Medical Genetics Commons^™

Pediatric Normal Tissue Effects In The Clinic (Pentec): An International Collaboration To Assess Normal Tissue Radiation Dose-Volume-Response Relationships For Children With Cancer, Louis S Constine, Arthur J Olch, Andrew Jackson, Chia-Ho Hua, Cecile M Ronckers, Michael T Milano, Karen J Marcus, Ellen Yorke, David C Hodgson, Rebecca M Howell, Melissa M Hudson, Jacqueline P Williams, Brian Marples, Leontien C M Kremer, Lawrence B Marks, Søren M Bentzen

Faculty, Staff and Student Publications

No abstract provided.

Cardiovascular Disease In Childhood, Adolescent, And Young Adult Cancer Survivors: The Impact Of Family History Of Premature Heart Disease, Amy M Berkman, Clark R Andersen, Andrew P Landstrom, Michelle A T Hildebrandt, Susan C Gilchrist, Michael E Roth

Faculty, Staff and Student Publications

No abstract provided.

A Phase 1/2 Study Of Pepinemab In Children, Adolescents, Or Young Adults With Recurrent Or Refractory Solid Tumors: A Children’S Oncology Group Consortium Report (Advl1614), Emily Greengard, Robin Williams, Branden Moriarity, Xiaowei Liu, Charles G Minard, Joel M Reid, Terrence Fisher, Elizabeth Evans, Desa Rae Pastore, Maurice Zauderer, Stephan Voss, Elizabeth Fox, Brenda J Weigel

Faculty, Staff and Students Publications

PURPOSE: Pepinemab, a humanized IgG4 monoclonal antibody, targets the SEMA4D (CD100) antigen to inhibit binding to its high-affinity receptors (plexin B1/PLXNB1, plexin B2/PLXNB2) and low-affinity receptor (CD72). SEMA4D blockade leads to increased cytotoxic T-cell infiltration, delayed tumor growth, and durable tumor rejection in murine tumor models. Pepinemab was well tolerated and improved T cell infiltration in clinical studies in adults with refractory tumors. SEMA4D was identified as a strong candidate proto-oncogene in a model of osteosarcoma. Based on these preclinical and clinical data, we conducted a phase 1/2 study to determine the recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and …

Hyperkinetic Movement Disorder Caused By The Recurrent C892c>T Nacc1 Variant, Jonna Komulainen-Ebrahim, Salla M Kangas, Estrella López-Martín, Timothy Feyma, Fernando Scaglia, Beatriz Martínez-Delgado, Outi Kuismin, Maria Suo-Palosaari, Lucinda Carr, Reetta Hinttala, Manju A Kurian, Johanna Uusimaa

Faculty, Staff and Students Publications

BACKGROUND: Genetic syndromes of hyperkinetic movement disorders associated with epileptic encephalopathy and intellectual disability are becoming increasingly recognized. Recently, a de novo heterozygous NACC1 (nucleus accumbens-associated 1) missense variant was described in a patient cohort including one patient with a combined mitochondrial oxidative phosphorylation (OXPHOS) deficiency.

OBJECTIVES: The objective is to characterize the movement disorder in affected patients with the recurrent c.892C>T NACC1 variant and study the NACC1 protein and mitochondrial function at the cellular level.

METHODS: The movement disorder was analyzed on four patients with the NACC1 c.892C>T (p.Arg298Trp) variant. Studies on NACC1 protein and mitochondrial function …

Expanding The Phenotype Of Ppp1r21-Related Neurodevelopmental Disorder, Mohammed Almannai, Dana Marafi, Maha S Zaki, Reza Maroofian, Stephanie Efthymiou, Nebal Waill Saadi, Bilal Filimban, Hormos Salimi Dafsari, Fatima Rahman, Shazia Maqbool, Eissa Faqeih, Fuad Al Mutairi, Hind Alsharhan, Omar Abdelaty, Saadoun Bin-Hasan, Ruizhi Duan, Mahmoud M Noureldeen, Alaa Alqattan, Henry Houlden, Jill V Hunter, Jennifer E Posey, James R Lupski, Ayman W El-Hattab

