Medicine and Health Sciences Commons^™

Characteristics And Prognostic Impact Of Idh Mutations In Aml: A Cog, Swog, And Ecog Analysis., Sara Zarnegar-Lumley, Todd A. Alonzo, Robert B. Gerbing, Megan Othus, Zhuoxin Sun, Rhonda E. Ries, Jim Wang, Amanda Leonti, Matthew A. Kutny, Fabiana Ostronoff, Jerald P. Radich, Frederick R. Appelbaum, Era L. Pogosova-Agadjanyan, Kristen O'Dwyer, Martin S. Tallman, Mark Litzow, Ehab Atallah, Todd M. Cooper, Richard A. Aplenc, Omar Abdel-Wahab, Alan S. Gamis, Selina Luger, Harry Erba, Ross Levine, E Anders Kolb, Derek L. Stirewalt, Soheil Meshinchi, Katherine Tarlock

Manuscripts, Articles, Book Chapters and Other Papers

Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, mutational profile, and prognostic significance of IDH mutations in AML across age. Our cohort included 3141 patients aged betweenChildren's Cancer Group/Children's Oncology Group (n = 1872), Southwest Oncology Group (n = 359), Eastern Cooperative Oncology Group (n = 397) trials, and in Beat AML (n = 333) and The Cancer Genome Atlas (n = 180) genomic characterization cohorts. We retrospectively analyzed patients in 4 age groups (age range, n): …

Potassium Channel Subfamily T Member 1(Kcnt1) Pathological Variant Causing Epilepsy Of Infancy With Migrating Focal Seizures: A Case Report, Prem Chand, Meher Angez, Ayesha Nasir Hameed, Salman Kirmani

Department of Paediatrics and Child Health

Pathological mutation of potassium channel subfamily T member 1 (KCNT1) gene causes an autosomal dominant disorder characterised by secondarily generalised seizures/migratory focal seizure, cyanosis, and dysmorphic features. We report the case of a five-month old male with pathological KCNT1 variant who presented with focal clonic seizures, Mongol spots, and grade two systolic murmur at the left lower sternal border and loud P2. The seizures were refractory to most anti-epileptic drugs but showed some response to Valproic acid. This case demonstrated that EIMFS is a grave infantile epileptic encephalopathy which is refractory to anti epileptic drugs and can present with a …

Comprehensive Molecular And Clinical Characterization Of Nup98 Fusions In Pediatric Acute Myeloid Leukemia, Eline J M Bertrums, Jenny L. Smith, Lauren Harmon, Rhonda E. Ries, Yi-Cheng J. Wang, Todd A. Alonzo, Andrew J. Menssen, Karen M. Chisholm, Amanda R. Leonti, Katherine Tarlock, Fabiana Ostronoff, Era L. Pogosova-Agadjanyan, Gertjan J L Kaspers, Henrik Hasle, Michael Dworzak, Christiane Walter, Nora Muhlegger, Cristina Morerio, Laura Pardo, Betsy Hirsch, Susana Raimondi, Todd M. Cooper, Richard Aplenc, Alan S. Gamis, Edward A. Kolb, Jason E. Farrar, Derek Stirewalt, Xiaotu Ma, Tim I. Shaw, Scott N. Furlan, Lisa Eidenschink Brodersen, Michael R. Loken, Marry M. Van Den Heuvel-Eibrink, C Michel Zwaan, Timothy J. Triche, Bianca F. Goemans, Soheil Meshinchi

Manuscripts, Articles, Book Chapters and Other Papers

NUP98 fusions comprise a family of rare recurrent alterations in AML, associated with adverse outcomes. In order to define the underlying biology and clinical implications of this family of fusions, we performed comprehensive transcriptome, epigenome, and immunophenotypic profiling of 2,235 children and young adults with AML and identified 160 NUP98 rearrangements (7.2%), including 108 NUP98-NSD1 (4.8%), 32 NUP98-KDM5A (1.4%) and 20 NUP98-X cases (0.9%) with 13 different fusion partners. Fusion partners defined disease characteristics and biology; patients with NUP98-NSD1 or NUP98-KDM5A had distinct immunophenotypic, transcriptomic, and epigenomic profiles. Unlike the two most prevalent NUP98 fusions, NUP98-X variants are typically not …

