41 results on '"Kristen Wigby"'
Search Results
2. P339: Whole genome sequencing identifies biallelic variants in newly described EMC10-related neurodevelopmental disorder not detected by prior genetic testing
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Jerica Lenberg, Kristen Wigby, Jennifer Friedman, Mari Tokita, Alaina Heinen, and Soofia Khan
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Genetics ,QH426-470 ,Medicine - Published
- 2024
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3. P470: A novel inherited frameshifting variant in UBA2 gene: A case study of highly variable phenotype in a family
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Kanika Parashar, Kristen Wigby, Annette Feigenbaum, and Miguel Del Campo
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Genetics ,QH426-470 ,Medicine - Published
- 2024
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4. P610: Identification of trinucleotide repeat expansions in DMPK using rapid whole genome sequencing
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Lucia Guidugli, Monia Hammer, Bryant Cao, Joseph Shen, Daniel Rito, Claire Botsford, David Chitayat, Jerica Lenberg, Kristen Wigby, Kelly Watkins, Stephen Kingsmore, and Mari Tokita
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Genetics ,QH426-470 ,Medicine - Published
- 2024
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5. Approaches to long-read sequencing in a clinical setting to improve diagnostic rate
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Erica Sanford Kobayashi, Serge Batalov, Aaron M. Wenger, Christine Lambert, Harsharan Dhillon, Richard J. Hall, Primo Baybayan, Yan Ding, Seema Rego, Kristen Wigby, Jennifer Friedman, Charlotte Hobbs, and Matthew N. Bainbridge
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Medicine ,Science - Abstract
Abstract Over the past decade, advances in genetic testing, particularly the advent of next-generation sequencing, have led to a paradigm shift in the diagnosis of molecular diseases and disorders. Despite our present collective ability to interrogate more than 90% of the human genome, portions of the genome have eluded us, resulting in stagnation of diagnostic yield with existing methodologies. Here we show how application of a new technology, long-read sequencing, has the potential to improve molecular diagnostic rates. Whole genome sequencing by long reads was able to cover 98% of next-generation sequencing dead zones, which are areas of the genome that are not interpretable by conventional industry-standard short-read sequencing. Through the ability of long-read sequencing to unambiguously call variants in these regions, we discovered an immunodeficiency due to a variant in IKBKG in a subject who had previously received a negative genome sequencing result. Additionally, we demonstrate the ability of long-read sequencing to detect small variants on par with short-read sequencing, its superior performance in identifying structural variants, and thirdly, its capacity to determine genomic methylation defects in native DNA. Though the latter technical abilities have been demonstrated, we demonstrate the clinical application of this technology to successfully identify multiple types of variants using a single test.
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- 2022
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6. An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases
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Mallory J. Owen, Sebastien Lefebvre, Christian Hansen, Chris M. Kunard, David P. Dimmock, Laurie D. Smith, Gunter Scharer, Rebecca Mardach, Mary J. Willis, Annette Feigenbaum, Anna-Kaisa Niemi, Yan Ding, Luca Van Der Kraan, Katarzyna Ellsworth, Lucia Guidugli, Bryan R. Lajoie, Timothy K. McPhail, Shyamal S. Mehtalia, Kevin K. Chau, Yong H. Kwon, Zhanyang Zhu, Sergey Batalov, Shimul Chowdhury, Seema Rego, James Perry, Mark Speziale, Mark Nespeca, Meredith S. Wright, Martin G. Reese, Francisco M. De La Vega, Joe Azure, Erwin Frise, Charlene Son Rigby, Sandy White, Charlotte A. Hobbs, Sheldon Gilmer, Gail Knight, Albert Oriol, Jerica Lenberg, Shareef A. Nahas, Kate Perofsky, Kyu Kim, Jeanne Carroll, Nicole G. Coufal, Erica Sanford, Kristen Wigby, Jacqueline Weir, Vicki S. Thomson, Louise Fraser, Seka S. Lazare, Yoon H. Shin, Haiying Grunenwald, Richard Lee, David Jones, Duke Tran, Andrew Gross, Patrick Daigle, Anne Case, Marisa Lue, James A. Richardson, John Reynders, Thomas Defay, Kevin P. Hall, Narayanan Veeraraghavan, and Stephen F. Kingsmore
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Science - Abstract
Rapid diagnosis and implementation of treatments is crucial in many genetic conditions. Here the authors describe Genome-to-Treatment, a virtual disease management system that can achieve a rapid diagnosis by expedited whole genome sequencing in 13.5 hours and provide guidance to clinicians for possible therapies.
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- 2022
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7. Activated phosphoinositide 3-kinase δ syndrome associated with nephromegaly, growth hormone deficiency, bronchiectasis: a case report
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Megan Craig, Bob Geng, Kristen Wigby, Susan A. Phillips, Christine Bakhoum, John Naheedy, and Mateja Cernelc-Kohan
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Primary immunodeficiency ,Bronchiectasis ,Asthma ,Pituitary abnormality ,Growth hormone deficiency ,Nephromegaly ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Activated phosphoinositide 3-kinase (PI3K) δ syndrome (APDS) is a rare form of primary immunodeficiency with 243 known cases reported in the literature. Known findings associated with the condition include recurrent sinusitis and bronchitis, bronchiectasis, immune cytopenias, mild developmental delay, splenomegaly, and lymphadenopathy. We report the case of a child with APDS accompanied by unique clinical features: nephromegaly and growth hormone deficiency with associated pituitary anatomic abnormality. Case presentation The patient is a nine-year-old boy with a heterozygous de novo variant in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ (p.E1021K), previously reported in association with APDS. Our patient, who had no family history of immunodeficiency, exhibits classic findings of this syndrome but also has unique features that extend the phenotypic spectrum of this disorder. At 5 years of age, the patient showed marked growth deceleration and was demonstrated to have growth hormone (GH) deficiency with associated pituitary anatomic abnormality. He started GH therapy with an excellent response. He additionally has bilateral nephromegaly of unclear etiology, microscopic hematuria and proteinuria, asthma, and has developed left hip pain with arthrocentesis consistent with oligoarticular juvenile idiopathic arthritis. At age nine, the patient was referred to genetics and whole exome sequencing revealed APDS. Though there was initial concern that GH may increase risk for malignancy as GH signals through the PI3K pathway, he was allowed to continue treatment as the PI3K pathway was considered constitutively active at baseline. Conclusions Our patient’s unique presentation adds to the clinical information regarding APDS, demonstrates the utility of genetic testing and illustrates the importance of a multidisciplinary collaborative approach in managing this complex syndrome.
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- 2022
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8. P483: Genome sequence re-analysis reveals de-novo FBXW7 canonical splice variant in newly described neurodevelopmental syndrome
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Daniel Helbling, Jerica Lenberg, Arivudainambi Ramalingam, and Kristen Wigby
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Genetics ,QH426-470 ,Medicine - Published
- 2023
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9. Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5
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Deepa S. Rajan, Sukhleen Kour, Tyler R. Fortuna, Margot A. Cousin, Sarah S. Barnett, Zhiyv Niu, Dusica Babovic-Vuksanovic, Eric W. Klee, Brian Kirmse, Micheil Innes, Siri Lynne Rydning, Kaja K. Selmer, Magnus Dehli Vigeland, Anne Kjersti Erichsen, Andrea H. Nemeth, Francisca Millan, Catherine DeVile, Katherine Fawcett, Adrien Legendre, David Sims, Ricardo Parolin Schnekenberg, Lydie Burglen, Sandra Mercier, Somayeh Bakhtiari, Rosario Francisco-Velilla, Azman Embarc-Buh, Encarnacion Martinez-Salas, Kristen Wigby, Jerica Lenberg, Jennifer R. Friedman, Michael C. Kruer, and Udai Bhan Pandey
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Gemin5 ,ataxia ,cerebellar atrophy ,developmental delay ,neurodegeneration ,cell death ,Biology (General) ,QH301-705.5 - Abstract
The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the GEMIN5 gene among seven unrelated families with nine affected individuals presenting with spastic ataxia and cerebellar atrophy. GEMIN5, an RNA-binding protein, has been shown to regulate transcription and translation machinery. GEMIN5 is a component of small nuclear ribonucleoprotein (snRNP) complexes and helps in the assembly of the spliceosome complexes. We found that biallelic GEMIN5 variants cause structural abnormalities in the encoded protein and reduce expression of snRNP complex proteins in patient cells compared with unaffected controls. Finally, knocking out endogenous Gemin5 in mice caused early embryonic lethality, suggesting that Gemin5 expression is crucial for normal development. Our work further expands on the phenotypic spectrum associated with GEMIN5-related disease and implicates the role of GEMIN5 among patients with spastic ataxia, cerebellar atrophy, and motor predominant developmental delay.