Faculty, Staff and Students Publications

PPP1R21 encodes for a conserved protein that is involved in endosomal maturation. Biallelic pathogenic variants in PPP1R21 have been associated with a syndromic neurodevelopmental disorder from studying 13 affected individuals. In this report, we present 11 additional individuals from nine unrelated families and their clinical, radiological, and molecular findings. We identified eight different variants in PPP1R21, of which six were novel variants. Global developmental delay and hypotonia are neurological features that were observed in all individuals. There is also a similar pattern of dysmorphic features with coarse faces as a gestalt observed in several individuals. Common findings in 75% of …

Lacl3-Based Sodium Halide Solid Electrolytes With High Ionic Conductivity For All-Solid-State Batteries, Chengyu Fu, Yifan Li, Wenjie Xu, Xuyong Feng, Weijian Gu, Jue Liu, Wenwen Deng, Wei Wang, A M Milinda Abeykoon, Laisuo Su, Lingyun Zhu, Xiaojun Wu, Hongfa Xiang

Faculty, Staff and Student Publications

To enable high performance of all solid-state batteries, a catholyte should demonstrate high ionic conductivity, good compressibility and oxidative stability. Here, a LaCl3-based Na+ superionic conductor (Na1−xZrxLa1−xCl4) with high ionic conductivity of 2.9 × 10−4 S cm−1 (30 °C), good compressibility and high oxidative potential (3.80 V vs. Na2Sn) is prepared via solid state reaction combining mechanochemical method. X-ray diffraction reveals a hexagonal structure (P63/m) of Na1−xZrxLa1−xCl4, with Na+ ions forming a one-dimensional diffusion channel along the c-axis. First-principle calculations combining with …

Clinical, Genetic, And Cognitive Correlates Of Seizure Occurrences In Phelan-Mcdermid Syndrome, Tess Levy, Jacob Gluckman, Paige M Siper, Danielle Halpern, Jessica Zweifach, Rajna Filip-Dhima, J Lloyd Holder, M Pilar Trelles, Kristina Johnson, Jonathan A Bernstein, Elizabeth Berry-Kravis, Craig M Powell, Latha Valluripalli Soorya, Audrey Thurm, Joseph D Buxbaum, Mustafa Sahin, Alexander Kolevzon, Siddharth Srivastava

Duncan NRI Faculty and Staff Publications

Background: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome.

Methods: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, …

Imaging Features Of Primary Intracranial Sarcoma With Dicer1 Mutation: A Multicenter Case Series, Rami W Eldaya, Richard J Fagan, Samir A Dagher, Angshumoy Roy, Sonika Dahyia, Gregory N Fuller, Max Wintermark, Matthew S Parsons, Thierry A G M Huisman

Faculty, Staff and Student Publications

Primary intracranial sarcoma, DICER1-mutant, is a rare, recently described entity in the fifth edition of the WHO Classification of CNS Tumors. Given the entity's rarity and recent description, imaging data on primary intracranial sarcoma, DICER1-mutant, remains scarce. In this multicenter case series, we present detailed multimodality imaging features of primary intracranial sarcoma, DICER1-mutant, with emphasis on the appearance of the entity on MR imaging. In total, 8 patients were included. In all 8 patients, the lesion demonstrated blood products on T1WI. In 7 patients, susceptibility-weighted imaging was obtained and demonstrated blood products. Primary intracranial sarcoma, DICER1-mutant, …

Exome Sequencing Implicates Ancestry-Related Mendelian Variation At Syne1 In Childhood-Onset Essential Hypertension, Ian Copeland, Edmond Wonkam-Tingang, Monesha Gupta-Malhotra, S Shahrukh Hashmi, Yixing Han, Aarti Jajoo, Nancy J Hall, Paula P Hernandez, Natasha Lie, Dan Liu, Jun Xu, Jill Rosenfeld, Aparna Haldipur, Zelene Desire, Zeynep H Coban-Akdemir, Daryl A Scott, Qing Li, Hsiao-Tuan Chao, Ana M Zaske, James R Lupski, Dianna M Milewicz, Sanjay Shete, Jennifer E Posey, Neil A Hanchard