Long Noncoding Rna Expression Independently Predicts Outcome In Pediatric Acute Myeloid Leukemia., Jason E. Farrar, Jenny L. Smith, Megan Othus, Benjamin J. Huang, Yi-Cheng Wang, Rhonda Ries, Tiffany Hylkema, Era L. Pogosova-Agadjanyan, Sneha Challa, Amanda Leonti, Timothy I. Shaw, Timothy J. Triche, Alan S. Gamis, Richard Aplenc, E Anders Kolb, Xiaotu Ma, Derek L. Stirewalt, Todd A. Alonzo, Soheil Meshinchi

Manuscripts, Articles, Book Chapters and Other Papers

Purpose: Optimized strategies for risk classification are essential to tailor therapy for patients with biologically distinctive disease. Risk classification in pediatric acute myeloid leukemia (pAML) relies on detection of translocations and gene mutations. Long noncoding RNA (lncRNA) transcripts have been shown to associate with and mediate malignant phenotypes in acute myeloid leukemia (AML) but have not been comprehensively evaluated in pAML.

Methods: To identify lncRNA transcripts associated with outcomes, we evaluated the annotated lncRNA landscape by transcript sequencing of 1,298 pediatric and 96 adult AML specimens. Upregulated lncRNAs identified in the pAML training set were used to establish a regularized …

Clinical Utility Of Anti-Mullerian Hormone In Pediatrics, Roopa Kanakatti Shankar, Tazim Dowlut-Mcelroy, Andrew Dauber, Veronica Gomez-Lobo

Pediatrics Faculty Publications

CONTEXT: Anti-Mullerian hormone (AMH) was originally described in the context of sexual differentiation in the male fetus but has gained prominence now as a marker of ovarian reserve and fertility in females. In this mini-review, we offer an updated synopsis on AMH and its clinical utility in pediatric patients.

DESIGN AND RESULTS: A systematic search was undertaken for studies related to the physiology of AMH, normative data, and clinical role in pediatrics. In males, AMH, secreted by Sertoli cells, is found at high levels prenatally and throughout childhood and declines with progression through puberty to overlap with levels in females. …

Phenotype Expression Variability In Children With Gabrb3 Heterozygous Mutations., Abdulhafeez M. Khair, Alana E. Salvucci

Department of Pediatrics Faculty Papers

GABRB3 gene is a recently identified gene located in 15q12 chromosome and encodes for gamma-aminobutyric acid (GABA) receptor subunit beta-3 protein, which is linked to the GABAA receptor. The gene is believed to share a role in inhibitory GABAergic synapses, GABA iron-gated channel function, and possible cellular response to histamine. The β3 subunit is expressed in cerebral grey matter, thalami, hippocampi, and cerebellum, among other structures. Faulty GABRB3 function is linked to several neurological disorders and clinical syndromes. However, the spectrum of such disorders is not yet well known. We present three case reports highlighting the potentially expanding clinical phenotype …

A Novel Sting1 Variant Causes A Recessive Form Of Sting-Associated Vasculopathy With Onset In Infancy (Savi)., Bin Lin, Roberta Berard, Abdulrahman Al Rasheed, Buthaina Aladba, Philip J Kranzusch, Maggie Henderlight, Alexi Grom, Dana Kahle, Sofia Torreggiani, Alexander G Aue, Jacob Mitchell, Adriana A De Jesus, Grant S Schulert, Raphaela Goldbach-Mansky

Paediatrics Publications

No abstract provided.

Transient Hyponatremia Of Prematurity Caused By Mild Bartter Syndrome Type Ii: A Case Report., Subhrata Verma, Rahul Chanchlani, Victoria Mok Siu, Guido Filler

Paediatrics Publications

BACKGROUND: Bartter syndrome subtypes are a group of rare renal tubular diseases characterized by impaired salt reabsorption in the tubule, specifically the thick ascending limb of Henle's loop. Clinically, they are characterized by the association of hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II. Bartter syndrome type II is caused by mutations in the renal outer medullary potassium channel (ROMK) gene (KCNJ1), can present in the newborn period and typically requires lifelong therapy.