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- 2022
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10. Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
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Jennifer Friedman, Desiree E. Smith, Mahmoud Y. Issa, Valentina Stanley, Rengang Wang, Marisa I. Mendes, Meredith S. Wright, Kristen Wigby, Amber Hildreth, John R. Crawford, Alanna E. Koehler, Shimul Chowdhury, Shareef Nahas, Liting Zhai, Zhiwen Xu, Wing-Sze Lo, Kiely N. James, Damir Musaev, Andrea Accogli, Kether Guerrero, Luan T. Tran, Tarek E. I. Omar, Tawfeg Ben-Omran, David Dimmock, Stephen F. Kingsmore, Gajja S. Salomons, Maha S. Zaki, Geneviève Bernard, and Joseph G. Gleeson
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Science - Abstract
Valyl-tRNA synthetase (VARS) charges valyl-tRNA with the amino acid valine, required for translation. Here, the authors describe a progressive epileptic encephalopathy in individuals from five families carrying biallelic mutations in the VARS gene that leave the enzyme activity partially intact.
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- 2019
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11. Further delineation of the <scp> CWC27 ‐associated </scp> spliceosomeopathy: Case report and review of the literature
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Shaden H. Yassin, Riley Henderson, Jerica Lenberg, Viridiana Murillo, David R. Murdock, Jennifer Friedman, Marilyn C. Jones, Kristen Wigby, and Shyamanga Borooah
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Genetics ,Genetics (clinical) - Published
- 2023
12. Insights into the perinatal phenotype of Kabuki syndrome in infants identified by genome‐wide sequencing
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Kristen Wigby, Monia Hammer, Mari Tokita, Priyanka Patel, Marilyn C. Jones, Austin Larson, Frances Velez Bartolomei, Natalie Dykzeul, Anne Slavotinek, Tiffany Yip, Sara Bandres‐Ciga, Brittany N. Simpson, Kristen Suhrie, Suma Shankar, Regan Veith, Jennifer Bragg, Cynthia Powell, Stephen F. Kingsmore, David Dimmock, Jill Maron, Jonathan Davis, and Miguel Del Campo
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Genetics ,Genetics (clinical) - Published
- 2023
13. A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases
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Stephen F. Kingsmore, Laurie D. Smith, Chris M. Kunard, Matthew Bainbridge, Sergey Batalov, Wendy Benson, Eric Blincow, Sara Caylor, Christina Chambers, Guillermo Del Angel, David P. Dimmock, Yan Ding, Katarzyna Ellsworth, Annette Feigenbaum, Erwin Frise, Robert C. Green, Lucia Guidugli, Kevin P. Hall, Christian Hansen, Charlotte A. Hobbs, Scott D. Kahn, Mark Kiel, Lucita Van Der Kraan, Chad Krilow, Yong H. Kwon, Lakshminarasimha Madhavrao, Jennie Le, Sebastien Lefebvre, Rebecca Mardach, William R. Mowrey, Danny Oh, Mallory J. Owen, George Powley, Gunter Scharer, Seth Shelnutt, Mari Tokita, Shyamal S. Mehtalia, Albert Oriol, Stavros Papadopoulos, James Perry, Edwin Rosales, Erica Sanford, Steve Schwartz, Duke Tran, Martin G. Reese, Meredith Wright, Narayanan Veeraraghavan, Kristen Wigby, Mary J. Willis, Aaron R. Wolen, and Thomas Defay.
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clinical decision support ,UK Biobank ,diagnosis ,Critical Illness ,clinical utility ,specificity ,rapid whole-genome sequencing ,Medical and Health Sciences ,Neonatal Screening ,Rare Diseases ,genetic disease ,Clinical Research ,Genetics ,Humans ,Genetic Testing ,Precision Medicine ,Child ,Genetics (clinical) ,Retrospective Studies ,Pediatric ,Genetics & Heredity ,virtual management guidance ,newborn screening ,Prevention ,diagnostic odyssey ,Human Genome ,Infant, Newborn ,Infant ,Perinatal Period - Conditions Originating in Perinatal Period ,Biological Sciences ,Newborn ,sensitivity ,gene therapy ,orphan drug ,Brain Disorders ,Good Health and Well Being - Abstract
Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.
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- 2022
14. Characterization of a patient-derived variant of GPX4 for precision therapy
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Hengrui Liu, Farhad Forouhar, Tobias Seibt, Russell Saneto, Kristen Wigby, Jennifer Friedman, Xin Xia, Mikhail S. Shchepinov, Sanath Kumar Ramesh, Marcus Conrad, and Brent R. Stockwell
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Humans ,Point Mutation ,Cell Biology ,Precision Medicine ,Phospholipid Hydroperoxide Glutathione Peroxidase ,Proof of Concept Study ,Molecular Biology - Abstract
Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia. Using structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants and a deuterated polyunsaturated fatty acid were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations of therapeutic strategies targeting GPX4.
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- 2021
15. Development of therapies for rare genetic disorders of GPX4: roadmap and opportunities
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Simon C. Johnson, Qitao Ran, Kristen Wigby, Dorian M. Cheff, Sanath Kumar Ramesh, Elias S.J. Arnér, Reena V. Kartha, Edward E. Schmidt, Brent R. Stockwell, Matthew D. Hall, Plavi Mittal, and Alysson R. Muotri
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medicine.medical_specialty ,Future studies ,Sequencing data ,Pharmacology toxicology ,Sedaghatian-type spondylometaphyseal dysplasia ,Review ,Disease ,Glutathione peroxidase 4 ,Osteochondrodysplasias ,Rare genetic disorder ,Rare Diseases ,Therapy development ,Genetics ,medicine ,Humans ,2.1 Biological and endogenous factors ,Ultra-rare disease ,Pharmacology (medical) ,Aetiology ,Intensive care medicine ,Genetics (clinical) ,Genetics & Heredity ,Other Medical and Health Sciences ,business.industry ,allergology ,General Medicine ,Human genetics ,Drug repositioning ,Roadmap ,Orphan Drug ,Good Health and Well Being ,Spondylometaphyseal dysplasia ,SSMD ,Medicine ,business ,GPX4 - Abstract
Background Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have linked this disease to mutations in GPX4, with consequences in the resulting enzyme, glutathione peroxidase 4. This offers potential diagnostic and therapeutic avenues for those suffering from this disease, though the steps toward these treatments is often convoluted, expensive, and time-consuming. Main body The CureGPX4 organization was developed to promote awareness of GPX4-related diseases like SSMD, as well as support research that could lead to essential therapeutics for patients. We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis. We outline in detail the steps CureGPX4 has taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies. Conclusion The primary aim of this review is to provide a roadmap for therapy development for rare, ultra-rare, and difficult to diagnose diseases, as well as increase awareness of the genetic component of SSMD. This work will offer a better understanding of GPx4-related diseases, and help guide researchers, clinicians, and patients interested in other rare diseases find a path towards treatments.