Faculty, Staff and Student Publications

Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope …

Gain-Of-Function And Loss-Of-Function Variants In Gria3 Lead To Distinct Neurodevelopmental Phenotypes, Berardo Rinaldi, Allan Bayat, Linda G Zachariassen, Jia-Hui Sun, Yu-Han Ge, Dan Zhao, Kristine Bonde, Laura H Madsen, Ilham Abdimunim Ali Awad, Duygu Bagiran, Amal Sbeih, Syeda Maidah Shah, Shaymaa El-Sayed, Signe M Lyngby, Miriam G Pedersen, Charlotte Stenum-Berg, Louise Claudia Walker, Ilona Krey, Andrée Delahaye-Duriez, Lisa T Emrick, Krystal Sully, Chaya N Murali, Lindsay C Burrage, Julie Ana Plaud Gonzalez, Mered Parnes, Jennifer Friedman, Bertrand Isidor, Jérémie Lefranc, Sylvia Redon, Delphine Heron, Cyril Mignot, Boris Keren, Mélanie Fradin, Christele Dubourg, Sandra Mercier, Thomas Besnard, Benjamin Cogne, Wallid Deb, Clotilde Rivier, Donatella Milani, Maria Francesca Bedeschi, Claudia Di Napoli, Federico Grilli, Paola Marchisio, Suzanna Koudijs, Danielle Veenma, Emanuela Argilli, Sally Ann Lynch, Ping Yee Billie Au, Fernando Eduardo Ayala Valenzuela, Carolyn Brown, Diane Masser-Frye, Marilyn Jones, Leslie Patron Romero, Wenhui Laura Li, Erin Thorpe, Laura Hecher, Jessika Johannsen, Jonas Denecke, Vanda Mcniven, Anna Szuto, Emma Wakeling, Vincent Cruz, Valerie Sency, Heng Wang, Juliette Piard, Fanny Kortüm, Theresia Herget, Tatjana Bierhals, Angelo Condell, Bruria Ben-Zeev, Simranpreet Kaur, John Christodoulou, Amelie Piton, Christiane Zweier, Cornelia Kraus, Alessia Micalizzi, Marina Trivisano, Nicola Specchio, Gaetan Lesca, Rikke S Møller, Zeynep Tümer, Maria Musgaard, Benedicte Gerard, Johannes R Lemke, Yun Stone Shi, Anders S Kristensen

Faculty, Staff and Students Publications

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1–GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally.

Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function or gain-of-function properties, whereas 13 appeared neutral.

We collected detailed …

Development Of A Weight-Band Dosing Approach For Vosoritide In Children With Achondroplasia Using A Population Pharmacokinetic Model, Yulan Qi, Ming Liang Chan, Diane R Mould, Kevin Larimore, Elena Fisheleva, Anu Cherukuri, Jonathan Day, Ravi Savarirayan, Melita Irving, Carlos A Bacino, Julie Hoover-Fong, Keiichi Ozono, Klaus Mohnike, William R Wilcox, Michael B Bober, Joshua Henshaw

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.

METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was …

Genome-Wide Association Analyses Identify 95 Risk Loci And Provide Insights Into The Neurobiology Of Post-Traumatic Stress Disorder, Caroline M Nievergelt, Adam X Maihofer, Elizabeth G Atkinson, Chia-Yen Chen, Karmel W Choi, Jonathan R I Coleman, Nikolaos P Daskalakis, Laramie E Duncan, Renato Polimanti, Cindy Aaronson, Ananda B Amstadter, Soren B Andersen, Ole A Andreassen, Paul A Arbisi, Allison E Ashley-Koch, S Bryn Austin, Esmina Avdibegoviç, Dragan Babić, Silviu-Alin Bacanu, Dewleen G Baker, Anthony Batzler, Jean C Beckham, Sintia Belangero, Corina Benjet, Carisa Bergner, Linda M Bierer, Joanna M Biernacka, Laura J Bierut, Jonathan I Bisson, Marco P Boks, Elizabeth A Bolger, Amber Brandolino, Gerome Breen, Rodrigo Affonseca Bressan, Richard A Bryant, Angela C Bustamante, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Anders D Børglum, Sigrid Børte, Leah Cahn, Joseph R Calabrese, Jose Miguel Caldas-De-Almeida, Chris Chatzinakos, Sheraz Cheema, Sean A P Clouston, Lucía Colodro-Conde, Brandon J Coombes, Carlos S Cruz-Fuentes, Anders M Dale, Shareefa Dalvie, Lea K Davis, Jürgen Deckert, Douglas L Delahanty, Michelle F Dennis, Frank Desarnaud, Christopher P Dipietro, Seth G Disner, Anna R Docherty, Katharina Domschke, Grete Dyb, Alma Džubur Kulenović, Howard J Edenberg, Alexandra Evans, Chiara Fabbri, Negar Fani, Lindsay A Farrer, Adriana Feder, Norah C Feeny, Janine D Flory, David Forbes, Carol E Franz, Sandro Galea, Melanie E Garrett, Bizu Gelaye, Joel Gelernter, Elbert Geuze, Charles F Gillespie, Slavina B Goleva, Scott D Gordon, Aferdita Goçi, Lana Ruvolo Grasser, Camila Guindalini, Magali Haas, Saskia Hagenaars, Michael A Hauser, Andrew C Heath, Sian M J Hemmings, Victor Hesselbrock, Ian B Hickie, Kelleigh Hogan, David Michael Hougaard, Hailiang Huang, Laura M Huckins, Kristian Hveem, Miro Jakovljević, Arash Javanbakht, Gregory D Jenkins, Jessica Johnson, Ian Jones, Tanja Jovanovic, Karen-Inge Karstoft, Milissa L Kaufman, James L Kennedy, Ronald C Kessler, Alaptagin Khan, Nathan A Kimbrel, Anthony P King, Nastassja Koen, Roman Kotov, Henry R Kranzler, Kristi Krebs, William S Kremen, Pei-Fen Kuan, Bruce R Lawford, Lauren A M Lebois, Kelli Lehto, Daniel F Levey, Catrin Lewis, Israel Liberzon, Sarah D Linnstaedt, Mark W Logue, Adriana Lori, Yi Lu, Benjamin J Luft, Michelle K Lupton, Jurjen J Luykx, Iouri Makotkine, Jessica L Maples-Keller, Shelby Marchese, Charles Marmar, Nicholas G Martin, Gabriela A Martínez-Levy, Kerrie Mcaloney, Alexander Mcfarlane, Katie A Mclaughlin, Samuel A Mclean, Sarah E Medland, Divya Mehta, Jacquelyn Meyers, Vasiliki Michopoulos, Elizabeth A Mikita, Lili Milani, William Milberg, Mark W Miller, Rajendra A Morey, Charles Phillip Morris, Ole Mors, Preben Bo Mortensen, Mary S Mufford, Elliot C Nelson, Merete Nordentoft, Sonya B Norman, Nicole R Nugent, Meaghan O'Donnell, Holly K Orcutt, Pedro M Pan, Matthew S Panizzon, Gita A Pathak, Edward S Peters, Alan L Peterson, Matthew Peverill, Robert H Pietrzak, Melissa A Polusny, Bernice Porjesz, Abigail Powers, Xue-Jun Qin, Andrew Ratanatharathorn, Victoria B Risbrough, Andrea L Roberts, Alex O Rothbaum, Barbara O Rothbaum, Peter Roy-Byrne, Kenneth J Ruggiero, Ariane Rung, Heiko Runz, Bart P F Rutten, Stacey Saenz De Viteri, Giovanni Abrahão Salum, Laura Sampson, Sixto E Sanchez, Marcos Santoro, Carina Seah, Soraya Seedat, Julia S Seng, Andrey Shabalin, Christina M Sheerin, Derrick Silove, Alicia K Smith, Jordan W Smoller, Scott R Sponheim, Dan J Stein, Synne Stensland, Jennifer S Stevens, Jennifer A Sumner, Martin H Teicher, Wesley K Thompson, Arun K Tiwari, Edward Trapido, Monica Uddin, Robert J Ursano, Unnur Valdimarsdóttir, Miranda Van Hooff, Eric Vermetten, Christiaan H Vinkers, Joanne Voisey, Yunpeng Wang, Zhewu Wang, Monika Waszczuk, Heike Weber, Frank R Wendt, Thomas Werge, Michelle A Williams, Douglas E Williamson, Bendik S Winsvold, Sherry Winternitz, Christiane Wolf, Erika J Wolf, Yan Xia, Ying Xiong, Rachel Yehuda, Keith A Young, Ross Mcd Young, Clement C Zai, Gwyneth C Zai, Mark Zervas, Hongyu Zhao, Lori A Zoellner, John-Anker Zwart, Terri Deroon-Cassini, Sanne J H Van Rooij, Leigh L Van Den Heuvel, Murray B Stein, Kerry J Ressler, Karestan C Koenen