CASE PRESENTATION: We describe a case of a prematurely born female infant presenting with …

Effects Of A Postnatal Atrx Conditional Knockout In Neurons On Autism-Like Behaviours In Male And Female Mice., Nicole Martin-Kenny, Nathalie G Bérubé

Paediatrics Publications

BACKGROUND: Alpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in excitatory neurons of the forebrain and performed a battery of behavioural assays that assess autistic-like behaviours.

METHODS: Male and female mice with a postnatal conditional ablation of ATRX were generated using the Cre/lox system under the …

Growth Hormone Deficiency In Megalencephaly-Capillary Malformation Syndrome: An Association With Activating Mutations In Pik3ca, Shanlee Davis, Meredith A Ware, Jordan Zeiger, Matthew A Deardorff, Katheryn Grand, Adda Grimberg, Stephanie Hsu, Megan Kelsey, Shideh Majidi, Revi P Matthew, Melanie Napier, Natalie Nokoff, Chitra Prasad, Andrew C Riggs, Margaret L Mckinnon, Ghayda Mirzaa

Paediatrics Publications

Megalencephaly-capillary malformation syndrome (MCAP) is a brain overgrowth disorder characterized by cortical malformations (specifically polymicrogyria), vascular anomalies, and segmental overgrowth secondary to somatic activating mutations in the PI3K-AKT-MTOR pathway (PIK3CA). Cases of growth failure and hypoglycemia have been reported in patients with MCAP, raising the suspicion for unappreciated growth hormone (GH) deficiency. Here we report an observational multicenter study of children with MCAP and GH deficiency. Eleven participants were confirmed to have GH deficiency, all with very low or undetectable circulating concentrations of insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Seven underwent GH stimulation testing and all had …

A Primer On A Comprehensive Genetic Approach To Vascular Anomalies, A. J. Borst, T. A. Nakano, F. Blei, D. M. Adams, J. Duis

Journal Articles

No abstract provided.

Precision Medicine In Pediatric Cancer: Current Applications And Future Prospects., Atif Ahmed, Divya S. Vundamati, Midhat S. Farooqi, Erin M. Guest

Manuscripts, Articles, Book Chapters and Other Papers

Precision oncologic medicine is an emerging approach for cancer treatment that has recently taken giant steps in solid clinical practice. Recent advances in molecular diagnostics that can analyze the individual tumor's variability in genes have provided greater understanding and additional strategies to treat cancers. Although tumors can be tested by several molecular methods, the use of next-generation sequencing (NGS) has greatly facilitated our understanding of pediatric cancer and identified additional therapeutic opportunities. Pediatric tumors have a different genetic make-up, with a fewer number of actionable targets than adult tumors. Nevertheless, precision oncology in the pediatric population has greatly improved the …

Bafopathies' Dna Methylation Epi-Signatures Demonstrate Diagnostic Utility And Functional Continuum Of Coffin-Siris And Nicolaides-Baraitser Syndromes., Erfan Aref-Eshghi, Eric G Bend, Rebecca L Hood, Laila C Schenkel, Deanna Alexis Carere, Rana Chakrabarti, Sandesh C S Nagamani, Sau Wai Cheung, Philippe M Campeau, Chitra Prasad, Victoria Mok Siu, Lauren Brady, Mark A Tarnopolsky, David J Callen, A Micheil Innes, Susan M White, Wendy S Meschino, Andrew Y Shuen, Guillaume Paré, Dennis E Bulman, Peter J Ainsworth, Hanxin Lin, David I Rodenhiser, Raoul C Hennekam, Kym M Boycott, Charles E Schwartz, Bekim Sadikovic

Paediatrics Publications

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across …

App21 Transgenic Rats Develop Age-Dependent Cognitive Impairment And Microglia Accumulation Within White Matter Tracts., Nina Weishaupt, Qingfan Liu, Sheojung Shin, Ramandeep Singh, Yuksel Agca, Cansu Agca, Vladimir Hachinski, Shawn Narain Whitehead

Paediatrics Publications

Background

Most of the animal models commonly used for preclinical research into Alzheimer's disease (AD) largely fail to address the pathophysiology, including the impact of known risk factors, of the widely diagnosed sporadic form of the disease. Here, we use a transgenic rat (APP21) that does not develop AD-like pathology spontaneously with age, but does develop pathology following vascular stress. To further the potential of this novel rat model as a much-needed pre-clinical animal model of sporadic AD, we characterize APP21 transgenic rats behaviorally and histologically up to 19 months of age.