- Published
- 2021
16. Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children’s hospitals demonstrates improved clinical outcomes and reduced costs of care
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Christina Ashburner, Arthur D’Harlingue, Rosanna Spicer, Suma P. Shankar, Shimul Chowdhury, Juliette Hunt, David Dimmock, Katarzyna A. Ellsworth, Neda Zadeh, Bryce Waldman, Lauge Farnaes, Wendy Benson, Madelena Martin, Jason Knight, Sara A. Caylor, Ofelia Vargas-Shiraishi, Aaina Kochhar, Mario Augusto Rojas, Charlotte A. Hobbs, Priscilla Joe, Katherine A. Rauen, Maries Joseph, Kathleen Houtchens, Richard Kronick, Ami Doshi, Adam Schwarz, Stephen F. Kingsmore, Carolina I. Galarreta, Jason Carmichael, Jolie Limon, Elaine Cham, Robert H. Kaplan, Jeanne Carroll, Kristen Wigby, and John P. Cleary
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Male ,0301 basic medicine ,Comparative Effectiveness Research ,Quality management ,030105 genetics & heredity ,Medical and Health Sciences ,Tertiary care ,California ,quality improvement ,Cohort Studies ,Cost of Illness ,neonatal intensive care ,Prospective Studies ,Economic impact analysis ,Precision Medicine ,Genetics (clinical) ,Pediatric ,Genetics & Heredity ,Health Services ,Biological Sciences ,Hospitals, Pediatric ,Hospitals ,Treatment Outcome ,Female ,health outcomes research ,Medical emergency ,Critical Care ,pediatrics ,Critical Illness ,Clinical Trials and Supportive Activities ,Comparative effectiveness research ,rare disease ,QUALY ,Article ,03 medical and health sciences ,genetic disease ,Clinical Research ,Intensive care ,Genetics ,medicine ,Humans ,quality-adjusted life years ,Whole Genome Sequencing ,Medicaid ,business.industry ,Infant, Newborn ,Infant ,Newborn ,medicine.disease ,Precision medicine ,United States ,Quality-adjusted life year ,Good Health and Well Being ,030104 developmental biology ,MediCal ,real-world care ,business - Abstract
Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were
- Published
- 2021
17. Expanding the phenotypic and molecular spectrum of NFS1-related disorders that cause functional deficiencies in mitochondrial and cytosolic iron-sulfur cluster containing enzymes
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Jennifer H. Yang, Marisa W. Friederich, Katarzyna A. Ellsworth, Aliya Frederick, Emily Foreman, Denise Malicki, David Dimmock, Jerica Lenberg, Chitra Prasad, Andrea C. Yu, C. Anthony Rupar, Robert A. Hegele, Kandamurugu Manickam, Daniel C. Koboldt, Erin Crist, Samantha S. Choi, Sali M.K. Farhan, Helen Harvey, Shifteh Sattar, Natalya Karp, Terence Wong, Richard Haas, Johan L. K. Van Hove, and Kristen Wigby
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Iron-Sulfur Proteins ,Pediatric ,Genetics & Heredity ,Electron Transport Complex I ,iron-sulfur clusteropathies ,Iron ,Clinical Sciences ,NFS1 ,mitochondrial ,Article ,Mitochondria ,Mitochondrial Proteins ,Carbon-Sulfur Lyases ,Young Adult ,lactic acidosis ,Clinical Research ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Aetiology ,Genetics (clinical) ,Sulfur - Abstract
Iron-sulfur cluster proteins are involved in critical functions for gene expression regulation and mitochondrial bioenergetics including the oxidative phosphorylation system. The c.215G>A p.(Arg72Gln) variant in NFS1 has been previously reported to cause infantile mitochondrial complex II and III deficiency. We describe three additional unrelated patients with the same missense variant. Two infants with the same homozygous variant presented with hypotonia, weakness and lactic acidosis, and one patient with compound heterozygous p.(Arg72Gln) and p.(Arg412His) variants presented as a young adult with gastrointestinal symptoms and fatigue. Skeletal muscle biopsy from patients 1 and 3 showed abnormal mitochondrial morphology, and functional analyses demonstrated decreased activity in respiratory chain complex II and variably in complexes I and III. We found decreased mitochondrial and cytosolic aconitase activities but only mildly affected lipoylation of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase enzymes. Our studies expand the phenotypic spectrum and provide further evidence for the pathogenicity and functional sequelae of NFS1-related disorders with disturbances in both mitochondrial and cytosolic iron-sulfur cluster containing enzymes.
- Published
- 2022
18. Genetic testing strategies in the newborn
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Sarah S. Murray, Kristen Wigby, and Jeanne Carroll
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medicine.medical_specialty ,Neonatal intensive care unit ,Modalities ,medicine.diagnostic_test ,business.industry ,Genetic counseling ,MEDLINE ,Obstetrics and Gynecology ,Disease ,Pediatrics, Perinatology and Child Health ,medicine ,Medical genetics ,Neonatology ,business ,Intensive care medicine ,Genetic testing - Abstract
Genetic disorders presenting in the neonatal period can have a significant impact on morbidity and mortality. Early diagnosis can facilitate timely prognostic counseling to families and possibility of precision care, which could improve outcome. As availability of diagnostic testing expands, the required knowledge base of the neonatologist must also expand to include proper application and understanding of genetic testing modalities, especially where availability of clinical genetics consultation is limited. Herein, we review genetic tests utilized in the neonatal intensive care unit (NICU) providing background on the technology, clinical indications, advantages, and limitations of the tests. This review will span from classic cytogenetics to the evolving role of next generation sequencing and its impact on the management of neonatal disease.
- Published
- 2020
19. Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in
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Deepa S, Rajan, Sukhleen, Kour, Tyler R, Fortuna, Margot A, Cousin, Sarah S, Barnett, Zhiyv, Niu, Dusica, Babovic-Vuksanovic, Eric W, Klee, Brian, Kirmse, Micheil, Innes, Siri Lynne, Rydning, Kaja K, Selmer, Magnus Dehli, Vigeland, Anne Kjersti, Erichsen, Andrea H, Nemeth, Francisca, Millan, Catherine, DeVile, Katherine, Fawcett, Adrien, Legendre, David, Sims, Ricardo Parolin, Schnekenberg, Lydie, Burglen, Sandra, Mercier, Somayeh, Bakhtiari, Rosario, Francisco-Velilla, Azman, Embarc-Buh, Encarnacion, Martinez-Salas, Kristen, Wigby, Jerica, Lenberg, Jennifer R, Friedman, Michael C, Kruer, and Udai Bhan, Pandey
- Abstract
The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the
- Published
- 2021
20. To Be or No B2: A Rare Cause of Stridor and Weakness in a Toddler
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Jennifer H. Yang, Lucia Guidugli, Sarah Schneider, Melissa Cameron, Kristen Wigby, Alexis Quade, and Aliya Frederick
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Pediatrics ,medicine.medical_specialty ,Weakness ,Stridor ,Case Report ,Gene mutation ,Compound heterozygosity ,Autoimmune Disease ,RJ1-570 ,Rare Diseases ,medicine ,Genetics ,2.1 Biological and endogenous factors ,gene mutation ,riboflavin ,Aetiology ,RC346-429 ,muscle weakness ,SLC52A3 ,Pediatric ,whole genome sequencing ,screening and diagnosis ,business.industry ,Metabolic disorder ,Autoantibody ,Neurosciences ,General Medicine ,medicine.disease ,Myasthenia gravis ,Detection ,Neurology. Diseases of the nervous system ,Differential diagnosis ,medicine.symptom ,business ,4.2 Evaluation of markers and technologies - Abstract
We present a case of a young child with a rare metabolic disorder whose clinical presentation resembled that of autoimmune myasthenia gravis. The differential diagnosis was expanded when autoantibody testing was negative and the patient did not respond to standard immunomodulatory therapies. Rapid whole genome sequencing identified 2 rare variants of uncertain significance in the SLC52A3 gene shown to be in compound heterozygous state after parental testing. Biallelic mutations in SLC52A3 are associated with Riboflavin Transporter Deficiency, which in its untreated form, results in progressive neurodegeneration and death. Supplementation with oral riboflavin has been shown to limit disease progression and improve symptoms in some patients. When the diagnosis is suspected, patients should be started on supplementation immediately while awaiting results from genetic studies.