Faculty, Staff and Students Publications

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), …

Proton Therapy Mediates Dose Reductions To Brain Structures Associated With Cognition In Children With Medulloblastoma, Julianna Sienna, Lisa S Kahalley, Donald Mabbott, David Grosshans, Anna Theresa Santiago, Arnold Dela Cruz Paulino, Thomas E Merchant, Gohar S Manzar, Hitesh Dama, David C Hodgson, Murali Chintagumpala, Mehmet Fatih Okcu, William E Whitehead, Normand Laperriere, Vijay Ramaswamy, Ute Bartels, Uri Tabori, Julie M Bennett, Anirban Das, Tim Craig, Derek S Tsang

Faculty, Staff and Student Publications

Purpose: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy.

Methods and materials: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores.

Results: The mean dose and dose to …

Financial Hardship And Neighborhood Socioeconomic Disadvantage In Long-Term Childhood Cancer Survivors, Alex J Fauer, Weiyu Qiu, I-Chan Huang, Patricia A Ganz, Jacqueline N Casillas, K Robin Yabroff, Gregory T Armstrong, Wendy Leisenring, Rebecca Howell, Carrie R Howell, Anne C Kirchhoff, Yutaka Yasui, Paul C Nathan

Faculty, Staff and Student Publications

Background: Long-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships.

Methods: We performed a cross-sectional analysis of data from the Childhood Cancer Survivor Study between 1970 and 1999 and self-reported financial information from 2017 to 2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material and financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear …

Bi-Allelic Acbd6 Variants Lead To A Neurodevelopmental Syndrome With Progressive And Complex Movement Disorders, Rauan Kaiyrzhanov, Aboulfazl Rad, Sheng-Jia Lin, Aida Bertoli-Avella, Wouter W Kallemeijn, Annie Godwin, Maha S Zaki, Kevin Huang, Tracy Lau, Cassidy Petree, Stephanie Efthymiou, Ehsan Ghayoor Karimiani, Maja Hempel, Elizabeth A Normand, Sabine Rudnik-Schöneborn, Ulrich A Schatz, Marc P Baggelaar, Muhammad Ilyas, Tipu Sultan, Javeria Raza Alvi, Manizha Ganieva, Ben Fowler, Ruxandra Aanicai, Gulsen Akay Tayfun, Abdulaziz Al Saman, Abdulrahman Alswaid, Nafise Amiri, Nilufar Asilova, Vorasuk Shotelersuk, Patra Yeetong, Matloob Azam, Meisam Babaei, Gholamreza Bahrami Monajemi, Pouria Mohammadi, Saeed Samie, Selina Husna Banu, Jorge Pinto Basto, Fanny Kortüm, Mislen Bauer, Peter Bauer, Christian Beetz, Masoud Garshasbi, Awatif Hameed Issa, Wafaa Eyaid, Hind Ahmed, Narges Hashemi, Kazem Hassanpour, Isabella Herman, Sherozjon Ibrohimov, Ban A Abdul-Majeed, Maria Imdad, Maksudjon Isrofilov, Qassem Kaiyal, Suliman Khan, Brian Kirmse, Janet Koster, Charles Marques Lourenço, Tadahiro Mitani, Oana Moldovan, David Murphy, Maryam Najafi, Davut Pehlivan, Maria Eugenia Rocha, Vincenzo Salpietro, Miriam Schmidts, Adel Shalata, Mohammad Mahroum, Jawabreh Kassem Talbeya, Robert W Taylor, Dayana Vazquez, Annalisa Vetro, Hans R Waterham, Mashaya Zaman, Tina A Schrader, Wendy K Chung, Renzo Guerrini, James R Lupski, Joseph Gleeson, Mohnish Suri, Yalda Jamshidi, Kailash P Bhatia, Barbara Vona, Michael Schrader, Mariasavina Severino, Matthew Guille, Edward W Tate, Gaurav K Varshney, Henry Houlden, Reza Maroofian

