missense, two nonsense, and one splice site; six of which are confirmed de novo). The mutation spectrum is diverse, and there is no clustering of mutations across the protein. The clinical phenotype of these individuals is consistent with previous reports and includes behavioral problems, intellectual disability, developmental delay, hypotonia, and dysmorphic features. The additional individuals we report have a lower frequency of obesity than previous reports and a higher frequency of gastrointestinal problems, social deficits, and behavioral challenges. Characterizing additional individuals with diverse mutations longitudinally will provide better natural history data to assist with medical management and educational and behavioral support.
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- 2019
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8. Multi-systemic involvement in NGLY1-related disorder caused by two novel mutations
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Marwan Shinawi and Jennifer Heeley
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Male ,Proband ,medicine.medical_specialty ,Microcephaly ,Mutation ,Adolescent ,DNA Mutational Analysis ,Biology ,medicine.disease ,medicine.disease_cause ,Hypotonia ,Hypocholesterolemia ,Exon ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Humans ,Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase ,Abnormalities, Multiple ,Global developmental delay ,medicine.symptom ,Genetics (clinical) ,Exome sequencing - Abstract
NGLY1-related disorder is a newly described autosomal recessive condition characterized by neurological, hepatic, ophthalmological findings and associated with dysmorphic features, constipation and scoliosis. It is caused by mutations in NGLY1, which encodes an enzyme, N-glycanase 1, involved in deglycosylation of glycoproteins, an essential step in the endoplasmic reticulum–associated degradation (ERAD) pathway. The disorder has been described in eight patients. We investigated the molecular basis and phenotype of NGLY1-related disorder in an additional patient. The proband is a 14-year-old who presented in early infancy with profound hypotonia and elevated transaminases. Liver biopsy showed lipid accumulation with dilated endoplasmic reticulum. He exhibited global developmental delay, acquired microcephaly, seizures, involuntary body movements, muscle atrophy, absent reflexes, and poor growth. He had multiple procedures for lacrimal duct stenosis and strabismus and had intractable blepharitis. He had severe osteopenia and persistent hypocholesterolemia. Whole exome sequencing revealed two novel variants in NGLY1: a truncating mutation, c.347C > G (p.S116X), and a splicing mutation, c.881 + 5G (p.IVS5 + 5G>T), predicted to abolish the splice donor site of exon 5. This study, along with previously reported cases, suggests that mutations in NGLY1 cause a recognizable phenotype and targeted sequencing should be considered in patients with typical presentation. This study expands the molecular spectrum of NGLY1-related condition and suggests that osteopenia and hypocholesterolemia may be part of the phenotype. © 2015 Wiley Periodicals, Inc.
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- 2015
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9. Risk association of congenital anomalies in patients with ambiguous genitalia: A 22-year single-center experience
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Paul F. Austin, Abby S. Hollander, Jennifer Heeley, Ina E Amarillo, Victoria Wesevich, and Diane F. Merritt
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0301 basic medicine ,Male ,Pediatrics ,medicine.medical_specialty ,Time Factors ,Databases, Factual ,Urology ,Population ,Clinical Decision-Making ,Disorders of Sex Development ,Gonadoblastoma ,030209 endocrinology & metabolism ,Risk Assessment ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Humans ,Congenital adrenal hyperplasia ,education ,Retrospective Studies ,Chromosome 7 (human) ,Gonadal Dysgenesis, 46,XY ,education.field_of_study ,Academic Medical Centers ,Adrenal Hyperplasia, Congenital ,business.industry ,Incidence (epidemiology) ,Sexual Development ,Infant, Newborn ,Karyotype ,medicine.disease ,030104 developmental biology ,Clinical research ,Treatment Outcome ,Pediatrics, Perinatology and Child Health ,Failure to thrive ,Female ,medicine.symptom ,business ,Follow-Up Studies - Abstract
Summary Background Ambiguous genitalia refers to a form of differences of sex development (DSD) wherein the appearance of the external genitalia is atypical. This rare condition presents challenges in decision-making and clinical management. Review of historical data may reveal areas for clinical research to improve care for patients with ambiguous genitalia. Objective This chart review was performed to identify patients with ambiguous genitalia, and to classify them as having 46,XX DSD, 46,XY DSD, or sex chromosome DSD. Within these categories, we looked at establishment of specific diagnoses, type and frequency of other congenital anomalies and neoplasms, and gender assignment, as well as incidence of gender reassignment and transition. Methods We performed a retrospective chart review of patients diagnosed with DSD conditions from 1995 to 2016 using ICD9 codes. For the purpose of this study, review was limited to individuals assessed to have neonatal “ambiguous genitalia” or “indeterminate sex.” Results Review identified 128 patients evaluated for ambiguous genitalia from 22 years of experience (Figure). Approximately half of these (53%) had 46,XY karyotype, 35% had 46,XX, and the remaining 12% had sex chromosome aberrations. Diagnostic rate for 46,XX DSD was higher at 64%, all of which were congenital adrenal hyperplasia, while diagnostic rate for 46,XY DSD was 11.7% for a molecularly confirmed diagnosis and 24% if clinical diagnoses were included. The most common anomalies included cardiac anomalies in 28/128 (22%), skeletal anomalies in 19/128 (15%), and failure to thrive or growth problems in 19/128 (15%). Additional congenital anomalies were found in 53 out of 128 patients (41%). There were three reported neoplasms in this group: gonadoblastoma, hepatoblastoma, and myelodysplastic syndrome with monosomy 7. Gender assignment was consistent with chromosomes in approximately 90% of XX and XY patients. There were three recorded gender reassignments or transitions. Discussion Diagnostic rate for ambiguous genitalia is low, especially in 46,XY DSD. Most neonates were assigned gender consistent with their chromosomes. Given the high rate of associated anomalies, screening for cardiac or other anomalies in patients with ambiguous genitalia may be beneficial. Conclusion Patients with ambiguous genitalia often have additional congenital anomalies. Establishment of a specific diagnosis is uncommon in 46,XY patients. A few patients have gender reassignment outside of the newborn period. Ongoing collection of clinical data on this population may reveal new information regarding long-term health, quality of life, and establishment of more diagnoses with improved molecular techniques. Download : Download high-res image (136KB) Download : Download full-size image Figure . Flow chart of patients with ambiguous genitalia.