Methods

The open field test was used as …

Peripheral Blood Epi-Signature Of Claes-Jensen Syndrome Enables Sensitive And Specific Identification Of Patients And Healthy Carriers With Pathogenic Mutations In Kdm5c, Laila C Schenkel, Erfan Aref-Eshghi, Cindy Skinner, Peter Ainsworth, Hanxin Lin, Guillaume Paré, David I Rodenhiser, Charles Schwartz, Bekim Sadikovic

Paediatrics Publications

Background

Claes-Jensen syndrome is an X-linked inherited intellectual disability caused by mutations in the

Results

Genome-wide DNA methylation analysis of 7 male patients affected with Claes-Jensen syndrome and 56 age- and sex-matched controls identified a specific DNA methylation defect (epi-signature) in the peripheral blood of these patients, including 1769 individual CpGs and 9 genomic regions. Six healthy female carriers showed less pronounced but distinctive changes in the same regions enabling their differentiation from both patients and controls. Highly specific computational model using the most significant methylation changes demonstrated 100% accuracy in differentiating patients, carriers, and controls in the training cohort, …

Fasoracetam In Adolescents With Adhd And Glutamatergic Gene Network Variants Disrupting Mglur Neurotransmitter Signaling., Josephine Elia, Grace Ungal, Charlly Kao, Alexander Ambrosini, Nilsa De Jesus-Rosario, Lene Larsen, Rosetta Chiavacci, Tiancheng Wang, Christine Kurian, Kanani Titchen, Brian Sykes, Sharon Hwang, Bhumi Kumar, Jacqueline Potts, Joshua Davis, Jeffrey Malatack, Emma Slattery, Ganesh Moorthy, Athena Zuppa, Andrew Weller, Enda Byrne, Yun R. Li, Walter K. Kraft, Hakon Hakonarson

Department of Pediatrics Faculty Papers

The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12-17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50-800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks. NFC-1 treatment resulted in significant improvement. Mean Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores were, respectively, 3.79 …

Mutations In Keops-Complex Genes Cause Nephrotic Syndrome With Primary Microcephaly, Daniela A Braun, Jia Rao, Geraldine Mollet, David Schapiro, Marie-Claire Daugeron, Weizhen Tan, Olivier Gribouval, Olivia Boyer, Patrick Revy, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Jennifer A Lawson, Denny Schanze, Shazia Ashraf, Jeremy F P Ullmann, Charlotte A Hoogstraten, Nathalie Boddaert, Bruno Collinet, Gaëlle Martin, Dominique Liger, Svjetlana Lovric, Monica Furlano, I Chiara Guerrera, Oraly Sanchez-Ferras, Jennifer F Hu, Anne-Claire Boschat, Sylvia Sanquer, Björn Menten, Sarah Vergult, Nina De Rocker, Merlin Airik, Tobias Hermle, Shirlee Shril, Eugen Widmeier, Heon Yung Gee, Won-Il Choi, Carolin E Sadowski, Werner L Pabst, Jillian K Warejko, Ankana Daga, Tamara Basta, Verena Matejas, Karin Scharmann, Sandra D Kienast, Babak Behnam, Brendan Beeson, Amber Begtrup, Malcolm Bruce, Gaik-Siew Ch'ng, Shuan-Pei Lin, Jui-Hsing Chang, Chao-Huei Chen, Megan T Cho, Patrick M Gaffney, Patrick E Gipson, Chyong-Hsin Hsu, Jameela A Kari, Yu-Yuan Ke, Cathy Kiraly-Borri, Wai-Ming Lai, Emmanuelle Lemyre, Rebecca Okashah Littlejohn, Amira Masri, Mastaneh Moghtaderi, Kazuyuki Nakamura, Fatih Ozaltin, Marleen Praet, Chitra Prasad, Agnieszka Prytula, Elizabeth R Roeder, Patrick Rump, Rhonda E Schnur, Takashi Shiihara, Manish D Sinha, Neveen A Soliman, Kenza Soulami, David A Sweetser, Wen-Hui Tsai, Jeng-Daw Tsai, Rezan Topaloglu, Udo Vester, David H Viskochil, Nithiwat Vatanavicharn, Jessica L Waxler, Klaas J Wierenga, Matthias T F Wolf, Sik-Nin Wong, Sebastian A Leidel, Gessica Truglio, Peter C Dedon, Annapurna Poduri, Shrikant Mane, Richard P Lifton, Maxime Bouchard, Peter Kannu, David Chitayat, Daniella Magen, Bert Callewaert, Herman Van Tilbeurgh, Martin Zenker, Corinne Antignac, Friedhelm Hildebrandt