Faculty, Staff and Students Publications

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne …

De Novo Variants In Fryl Are Associated With Developmental Delay, Intellectual Disability, And Dysmorphic Features, Xueyang Pan, Alice M Tao, Shenzhao Lu, Mengqi Ma, Shabab B Hannan, Rachel Slaugh, Sarah Drewes Williams, Lauren O'Grady, Oguz Kanca, Richard Person, Melissa T Carter, Konrad Platzer, Franziska Schnabel, Rami Abou Jamra, Amy E Roberts, Jane W Newburger, Anya Revah-Politi, Jorge L Granadillo, Alexander P A Stegmann, Margje Sinnema, Andrea Accogli, Vincenzo Salpietro, Valeria Capra, Lina Ghaloul-Gonzalez, Martina Brueckner, Marleen E H Simon, David A Sweetser, Kevin E Glinton, Susan E Kirk, Baylor College Of Medicine Center For Precision Medicine Models, Michael F Wangler, Shinya Yamamoto, Wendy K Chung, Hugo J Bellen

Faculty, Staff and Students Publications

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is …

Samhd1 Compound Heterozygous Rare Variants Associated With Moyamoya And Mitral Valve Disease In The Absence Of Other Features Of Aicardi-Goutières Syndrome, Aamuktha R Karla, Amélie Pinard, Maura L Boerio, Dimitri Hemelsoet, Simon J Tavernier, Michel De Pauw, Elke Vereecke, Stuart Fraser, Michael J Bamshad, Dongchuan Guo, Bert Callewaert, Dianna M Milewicz

Faculty, Staff and Student Publications

Aicardi-Goutières syndrome (AGS) is an autosomal recessive inflammatory syndrome that manifests as an early-onset encephalopathy with both neurologic and extraneurologic clinical findings. AGS has been associated with pathogenic variants in nine genes: TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR, IFIH1, LSM11, and RNU7-1. Diagnosis is established by clinical findings (encephalopathy and acquired microcephaly, intellectual and physical impairments, dystonia, hepatosplenomegaly, sterile pyrexia, and/or chilblains), characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes), or the identification of pathogenic/likely pathogenic variants in the known genes. One of the genes associated with AGS, SAMHD1, has also …

Temporal Changes In Treatment And Late Mortality And Morbidity In Adult Survivors Of Childhood Glioma: A Report From The Childhood Cancer Survivor Study, Peter M K De Blank, Katharine R Lange, Mengqi Xing, Sedigheh Mirzaei Salehabadi, Deokumar Srivastava, Tara M Brinkman, Kirsten K Ness, Kevin C Oeffinger, Joseph Neglia, Kevin R Krull, Paul C Nathan, Rebecca Howell, Lucie M Turcotte, Wendy Leisenring, Gregory T Armstrong, M Fatih Okcu, Daniel C Bowers

Faculty, Staff and Student Publications

Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970-1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), …

Alk-Positive Histiocytosis Of External Auditory Canal In A 3-Year-Old Boy, Shu-Hsien Wang, Hsuan-Ying Huang, L Jeffrey Medeiros, Kung-Chao Chang

Faculty, Staff and Student Publications

No abstract provided.