- Published
- 2021
21. Further phenotypic characterization of Kaufman oculocerebrofacial syndrome: report of five new cases and literature review
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Kristen Wigby, Carolina I. Galarreta, and Marilyn C. Jones
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Male ,Microcephaly ,medicine.medical_specialty ,Hearing loss ,Ubiquitin-Protein Ligases ,Limb Deformities, Congenital ,Kaufman oculocerebrofacial syndrome ,Pathology and Forensic Medicine ,Ptosis ,Intellectual Disability ,Intellectual disability ,medicine ,Humans ,Laryngomalacia ,Genetic Predisposition to Disease ,Eye Abnormalities ,Craniofacial ,Genetic Association Studies ,Genetics (clinical) ,Whole Genome Sequencing ,business.industry ,Siblings ,Facies ,Infant ,General Medicine ,medicine.disease ,Dermatology ,Blepharophimosis ,Phenotype ,Child, Preschool ,Mutation ,Pediatrics, Perinatology and Child Health ,Female ,Anatomy ,medicine.symptom ,business - Abstract
Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder caused by biallelic variants in UBE3B. Kaufman oculocerebrofacial syndrome is characterized by a recognizable pattern of malformations including moderate to severe intellectual disability, growth deficiency, microcephaly and a distinctive facial gestalt. Common craniofacial features include short upslanting palpebral fissures, blepharophimosis or ptosis, ear anomalies, hearing loss, palate anomalies and stridor/laryngomalacia. The aim of this study was to describe the phenotypic features and the genotype of five new individuals from three unrelated families, and to review systematically the published information of 26 cases. The main features are summarized contributing to further characterize the natural history of the disease. Novel phenotypic features and two novel pathogenic variants in UBE3B are reported: A splice site variant (c.2569-1G > C) and a nonsense variant (c.518C > A, p.Ser173Ter). Kaufman oculocerebrofacial syndrome is likely an underdiagnosed disorder which can be clinically recognized based on its distinctive facial gestalt and relatively homogenous natural history.
- Published
- 2019
22. An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm
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David Dimmock, Cinnamon S. Bloss, Yan Ding, Kiely N. James, Katarzyna A. Ellsworth, Narayanan Veeraraghavan, Matthew N. Bainbridge, Amy S. Kimball, Jaime Barea, Christina Clarke, Jerica Lenberg, Shareef Nahas, Shimul Chowdhury, Erica Sanford, Patrick Mulrooney, Nathaly M. Sweeney, Sergey Batalov, Lauge Farnaes, Jennie Le, Cynthia Cheung, Mary Gaughran, Leila Schwanemann, Daniken Orendain, Maria Ortiz-Arechiga, Charlotte A. Hobbs, Marva Evans, Kelly Watkins, Marilyn C. Jones, Joshua J.A. Braun, Meredith S. Wright, Terence C. Wong, Carlos Diaz, Mari Tokita, Miguel Del Campo, Brian Lane, Stephen F. Kingsmore, Christian Hansen, Lisa Salz, Michelle M. Clark, Nicole G. Coufal, Casey Cohenmeyer, Joe Gleeson, Seema Rego, Kristen Wigby, Jennifer Friedman, Zaira Bezares, Mark Speziale, Sara A. Caylor, Lance Prince, Richard S. Song, Jose Honold, Albert Oriol, Catherine Yamada, Annette Feigenbaum, Lucitia Van Der Kraan, Sandra Leibel, Denise Suttner, Dana Mashburn, Laurel Moyer, Julie A. Cakici, Lynne M. Bird, Charles Sauer, Daeheon Oh, Iris Reyes, Gail Knight, Michele Feddock, and Jeanne Carroll
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Neonatal intensive care unit ,Time Factors ,Critical Illness ,Clinical Decision-Making ,Logistic regression ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,030225 pediatrics ,Intensive care ,Internal medicine ,Intensive Care Units, Neonatal ,Genetics ,Medicine ,Humans ,Genetic Testing ,Prospective Studies ,Genetics (clinical) ,Pediatric intensive care unit ,Whole Genome Sequencing ,business.industry ,Genome, Human ,Genetic Diseases, Inborn ,Infant, Newborn ,Chromosome Mapping ,Disease Management ,Infant ,Odds ratio ,Distress ,030104 developmental biology ,Logistic Models ,Etiology ,Female ,sense organs ,business - Abstract
The second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study was a randomized, controlled trial of rapid whole-genome sequencing (rWGS) or rapid whole-exome sequencing (rWES) in infants with diseases of unknown etiology in intensive care units (ICUs). Gravely ill infants were not randomized and received ultra-rapid whole-genome sequencing (urWGS). Herein we report results of clinician surveys of the clinical utility of rapid genomic sequencing (RGS). The primary end-point-clinician perception that RGS was useful- was met for 154 (77%) of 201 infants. Both positive and negative tests were rated as having clinical utility (42 of 45 [93%] and 112 of 156 [72%], respectively). Physicians reported that RGS changed clinical management in 57 (28%) infants, particularly in those receiving urWGS (p = 0.0001) and positive tests (p < 0.00001). Outcomes of 32 (15%) infants were perceived to be changed by RGS. Positive tests changed outcomes more frequently than negative tests (p < 0.00001). In logistic regression models, the likelihood that RGS was perceived as useful increased 6.7-fold when associated with changes in management (95% CI 1.8-43.3). Changes in management were 10.1-fold more likely when results were positive (95% CI 4.7-22.4) and turnaround time was shorter (odds ratio 0.92, 95% CI 0.85-0.99). RGS seldom led to clinician-perceived confusion or distress among families (6 of 207 [3%]). In summary, clinicians perceived high clinical utility and low likelihood of harm with first-tier RGS of infants in ICUs with diseases of unknown etiology. RGS was perceived as beneficial irrespective of whether results were positive or negative.
- Published
- 2020
23. Adaptive functioning in children and adolescents with Trisomy X: An exploratory analysis
- Author
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Lisa Cordeiro, Rebecca Wilson, Kristen Wigby, Nicole Tartaglia, Tony J. Simon, and Kathleen Angkustsiri
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0301 basic medicine ,Autism Spectrum Disorder ,Intelligence ,Psychological intervention ,Trisomy ,inattention ,030105 genetics & heredity ,Adaptive functioning ,Adaptive skills ,Executive Function ,Cognition ,adaptive skills ,Child ,Genetics (clinical) ,Sex Chromosome Aberrations ,Pediatric ,Genetics & Heredity ,Wechsler Adult Intelligence Scale ,Adaptation, Physiological ,Mental Health ,Female ,Psychology ,Clinical psychology ,Human ,prenatal ,Adolescent ,Physiological ,education ,Sex Chromosome Disorders of Sex Development ,Clinical Sciences ,Trisomy X ,behavioral disciplines and activities ,Basic Behavioral and Social Science ,Article ,Chromosomes ,03 medical and health sciences ,Social skills ,Clinical Research ,Behavioral and Social Science ,medicine ,Genetics ,Humans ,Adaptation ,Chromosomes, Human, X ,medicine.disease ,Adaptive Skills Composite Score ,030104 developmental biology ,Attention Deficit Disorder with Hyperactivity ,Triple X syndrome - Abstract
Identifying the factors related to adaptive functioning will improve the information available to families and providers of females with Trisomy X. Cognitive and behavioral features were assessed in 50 females ages 12.2 ± 3.6 years using the Behavior Assessment System for Children Second Edition (BASC-2) and Wechsler Scales of Intelligence. Executive functioning, social skills, and autistic traits were evaluated in a subset. Adaptive functioning was assessed using the BASC-2 adaptive skills composite score (ASC). Participants were classified as average adaptive skills (ASC T-score > 40) or deficits (ASC T-score
- Published
- 2020
24. De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy
- Author
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Marwan Shinawi, Jessica Van Ziffle, Carsten G. Bönnemann, Mohamad A. Mikati, Vandana Shashi, Konrad Platzer, Manju A. Kurian, Katy Barwick, Kathleen A. Leppig, Patrick Devine, F. Lucy Raymond, Tomi L. Toler, Johan Lundgren, Koen L.I. van Gassen, Anne Slavotinek, Saskia N. van der Crabben, Wendy K. Chung, Richard H. van Jaarsveld, Matias Wagner, Rikke S. Møller, Marie T. McDonald, Pia Zacher, Kristen Wigby, Heather C Mefford, Dewi P. Bakker, Jennifer Friedman, Angus John Clarke, Joseph T. Shieh, Holly E. Babcock, Julian R. Sampson, Amy McTague, Jamal Ghoumid, Bernt Popp, Saskia B. Wortmann, Emma Hobson, Michaela Bonfert, Gabriella Horvath, Chiara Klöckner, Virgina Lee, Cyril Mignot, Yuri A. Zarate, Jennifer A. Sullivan, Marie-José H. van den Boogaard, Johannes R. Lemke, Alba Sanchis-Juan, Tommy Stödberg, Heinrich Sticht, Eva H. Brilstra, Alyssa Gates, Caroline Nava, Nicholas Stong, Sandra Donkervoort, Alexandrea Wadley, Boris Keren, Jamie L. Fraser, Ashley C. Taylor, Jennifer Keller-Ramey, Human Genetics, Pediatric surgery, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Human genetics
- Subjects
medicine.medical_specialty ,Movement disorders ,Synaptosomal-Associated Protein 25 ,Bioinformatics ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Atrophy ,Intellectual Disability ,Intellectual disability ,Medicine ,STXBP1 ,Missense mutation ,Humans ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Brain Diseases ,business.industry ,STX1B ,medicine.disease ,Phenotype ,Neurodevelopmental Disorders ,Child, Preschool ,Medical genetics ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Purpose\ud This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.\ud \ud Methods\ud Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.\ud \ud Results\ud The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.\ud \ud Conclusion\ud We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed “SNAREopathies.”