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- 2017
10. Integrated small copy number variations and epigenome maps of disorders of sex development
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Abby S. Hollander, Joel F. Koenig, Ting Wang, Vishwa Huchthagowder, Andrew S. Hagan, Jennifer Heeley, Isabelle Nievera, Ina E Amarillo, and Paul F. Austin
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0301 basic medicine ,Genetics ,Regulation of gene expression ,Candidate gene ,Microarray analysis techniques ,Epigenome ,Biology ,medicine.disease ,Biochemistry ,Article ,03 medical and health sciences ,030104 developmental biology ,DNA methylation ,medicine ,Disorders of sex development ,Copy-number variation ,Molecular Biology ,Gene - Abstract
Small copy number variations (CNVs) have typically not been analyzed or reported in clinical settings and hence have remained underrepresented in databases and the literature. Here, we focused our investigations on these small CNVs using chromosome microarray analysis (CMA) data previously obtained from patients with atypical characteristics or disorders of sex development (DSD). Using our customized CMA track targeting 334 genes involved in the development of urogenital and reproductive structures and a less stringent analysis filter, we uncovered small genes with recurrent and overlapping CNVs as small as 1 kb, and small regions of homozygosity (ROHs), imprinting and position effects. Detailed analysis of these high-resolution data revealed CNVs and ROHs involving structural and functional domains, repeat elements, active transcription sites and regulatory regions. Integration of these genomic data with DNA methylation, histone modification and predicted RNA expression profiles in normal testes and ovaries suggested spatiotemporal and tissue-specific gene regulation. This study emphasized a DSD-specific and gene-targeted CMA approach that uncovered previously unanalyzed or unreported small genes and CNVs, contributing to the growing resources on small CNVs and facilitating the narrowing of the genomic gap for identifying candidate genes or regions. This high-resolution analysis tool could improve the diagnostic utility of CMA, not only in patients with DSD but also in other clinical populations. These integrated data provided a better genomic-epigenomic landscape of DSD and greater opportunities for downstream research.
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- 2016
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11. TRAIL and KILLER Are Expressed and Induce Apoptosis in the Murine Preimplantation Embryo1
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Amanda Wyman, Elizabeth L. Schlichting, Kelle H. Moley, Jennifer Heeley, and Joan K. Riley
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Embryogenesis ,Cell ,Embryo ,Cell Biology ,General Medicine ,Biology ,Cell biology ,Membrane glycoproteins ,medicine.anatomical_structure ,Reproductive Medicine ,Apoptosis ,embryonic structures ,Immunology ,medicine ,biology.protein ,Tumor necrosis factor alpha ,Blastocyst ,Receptor - Abstract
TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) and KILLER are a death-inducing ligand and receptor pair that belong to the TNF and TNF-receptor superfamilies, respectively. To date, only one apoptosis-inducing TRAIL receptor (murine KILLER [MK]) has been identified in mice, and it is a homologue of human Death Receptor 5. Whereas the expression of other death receptors, such as Fas and TNF receptor 1 have been documented in mammalian preimplantation embryos, no evidence currently demonstrates either the presence or the function of TRAIL and its corresponding death receptor, MK. Using reverse transcription-polymerase chain reaction and confocal immunofluorescent microscopy, we found that both TRAIL and MK are expressed from the 1-cell through the blastocyst stage of murine preimplantation embryo development. These proteins are localized mainly at the cell surface from the 1-cell through the morula stage. At the blastocyst stage, both TRAIL and MK exhibit an apical staining pattern in the trophectoderm cells. Finally, using the TUNEL assay, we demonstrated that MK induces apoptosis in blastocysts sensitized to TRAIL via actinomycin D. Taken together, these data are the first to demonstrate the presence and function of TRAIL and MK, a death-inducing ligand and its receptor, in mammalian preimplantation embryos.
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- 2004
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