Cranio-Cervical Abnormalities In Moderate-To-Severe Osteogenesis Imperfecta – Genotypic And Phenotypic Determinants, Juliana Marulanda, Jean-Marc Retrouvey, Brendan Lee, V Reid Sutton, Frank Rauch, Michelle Briner

Faculty, Staff and Students Publications

INTRODUCTION: Cranio-cervical anomalies are significant complications of osteogenesis imperfecta (OI), a rare bone fragility disorder that is usually caused by mutations in collagen type I encoding genes.

OBJECTIVE: To assess cranio-cervical anomalies and associated clinical findings in patients with moderate-to-severe OI using 3D cone beam computed tomography (CBCT) scans.

METHODS: Cross-sectional analysis of CBCT scans in 52 individuals with OI (age 10-37 years; 32 females) and 40 healthy controls (age 10-32 years; 26 females). Individuals with a diagnosis of OI type III (severe, n = 11), type IV (moderate, n = 33) and non-collagen OI (n = 8) were recruited …

Identification Of An Early Survival Prognostic Gene Signature For Localized Osteosarcoma Patients, Tajhal D Patel, Sandra L Grimm, Rupa S Kanchi, Tanmay Gandhi, Amrit Koirala, Jason T Yustein, Cristian Coarfa

Faculty, Staff and Students Publications

Osteosarcoma is the most prevalent bone tumor in pediatric patients. Neoadjuvant chemotherapy has improved osteosarcoma patient survival, however the 5-year survival rate for localized osteosarcoma is 75% with a 30-50% recurrence rate. We, therefore, sought to identify a prognostic gene signature which could predict poor prognosis in localized osteosarcoma patients. Using the TARGET osteosarcoma transcriptomic dataset, we identified a 13-hub gene signature associated with overall survival and time to death of localized osteosarcoma patients, with the high-risk group showing a 22% and the low-risk group showing 100% overall survival. Furthermore, network analysis identified five modules of co-expressed genes that significantly …

Identifying Potential Dietary Treatments For Inherited Metabolic Disorders Using Drosophila Nutrigenomics, Felipe Martelli, Jiayi Lin, Sarah Mele, Wendy Imlach, Oguz Kanca, Christopher K Barlow, Jefferson Paril, Ralf B Schittenhelm, John Christodoulou, Hugo J Bellen, Matthew D W Piper, Travis K Johnson

Faculty, Staff and Students Publications

Inherited metabolic disorders are a group of genetic conditions that can cause severe neurological impairment and child mortality. Uniquely, these disorders respond to dietary treatment; however, this option remains largely unexplored because of low disorder prevalence and the lack of a suitable paradigm for testing diets. Here, we screened 35 Drosophila amino acid disorder models for disease-diet interactions and found 26 with diet-altered development and/or survival. Using a targeted multi-nutrient array, we examine the interaction in a model of isolated sulfite oxidase deficiency, an infant-lethal disorder. We show that dietary cysteine depletion normalizes their metabolic profile and rescues development, neurophysiology, …

Prediabetes And Associated Risk Of Cardiovascular Events And Chronic Kidney Disease Among Adult Survivors Of Childhood Cancer In The St Jude Lifetime Cohort, Stephanie B Dixon, Fang Wang, Lu Lu, Carmen L Wilson, Daniel M Green, Thomas E Merchant, Deo Kumar Srivastava, Angela Delaney, Rebecca M Howell, John L Jefferies, Leslie L Robison, Kirsten K Ness, Melissa M Hudson, Wassim Chemaitilly, Gregory T Armstrong

Faculty, Staff and Student Publications

Purpose: Little is known about the prevalence of prediabetes and associated risk of cardiovascular events and chronic kidney disease (CKD) with this reversable condition in survivors.

Methods: Prevalence of prediabetes (fasting plasma glucose 100-125 mg/dL or hemoglobin A1c 5.7%-6.4%) and diabetes was clinically assessed in 3,529 adults ≥5 years from childhood cancer diagnosis and 448 controls stratified by age. Cox proportional hazards regression estimated progression from prediabetes to diabetes, and risk of future cardiac events, stroke, CKD, and death.