- Published
- 2020
25. Genetic testing strategies in the newborn
- Author
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Jeanne, Carroll, Kristen, Wigby, and Sarah, Murray
- Subjects
Intensive Care Units, Neonatal ,Infant, Newborn ,High-Throughput Nucleotide Sequencing ,Humans ,Genetic Counseling ,Genetic Testing ,Infant, Newborn, Diseases - Abstract
Genetic disorders presenting in the neonatal period can have a significant impact on morbidity and mortality. Early diagnosis can facilitate timely prognostic counseling to families and possibility of precision care, which could improve outcome. As availability of diagnostic testing expands, the required knowledge base of the neonatologist must also expand to include proper application and understanding of genetic testing modalities, especially where availability of clinical genetics consultation is limited. Herein, we review genetic tests utilized in the neonatal intensive care unit (NICU) providing background on the technology, clinical indications, advantages, and limitations of the tests. This review will span from classic cytogenetics to the evolving role of next generation sequencing and its impact on the management of neonatal disease.
- Published
- 2019
26. Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing
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David Dimmock, Dallas Reed, Matthew Gallen, Shimul Chowdhury, Bruce D. Gelb, Stephen F. Kingsmore, Thomas E Mullen, Annemarie Stroustrup, Cynthia M. Powell, Anne Kurfiss, Kristen Suhrie, Brenda B. Poindexter, Jill L. Maron, Jerry Vockley, Kristen Wigby, Pranoot Tanpaiboon, Thomas G. Diacovo, Jonathan M. Davis, and Andrea N. Trembath
- Subjects
Proband ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Comparative effectiveness research ,Interim analysis ,Clinical trial ,Patient recruitment ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Medical genetics ,030212 general & internal medicine ,Personalized medicine ,business ,Genetic testing - Abstract
Importance A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing. Objective To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy. Design, setting, and participants The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020. Interventions Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results. Main outcomes and measures Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing. Results Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes. Conclusions and relevance As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.
- Published
- 2021
27. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants
- Author
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David Dimmock, Dorjee Tamang, Sarah White, Peter Schols, Michelle M. Clark, Zaira Bezares, Richard S. Song, Sandra Leibel, Denise Suttner, Jennie Le, Charlotte A. Hobbs, Casey Cohenmeyer, Katarzyna A. Ellsworth, Brian Lane, Amber Hildreth, Lauge Farnaes, Kelly Watkins, Kiely N. James, Terence C. Wong, Cinnamon S. Bloss, Nicole G. Coufal, Laura Puckett, Mari Tokita, Lance Prince, Amy S. Kimball, Narayanan Veeraraghavan, Shareef Nahas, Cyrielle Kint, Yan Ding, Paulina Ordonez, Jaime Barea, Erica Sanford, Kristen Wigby, Daniken Orendain, Maria Ortiz-Arechiga, Meredith S. Wright, Dana Mashburn, Sara A. Caylor, Nathaly M. Sweeney, Joshua J.A. Braun, Christina Clarke, Audra Wise, Lisa Salz, Charles Sauer, Jenni Friedman, George Chiang, Jerica Lenberg, Mark Speziale, Laurel Moyer, Michele Feddock, Jeanne Carroll, Patrick Mulrooney, Raymond Hovey, Stephen F. Kingsmore, Marva Evans, Sergey Batalov, Albert Oriol, Joe Gleeson, Jose Honold, Carlos Diaz, Mary Gaughran, Julie A. Cakici, Crystal Le, Catherine Yamada, Shimul Chowdhury, Gail Knight, Matthew N. Bainbridge, Lucitia Van Der Kraan, Daeheon Oh, and Iris Reyes
- Subjects
0301 basic medicine ,ultra-rapid whole-genome sequencing ,Pediatrics ,medicine.medical_specialty ,diagnosis ,precision medicine ,RCIGM Investigators ,Clinical Trials and Supportive Activities ,030105 genetics & heredity ,Genome ,intensive care unit ,Medical and Health Sciences ,Article ,law.invention ,03 medical and health sciences ,Randomized controlled trial ,law ,genetic disease ,Clinical Research ,Exome Sequencing ,medicine ,Genetics ,Humans ,Genetic Testing ,whole-exome sequencing ,Genetics (clinical) ,Exome sequencing ,Whole genome sequencing ,Pediatric ,Genetics & Heredity ,Whole Genome Sequencing ,business.industry ,Singleton ,Human Genome ,Infant, Newborn ,Infant ,Biological Sciences ,Precision medicine ,Newborn ,Intensive care unit ,030104 developmental biology ,genomic medicine ,Good Health and Well Being ,whole-genome sequencing ,Etiology ,business - Abstract
The second Newborn Sequencing in Genomic Medicine and Public Health study was a randomized, controlled trial of the effectiveness of rapid whole-genome or -exome sequencing (rWGS or rWES, respectively) in seriously ill infants with diseases of unknown etiology. Here we report comparisons of analytic and diagnostic performance. Of 1,248 ill inpatient infants, 578 (46%) had diseases of unknown etiology. 213 infants (37% of those eligible) were enrolled within 96h of admission. 24 infants (11%) were very ill and received ultra-rapid whole-genome sequencing (urWGS). The remaining infants were randomized, 95 to rWES and 94 to rWGS. The analytic performance of rWGS was superior to rWES, including variants likely to affect protein function, and ClinVar pathogenic/likely pathogenic variants (p < 0.0001). The diagnostic performance of rWGS and rWES were similar (18 diagnoses in 94 infants [19%] versus 19 diagnoses in 95 infants [20%], respectively), as was time to result (median 11.0 versus 11.2days, respectively). However, the proportion diagnosed by urWGS (11 of 24 [46%]) was higher than rWES/rWGS (p = 0.004) and time to result was less (median 4.6days, p < 0.0001). The incremental diagnostic yield of reflexing to trio after negative proband analysis was 0.7% (1 of 147). In conclusion, rapid genomic sequencing can be performed as a first-tier diagnostic test in inpatient infants. urWGS had the shortest time to result, which was important in unstable infants, and those in whom a genetic diagnosis was likely to impact immediate management. Further comparison of urWGS and rWES is warranted because genomic technologies and knowledge of variant pathogenicity are evolving rapidly.