Paediatrics Publications

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced …

Therapeutic And Prognostic Implications Of Braf V600e In Pediatric Low-Grade Gliomas., Alvaro Lassaletta, Michal Zapotocky, Matthew Mistry, Vijay Ramaswamy, Marion Honnorat, Rahul Krishnatry, Ana Guerreiro Stucklin, Nataliya Zhukova, Anthony Arnoldo, Scott Ryall, Catriona Ling, Tara Mckeown, Jim Loukides, Ofelia Cruz, Carmen De Torres, Cheng-Ying Ho, Roger J Packer, Ruth Tatevossian, Ibrahim Qaddoumi, Julie H Harreld, James D Dalton, Jean Mulcahy-Levy, Nicholas Foreman, Matthias A Karajannis, Shiyang Wang, Matija Snuderl, Amulya Nageswara Rao, Caterina Giannini, Mark Kieran, Keith L Ligon, Maria Luisa Garre, Paolo Nozza, Samantha Mascelli, Alessandro Raso, Sabine Mueller, Theodore Nicolaides, Karen Silva, Romain Perbet, Alexandre Vasiljevic, Cécile Faure Conter, Didier Frappaz, Sarah Leary, Courtney Crane, Aden Chan, Ho-Keung Ng, Zhi-Feng Shi, Ying Mao, Elizabeth Finch, David Eisenstat, Bev Wilson, Anne Sophie Carret, Peter Hauser, David Sumerauer, Lenka Krskova, Valerie Larouche, Adam Fleming, Shayna Zelcer, Nada Jabado, James T Rutka, Peter Dirks, Michael D Taylor, Shiyi Chen, Ute Bartels, Annie Huang, David W Ellison, Eric Bouffet, Cynthia Hawkins, Uri Tabori

Paediatrics Publications

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown.

Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180).

Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a …

Exome Analysis Of Rare And Common Variants Within The Nod Signaling Pathway., Gaia Andreoletti, Valentina Shakhnovich, Kathy Christenson, Tracy Coelho, Rachel Haggarty, Nadeem A. Afzal, Akshay Batra, Britt-Sabina Petersen, Matthew Mort, R Mark Beattie, Sarah Ennis

Manuscripts, Articles, Book Chapters and Other Papers

Pediatric inflammatory bowel disease (pIBD) is a chronic heterogeneous disorder. This study looks at the burden of common and rare coding mutations within 41 genes comprising the NOD signaling pathway in pIBD patients. 136 pIBD and 106 control samples underwent whole-exome sequencing. We compared the burden of common, rare and private mutation between these two groups using the SKAT-O test. An independent replication cohort of 33 cases and 111 controls was used to validate significant findings. We observed variation in 40 of 41 genes comprising the NOD signaling pathway. Four genes were significantly associated with disease in the discovery cohort …

A Novel Compound-Heterozygous Epithelial Cell Adhesion Molecule Mutation In Tufting Enteropathy., Valentina Shakhnovich, Darrell Dinwiddie, Amber Hildreth, Thomas M. Attard, Stephen Kingsmore

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Biallelic Mutations In Tbcd, Encoding The Tubulin Folding Cofactor D, Perturb Microtubule Dynamics And Cause Early-Onset Encephalopathy., Elisabetta Flex, Marcello Niceta, Serena Cecchetti, Isabelle Thiffault, Margaret G. Au, Alessandro Capuano, Emanuela Piermarini, Anna A. Ivanova, Joshua W. Francis, Giovanni Chillemi, Balasubramanian Chandramouli, Giovanna Carpentieri, Charlotte A. Haaxma, Andrea Ciolfi, Simone Pizzi, Ganka V. Douglas, Kara Levine, Antonella Sferra, Maria Lisa Dentici, Rolph R. Pfundt, Jean-Baptist Lepichon, Emily G. Farrow, Frank Baas, Fiorella Piemonte, Bruno Dallapiccola, John M. Graham, Carol J. Saunders, Enrico Bertini, Richard A. Kahn, David A. Koolen, Marco Tartaglia

Manuscripts, Articles, Book Chapters and Other Papers

Microtubules are dynamic cytoskeletal elements coordinating and supporting a variety of neuronal processes, including cell division, migration, polarity, intracellular trafficking, and signal transduction. Mutations in genes encoding tubulins and microtubule-associated proteins are known to cause neurodevelopmental and neurodegenerative disorders. Growing evidence suggests that altered microtubule dynamics may also underlie or contribute to neurodevelopmental disorders and neurodegeneration. We report that biallelic mutations in TBCD, encoding one of the five co-chaperones required for assembly and disassembly of the αβ-tubulin heterodimer, the structural unit of microtubules, cause a disease with neurodevelopmental and neurodegenerative features characterized by early-onset cortical atrophy, secondary hypomyelination, microcephaly, thin …

Pik3ca-Associated Developmental Disorders Exhibit Distinct Classes Of Mutations With Variable Expression And Tissue Distribution, Ghayda Mirzaa, Andrew E Timms, Valerio Conti, Evan August Boyle, Katta M Girisha, Beth Martin, Martin Kircher, Carissa Olds, Jane Juusola, Sarah Collins, Kaylee Park, Melissa Carter, Ian Glass, Inge Krägeloh-Mann, David Chitayat, Aditi Shah Parikh, Rachael Bradshaw, Erin Torti, Stephen Braddock, Leah Burke, Sondhya Ghedia, Mark Stephan, Fiona Stewart, Chitra Prasad, Melanie Napier, Sulagna Saitta, Rachel Straussberg, Michael Gabbett, Bridget C O'Connor, Catherine E Keegan, Lim Jiin Yin, Angeline Hwei Meeng Lai, Nicole Martin, Margaret Mckinnon, Marie-Claude Addor, Luigi Boccuto, Charles E Schwartz, Agustina Lanoel, Robert L Conway, Koenraad Devriendt, Katrina Tatton-Brown, Mary Ella Pierpont, Michael Painter, Lisa Worgan, James Reggin, Raoul Hennekam, Karen Tsuchiya, Colin C Pritchard, Mariana Aracena, Karen W Gripp, Maria Cordisco, Hilde Van Esch, Livia Garavelli, Cynthia Curry, Anne Goriely, Hulya Kayserilli, Jay Shendure, John Graham, Renzo Guerrini, William B Dobyns

Articles, Abstracts, and Reports

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing ( …

Intracellular Cd24 Disrupts The Arf-Npm Interaction And Enables Mutational And Viral Oncogene-Mediated P53 Inactivation., Lizhong Wang, Runhua Liu, Peiying Ye, Chunshu Wong, Guo-Yun Chen, Penghui Zhou, +11 Additional Authors

Pediatrics Faculty Publications

CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the …

Mllt1 Yeats Domain Mutations In Clinically Distinctive Favourable Histology Wilms Tumours., Elizabeth J Perlman, Samantha Gadd, Stefan T Arold, Anand Radhakrishnan, Daniela S Gerhard, Jeffrey S. Dome, +19 Additional Authors

Pediatrics Faculty Publications

Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar …

Novel Napi-Iic Mutations Causing Hhrh And Idiopathic Hypercalciuria In Several Unrelated Families: Long-Term Follow-Up In One Kindred., Y Yu, S R. Sanderson, M Reyes, A Sharma, N Dunbar, Tarak Srivastava, H Jüppner, C Bergwitz

Manuscripts, Articles, Book Chapters and Other Papers

Homozygous and compound heterozygous mutations in SLC34A3, the gene encoding the sodium-dependent co-transporter NaPi-IIc, cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate-wasting resulting in hypophosphatemia, elevated 1,25(OH)(2) vitamin D levels, hypercalciuria, rickets/osteomalacia, and frequently kidney stones or nephrocalcinosis. Similar albeit less severe biochemical changes are also observed in heterozygous carriers, which are furthermore indistinguishable from those encountered in idiopathic hypercalciuria (IH). We now searched for SLC34A3 mutations (exons and introns) in two previously not reported HHRH kindreds, which resulted in the identification of three novel mutations. The affected members of kindred A were compound heterozygous …