- Published
- 2019
28. Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
- Author
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Kiely N. James, Shareef Nahas, Valentina Stanley, Gajja S. Salomons, Mahmoud Y. Issa, Tarek Omar, Geneviève Bernard, Kristen Wigby, Maha S. Zaki, Wing-Sze Lo, Luan T. Tran, David Dimmock, Damir Musaev, Marisa I. Mendes, Amber Hildreth, Andrea Accogli, Jennifer Friedman, Joseph G. Gleeson, Stephen F. Kingsmore, Zhiwen Xu, Desirée E.C. Smith, Alanna E. Koehler, John R. Crawford, Kether Guerrero, Shimul Chowdhury, Liting Zhai, Tawfeg Ben-Omran, Meredith S. Wright, Rengang Wang, Clinical chemistry, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and Amsterdam Reproduction & Development (AR&D)
- Subjects
Models, Molecular ,0301 basic medicine ,Male ,General Physics and Astronomy ,02 engineering and technology ,Neurodegenerative ,medicine.disease_cause ,Whole Exome Sequencing ,RNA, Transfer ,Models ,Loss of Function Mutation ,Protein biosynthesis ,Missense mutation ,2.1 Biological and endogenous factors ,Longitudinal Studies ,Aetiology ,lcsh:Science ,Child ,Genetics ,Pediatric ,Mutation ,Multidisciplinary ,Neurodegeneration ,021001 nanoscience & nanotechnology ,3. Good health ,Pedigree ,Child, Preschool ,Transfer RNA ,Microcephaly ,Disease Progression ,Female ,0210 nano-technology ,Valine-tRNA Ligase ,Science ,Intellectual and Developmental Disabilities (IDD) ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Rare Diseases ,Exome Sequencing ,medicine ,Anticodon ,Humans ,Genetic Predisposition to Disease ,Protein Interaction Domains and Motifs ,Preschool ,Gene ,Alleles ,Epilepsy ,Whole Genome Sequencing ,fungi ,Neurosciences ,RNA ,Molecular ,General Chemistry ,medicine.disease ,TRNA binding ,Brain Disorders ,Transfer ,030104 developmental biology ,Neurodevelopmental Disorders ,Protein Biosynthesis ,lcsh:Q - Abstract
Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes., Valyl-tRNA synthetase (VARS) charges valyl-tRNA with the amino acid valine, required for translation. Here, the authors describe a progressive epileptic encephalopathy in individuals from five families carrying biallelic mutations in the VARS gene that leave the enzyme activity partially intact.
- Published
- 2019
29. Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico
- Author
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Marilyn C. Jones, Carolina I. Galarreta, Denise L. Perry, Miguel Del Campo, Reporting Team, Vani Rajan, Diane Masser-Frye, Kristen Wigby, David R. Bentley, Ryan J. Taft, Alicia Scocchia, Subramanian S. Ajay, Keisha D Robinson, Julia McEachern, Andrew M. Gross, Erin Thorpe, Icsl Interpretation, and John W Belmont
- Subjects
0301 basic medicine ,Proband ,Pediatrics ,medicine.medical_specialty ,lcsh:QH426-470 ,MEDLINE ,lcsh:Medicine ,Disease ,Article ,03 medical and health sciences ,0302 clinical medicine ,Clinical Research ,medicine ,Genetics ,Copy-number variation ,Genetic Testing ,Medical diagnosis ,Molecular Biology ,Genetics (clinical) ,Whole genome sequencing ,Pediatric ,screening and diagnosis ,business.industry ,lcsh:R ,ICSL Interpretation and Reporting Team ,Human Genome ,medicine.disease ,Test (assessment) ,4.1 Discovery and preclinical testing of markers and technologies ,lcsh:Genetics ,Detection ,030104 developmental biology ,Good Health and Well Being ,030220 oncology & carcinogenesis ,Trisomy ,business ,4.2 Evaluation of markers and technologies - Abstract
Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the “diagnostic odyssey”. Patients in resource-limited areas face even greater challenges—a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% (n = 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% (n = 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% (n = 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders., Pediatrics: Philanthropic clinical whole-genome sequencing program helps children in Mexico Whole-genome sequencing (WGS) provides a valuable first-tier diagnostic test at pediatric clinics in resource-limited parts of the world, according to a study of children with suspected genetic disease treated in northern Mexico. A team led by Marilyn Jones from the Rady Children’s Hospital and Ryan Taft from Illumina Inc., both in San Diego, California, USA, describe a collaboration with a volunteer-led clinic in Tijuana, Mexico, where they offered genome sequencing for children with suspected genetic conditions—philanthropically through the iHope Program. Among the 60 families that participated, the clinical laboratory team identified genomic variants with diagnostic relevance in 41 (68%) cases. The genomic information contributed to changes in clinical management for 20 of these children, demonstrating the impact of WGS in places where patients generally don’t have access to medical specialists or other sophisticated molecular tests.
- Published
- 2019
30. A novel autosomal dominant mutation in SOX18 resulting in a fatal case of hypotrichosis–lymphedema–telangiectasia syndrome
- Author
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Hannah Wangberg, Kristen Wigby, and Marilyn C. Jones
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Genotype ,030105 genetics & heredity ,Hypotrichosis ,medicine.disease_cause ,03 medical and health sciences ,Fatal Outcome ,SOXF Transcription Factors ,Genetics ,medicine ,Humans ,Lymphedema ,Telangiectasis ,Telangiectasia ,Alleles ,Genetics (clinical) ,Genes, Dominant ,Mutation ,business.industry ,Infant, Newborn ,Chylothorax ,Exons ,medicine.disease ,Pulmonary hypertension ,Phenotype ,030104 developmental biology ,Hypotrichosis–lymphedema–telangiectasia syndrome ,medicine.symptom ,business - Abstract
Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a rare disorder caused by autosomal recessive and autosomal dominant mutations in SOX18. This gene encodes a transcription factor involved in the regulation and development of the human vasculature, lymphatic, and integumentary systems. Individuals with HLTS develop varying degrees of hypotrichosis, lymphedema, and telangiectasias. Other complications, such as renal failure and aortic dilation, have also been observed. Here, we report a neonate with a novel mutation in SOX18 (c.541C>T; p.Gln181stop) presenting with cardinal features of HLTS in addition to unique findings of severe chylothorax and relentless pulmonary hypertension that culminated in death. The purpose of this report is to summarize what is known about this evolving genetic syndrome and to speculate as to how mutations in SOX18 might produce the phenotype.
- Published
- 2018
31. Correction to: De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy
- Author
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Marwan Shinawi, Johan Lundgren, Jennifer A. Sullivan, Katy Barwick, Jessica Van Ziffle, Eva H. Brilstra, Tomi L. Toler, Alyssa Gates, Carsten G. Bönnemann, Amy McTague, Dewi P. Bakker, Manju A. Kurian, Saskia N. van der Crabben, Jamal Ghoumid, Ashley C. Taylor, F. Lucy Raymond, Yuri A. Zarate, Patrick Devine, Pia Zacher, Heather C Mefford, Marie T. McDonald, Konrad Platzer, Emma Hobson, Holly E. Babcock, Jennifer Keller-Ramey, Gabriella Horvath, Anne Slavotinek, Caroline Nava, Koen L.I. van Gassen, Richard H. van Jaarsveld, Chiara Klöckner, Virgina Lee, Cyril Mignot, Jamie L. Fraser, Angus John Clarke, Nicholas Stong, Bernt Popp, Wendy K. Chung, Jennifer Friedman, Johannes R. Lemke, Alexandrea Wadley, Julian R. Sampson, Rikke S. Møller, Tommy Stödberg, Michaela Bonfert, Mohamad A. Mikati, Kathleen A. Leppig, Sandra Donkervoort, Vandana Shashi, Boris Keren, Heather M. McLaughlin, Matias Wagner, Kristen Wigby, Marie-José H. van den Boogaard, Alba Sanchis-Juan, Heinrich Sticht, Joseph T. Shieh, and Saskia B. Wortmann
- Subjects
Text mining ,business.industry ,Epileptic encephalopathy ,MEDLINE ,SNAP25 ,Medicine ,business ,Bioinformatics ,Genetics (clinical) ,Early onset - Published
- 2021
32. Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy
- Author
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Miles D. Thompson, Alejandro D. Iglesias, Anik St-Denis, Philippe M. Campeau, Stephanie C. Laniewski, Julie M. Jones, Denise L. Perry, Justine Rousseau, Diane Masser-Frye, Marilyn C. Jones, Nissan V. Baratang, Angela E. Scheuerle, Françoise Le Deist, Thi Tuyet Mai Nguyen, Kristen Wigby, Ryan J. Taft, Jill A. Rosenfeld, Taroh Kinoshita, and Yoshiko Murakami
- Subjects
0301 basic medicine ,Male ,Developmental Disabilities ,Neurodegenerative ,Compound heterozygosity ,medicine.disease_cause ,Medical and Health Sciences ,Whole Exome Sequencing ,Epilepsy ,0302 clinical medicine ,2.1 Biological and endogenous factors ,PIGS ,Global developmental delay ,Aetiology ,Child ,Genetics (clinical) ,Genetics ,Pediatric ,Genetics & Heredity ,Arthrogryposis ,Mutation ,Syndrome ,Biological Sciences ,Phenotype ,Hypotonia ,Pedigree ,Child, Preschool ,Muscle Hypotonia ,Epilepsy, Generalized ,Female ,medicine.symptom ,Abnormalities ,Multiple ,Ataxia ,Cerebellar Ataxia ,Biology ,Nervous System Malformations ,Cell Line ,03 medical and health sciences ,Rare Diseases ,Seizures ,Report ,Intellectual Disability ,Exome Sequencing ,medicine ,glycosylphosphatidylinositol biosynthesis defect ,Humans ,Abnormalities, Multiple ,Preschool ,Loss function ,Generalized ,Human Genome ,Neurosciences ,medicine.disease ,Brain Disorders ,glycosylphosphatidylinositol ,030104 developmental biology ,HEK293 Cells ,inherited GPI deficiency ,Congenital Structural Anomalies ,030217 neurology & neurosurgery ,Acyltransferases - Abstract
Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result ofadvances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36∗) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36∗ variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs.
- Published
- 2018
33. Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation
- Author
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Terence C. Wong, Marie L. Janes, John Reynders, Martin G. Reese, Brett Williams, Patrick Mulrooney, Sergey Batalov, Kristen Wigby, Brandon Camp, Lauge Farnaes, Joshua J.A. Braun, Meredith S. Wright, Narayanan Veeraraghavan, Jeremy Gore, Shareef Nahas, David Dimmock, Sheldon Gilmer, Lisa Salz, Albert Oriol, Mari Tokita, Kejia Lin, Thomas Defay, Erica Sanford, Catherine Yamada, Nathaly M. Sweeney, Stephen F. Kingsmore, Yan Ding, Christina Clarke, Laura Puckett, Katarzyna A. Ellsworth, Richard Gain, Shauna George, Luca Van Der Kraan, Margaret Bray, Mary Gaughran, Curtis Beebe, Alison Frith, Kevin Hall, Kyle McBride, Amber Hildreth, Michelle M. Clark, Haiying Li Grunenwald, Julie Ryu, Cyrielle Kint, Kelly Watkins, Mitchell Creed, Jennifer Friedman, Shimul Chowdhury, Paul D. McDonagh, Zia Rady, Peter Schols, Joseph G. Gleeson, Julie A. Cakici, Lawrence Stewart, Raymond Hovey, Jeanne Carroll, Matthew N. Bainbridge, Daeheon Oh, Calum Yacoubian, Sara A. Caylor, and Sarah White
- Subjects
0301 basic medicine ,medicine.medical_specialty ,030105 genetics & heredity ,Phenome ,Genome ,DNA sequencing ,Diabetic Ketoacidosis ,03 medical and health sciences ,Intensive care ,medicine ,Electronic Health Records ,Humans ,Medical diagnosis ,Intensive care medicine ,Natural Language Processing ,Retrospective Studies ,Whole genome sequencing ,business.industry ,General Medicine ,Genomics ,Intensive Care Units ,030104 developmental biology ,DECIPHER ,Female ,Precision and recall ,business - Abstract
By informing timely targeted treatments, rapid whole-genome sequencing can improve the outcomes of seriously ill children with genetic diseases, particularly infants in neonatal and pediatric intensive care units (ICUs). The need for highly qualified professionals to decipher results, however, precludes widespread implementation. We describe a platform for population-scale, provisional diagnosis of genetic diseases with automated phenotyping and interpretation. Genome sequencing was expedited by bead-based genome library preparation directly from blood samples and sequencing of paired 100-nt reads in 15.5 hours. Clinical natural language processing (CNLP) automatically extracted children’s deep phenomes from electronic health records with 80% precision and 93% recall. In 101 children with 105 genetic diseases, a mean of 4.3 CNLP-extracted phenotypic features matched the expected phenotypic features of those diseases, compared with a match of 0.9 phenotypic features used in manual interpretation. We automated provisional diagnosis by combining the ranking of the similarity of a patient’s CNLP phenome with respect to the expected phenotypic features of all genetic diseases, together with the ranking of the pathogenicity of all of the patient’s genomic variants. Automated, retrospective diagnoses concurred well with expert manual interpretation (97% recall and 99% precision in 95 children with 97 genetic diseases). Prospectively, our platform correctly diagnosed three of seven seriously ill ICU infants (100% precision and recall) with a mean time saving of 22:19 hours. In each case, the diagnosis affected treatment. Genome sequencing with automated phenotyping and interpretation in a median of 20:10 hours may increase adoption in ICUs and, thereby, timely implementation of precise treatments.
- Published
- 2018
34. Whole Exome Sequencing Guides Pharmacotherapy for an Adolescent With Autism Spectrum Disorder and Psychosis
- Author
-
Kristen Wigby, Mary J H Willis, Matthew Carpinello, Michael T Ricciardi, and Samuel Nicolas
- Subjects
Psychosis ,Pediatrics ,medicine.medical_specialty ,business.industry ,MEDLINE ,medicine.disease ,Psychiatry and Mental health ,Pharmacotherapy ,Autism spectrum disorder ,Developmental and Educational Psychology ,medicine ,Personalized medicine ,Disease management (health) ,business ,Exome ,Exome sequencing - Abstract
Genomic testing, including whole exome sequencing (WES), can result in specific changes to medical management. To illustrate the clinical utility of WES for complex neuropsychiatric disease, we report a male adolescent with autism spectrum disorder, psychosis, and regression and discuss how the WES findings guided his pharmacologic management.
- Published
- 2019
35. Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay
- Author
-
Deciphering Developmental Disorders Study, Madeleine Fannemel, Natalie Beck, Paul Kruszka, Marilyn C. Jones, Neeti Ghali, Karin Weiss, Maximilian Muenke, Ada Hamosh, Kristen Wigby, Sondhya Ghedia, Lindsay B. Henderson, Johanna Lundin, and Britt-Marie Anderlid
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Developmental Disabilities ,Clinical Sciences ,Nerve Tissue Proteins ,Haploinsufficiency ,030105 genetics & heredity ,Biology ,Bioinformatics ,Corpus callosum ,Article ,Craniosynostosis ,Craniofacial Abnormalities ,03 medical and health sciences ,Dysgenesis ,Rare Diseases ,Ptosis ,Clinical Research ,medicine ,Genetics ,Humans ,Blepharoptosis ,2.1 Biological and endogenous factors ,Craniofacial ,Dental/Oral and Craniofacial Disease ,Aetiology ,Child ,Preschool ,Genetics (clinical) ,Pediatric ,Genetics & Heredity ,Human Genome ,Infant ,Syndrome ,medicine.disease ,Human genetics ,DNA-Binding Proteins ,030104 developmental biology ,Child, Preschool ,Medical genetics ,Congenital Structural Anomalies ,Female ,medicine.symptom ,Agenesis of Corpus Callosum ,Transcription Factors - Abstract
The introduction of whole-exome sequencing into the Pediatric Genetics clinic has increased the identification of novel genes associated with neurodevelopmental disorders and congenital anomalies. This agnostic approach has shed light on multiple proteins and pathways not previously known to be associated with disease. Here we report eight subjects from six families with predicted loss of function variants in ZNF462, a zinc-finger protein of unknown function. These individuals have overlapping phenotypes that include ptosis, metopic ridging, craniosynostosis, dysgenesis of the corpus callosum, and developmental delay. We propose that ZNF462 plays an important role in embryonic development, and is associated with craniofacial and neurodevelopmental abnormalities.
- Published
- 2017
36. Rapid whole-genome sequencing identifies a novel homozygous
- Author
-
Amber, Hildreth, Kristen, Wigby, Shimul, Chowdhury, Shareef, Nahas, Jaime, Barea, Paulina, Ordonez, Sergey, Batalov, David, Dimmock, and Stephen, Kingsmore
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,foam cells with lamellar inclusion bodies ,generalized neonatal hypotonia ,Niemann-Pick C1 Protein ,hemic and lymphatic diseases ,Humans ,abnormal cholesterol homeostasis ,Niemann-Pick Diseases ,clinodactyly of the 5th finger ,Cholestasis ,Genome ,Membrane Glycoproteins ,Liver Diseases ,Homozygote ,Intracellular Signaling Peptides and Proteins ,nutritional and metabolic diseases ,Infant ,Niemann-Pick Disease, Type C ,prolonged neonatal jaundice ,Sequence Analysis, DNA ,Cholesterol ,Mutation ,hepatosplenomegaly ,Carrier Proteins ,Rapid Communication - Abstract
Niemann–Pick type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1. Although characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction because of intrahepatocyte lipid accumulation. We report a 7-wk-old infant who was admitted with neonatal cholestasis, and who was diagnosed with a novel homozygous stop-gain variant in NPC1 by rapid whole-genome sequencing (WGS). WGS results were obtained 16 d before return of the standard clinical genetic test results and prompted initiation of targeted therapy.
- Published
- 2017
37. Gastrointestinal disorders in Curry-Jones syndrome: Clinical and molecular insights from an affected newborn
- Author
-
Kristen, Wigby, Stephen R F, Twigg, Ryan, Broderick, Katherine P, Davenport, Andrew O M, Wilkie, Stephen W, Bickler, and Marilyn C, Jones
- Subjects
gastrointestinal smooth muscle hamartomas ,Gastrointestinal Diseases ,Infant ,SMO somatic mosaic mutations ,Original Articles ,Smoothened Receptor ,Curry–Jones syndrome ,Craniofacial Abnormalities ,Intestines ,Craniosynostoses ,Mutation ,Skin Abnormalities ,Humans ,Female ,Original Article ,Syndactyly - Abstract
Curry–Jones syndrome (CJS) is a pattern of malformation that includes craniosynostosis, pre‐axial polysyndactyly, agenesis of the corpus callosum, cutaneous and gastrointestinal abnormalities. A recurrent, mosaic mutation of SMO (c.1234 C>T; p.Leu412Phe) causes CJS. This report describes the gastrointestinal and surgical findings in a baby with CJS who presented with abdominal obstruction and reviews the spectrum of gastrointestinal malformations in this rare disorder. A 41‐week, 4,165 g, female presented with craniosynostosis, pre‐axial polysyndactyly, and cutaneous findings consistent with a clinical diagnosis of CJS. The infant developed abdominal distension beginning on the second day of life. Surgical exploration revealed an intestinal malrotation for which she underwent a Ladd procedure. Multiple small nodules were found on the surface of the small and large bowel in addition to an apparent intestinal duplication that seemed to originate posterior to the pancreas. Histopathology of serosal nodules revealed bundles of smooth muscle with associated ganglion cells. Molecular analysis demonstrated the SMO c.1234 C>T mutation in varying amounts in affected skin (up to 35%) and intestinal hamartoma (26%). Gastrointestinal features including structural malformations, motility disorders, and upper GI bleeding are major causes of morbidity in CJS. Smooth muscle hamartomas are a recognized feature of children with CJS typically presenting with abdominal obstruction requiring surgical intervention. A somatic mutation in SMO likely accounts for the structural malformations and predisposition to form bowel hamartomas and myofibromas. The mutation burden in the involved tissues likely accounts for the variable manifestations.
- Published
- 2016
38. 225: ORTNER SYNDROME AS SYMPTOM OF HEREDITARY HEMORRHAGIC TELANGIECTASIA WITH PULMONARY HYPERTENSION
- Author
-
Nicole G. Coufal, Batool Alsheikh, Shareef Nahas, Justin Yeh, Helen Harvey, Shimul Chowdhury, Raghav Murthy, Kristen Wigby, David Dimmock, and Jeanne Carroll
- Subjects
medicine.medical_specialty ,business.industry ,Medicine ,medicine.symptom ,Critical Care and Intensive Care Medicine ,business ,medicine.disease ,Telangiectasia ,Dermatology ,Pulmonary hypertension - Published
- 2018
39. Expanding the phenotype of Triple X syndrome: A comparison of prenatal versus postnatal diagnosis
- Author
-
Amy Reicks, Kristen Wigby, Cheryl D’Epagnier, Nicole Tartaglia, Susan Howell, Rebecca Wilson, and Lisa Cordeiro
- Subjects
0301 basic medicine ,Adult ,Pediatrics ,medicine.medical_specialty ,Clinodactyly ,Adolescent ,Genetic counseling ,Developmental Disabilities ,Sex Chromosome Disorders of Sex Development ,Physical examination ,Prenatal diagnosis ,Neuroimaging ,Trisomy ,030105 genetics & heredity ,Triple X syndrome ,Neuropsychological Tests ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Dental disorder ,Prenatal Diagnosis ,Genetics ,medicine ,Humans ,Genetic Testing ,Child ,Physical Examination ,Genetics (clinical) ,Genetic Association Studies ,Sex Chromosome Aberrations ,Genetic testing ,Chromosomes, Human, X ,medicine.diagnostic_test ,business.industry ,Facies ,Infant ,medicine.disease ,Hypotonia ,Phenotype ,Child, Preschool ,Karyotyping ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Triple X syndrome (47, XXX) occurs in approximately 1:1,000 female births and has a variable phenotype of physical and psychological features. Prenatal diagnosis rates of 47, XXX are increasing due to non-invasive prenatal genetic testing. Previous studies suggest that prenatal diagnosed females have better neurodevelopmental outcomes. This cross-sectional study describes diagnosis, physical features, medical problems, and neurodevelopmental features in a large cohort of females with 47, XXX. Evaluation included review of medical and developmental history, physical exam, cognitive, and adaptive testing. Medical and developmental features were compared between the prenatal and postnatal diagnosis groups using rate calculations and Fisher's exact test. Cognitive and adaptive tests scores were compared using t-tests. Seventy-four females age 6 months-24 years (mean 8.3 years) participated. Forty-four (59.5%) females were in the prenatal diagnosis group. Mean age of postnatal diagnosis was 5.9 years; developmental delay was the most common indication for postnatal genetic testing. Common physical features included hypertelorism, epicanthal folds, clinodactyly, and hypotonia. Medical problems included dental disorders (44.4%), seizure disorders (16.2%), genitourinary malformations (12.2%). The prenatal diagnosis group had higher verbal (P
- Published
- 2015
40. Rapid whole-genome sequencing identifies a novel homozygous NPC1 variant associated with Niemann–Pick type C1 disease in a 7-week-old male with cholestasis
- Author
-
Jaime Barea, Sergey Batalov, Amber Hildreth, Shimul Chowdhury, Stephen F. Kingsmore, Shareef Nahas, David Dimmock, Paulina Ordonez, and Kristen Wigby
- Subjects
0301 basic medicine ,Whole genome sequencing ,congenital, hereditary, and neonatal diseases and abnormalities ,business.industry ,medicine.medical_treatment ,Hepatosplenomegaly ,nutritional and metabolic diseases ,General Medicine ,Disease ,Neurological disorder ,medicine.disease ,Bioinformatics ,3. Good health ,Targeted therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cholestasis ,Immunology ,Medicine ,Neonatal cholestasis ,NPC1 ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Niemann–Pick type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1. Although characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction because of intrahepatocyte lipid accumulation. We report a 7-wk-old infant who was admitted with neonatal cholestasis, and who was diagnosed with a novel homozygous stop-gain variant in NPC1 by rapid whole-genome sequencing (WGS). WGS results were obtained 16 d before return of the standard clinical genetic test results and prompted initiation of targeted therapy.
- Published
- 2017
41. Diagnosis of alpha mannosidosis after incidental finding of foamy cells on surgical specimen
- Author
-
Annette Feigenbaum, Kristen Wigby, Bruce A. Barshop, Lynne M. Bird, and Jaime Barea
- Subjects
Pathology ,medicine.medical_specialty ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Genetics ,Medicine ,business ,Surgical specimen ,medicine.disease ,Molecular Biology ,Biochemistry - Published
- 2017
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