Results: Among survivors, median age 30 years (IQR, 18-65), and the prevalence of prediabetes was 29.2% (95% CI, 27.7 to 30.7) …

Expanded Clinical Phenotype And Untargeted Metabolomics Analysis In Rars2-Related Mitochondrial Disorder: A Case Report, Ameya S Walimbe, Keren Machol, Stephen F Kralik, Elizabeth A Mizerik, Yoel Gofin, Mir Reza Bekheirnia, Charul Gijavanekar, Sarah H Elsea, Lisa T Emrick, Fernando Scaglia

Faculty, Staff and Students Publications

Background

RARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE). …

Germline Genetic Testing And Survival Outcomes Among Children With Rhabdomyosarcoma: A Report From The Children's Oncology Group, Bailey A Martin-Giacalone, He Li, Michael E Scheurer, Dana L Casey, Shannon Dugan-Perez, Deborah A Marquez-Do, Donna Muzny, Richard A Gibbs, Donald A Barkauskas, David Hall, Douglas R Stewart, Joshua D Schiffman, Matthew T Mcevoy, Javed Khan, David Malkin, Corinne M Linardic, Brian D Crompton, Jack F Shern, Stephen X Skapek, Rajkumar Venkatramani, Douglas S Hawkins, Aniko Sabo, Sharon E Plon, Philip J Lupo

Faculty, Staff and Students Publications

IMPORTANCE: Determining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma.

OBJECTIVE: To assess whether CPVs are associated with outcome among children with rhabdomyosarcoma.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, data were obtained for individuals, aged 0.01-23.23 years, newly diagnosed with rhabdomyosarcoma who were treated across 171 Children's Oncology Group sites from March 15, 1999, to December 8, 2017. Data analysis was performed from June 16, 2021, to May 15, 2023.

EXPOSURE: The presence of a CPV in 24 rhabdomyosarcoma-associated cancer-predisposition genes (CPGs) or an expanded set …

Congenital Tooth Agenesis And Risk Of Early-Onset Cancer, Saga Elise Eiset, Jeremy Schraw, Gitte Vrelits Sørensen, Pernille Axél Gregersen, Sonja A Rasmussen, Cecilia H Ramlau-Hansen, Philip J Lupo, Henrik Hasle

Faculty, Staff and Students Publications

IMPORTANCE: There is some evidence that tooth agenesis (congenital absence of 1 or more teeth) is associated with cancer risk, especially carcinomas of the colon and ovaries, but results of previous studies are conflicting, and associations have not yet been evaluated in a population-based setting.

OBJECTIVE: To examine the association between tooth agenesis and specific cancer types before 40 years of age.

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used linking data from nationwide registries in Denmark to assess all Danish live-born singletons born from January 1, 1977, to December 31, 2018, and followed up for up to 40 …

Role Of Non-Chromosomal Birth Defects On The Risk Of Developing Childhood Hodgkin Lymphoma: A Children’S Oncology Group Study, Erin C Peckham-Gregory, Lucas Maschietto Boff, Jeremy M Schraw, Logan G Spector, Amy M Linabery, Erik B Erhardt, Karina B Ribeiro, Carl E Allen, Michael E Scheurer, Philip J Lupo

Faculty, Staff and Students Publications

Background: Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk.

Procedure: Information on cases (n = 517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n = 784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including …

Case Series: Stenotrophomonas Maltophilia In Pediatric Oncology Patients, Sanila Sarkar, Lea M Stitzlein, Emily Rav, Miriam B Garcia, Shehla Razvi, Michael Chang, Ramia Zakhour

Faculty, Staff and Student Publications

Background: Stenotrophomonas maltophilia is a bacterial pathogen that can be fatal in hospitalized and immunocompromised patients with mortality as high as 69%. Pediatric cancer patients often have risk factors that are common for this infection, making them particularly susceptible. Managing S. maltophilia is especially challenging as it has inherent resistance to several antibiotics. Furthermore, soft tissue infections in neutropenic patients may deviate from the typical clinical presentation of S. maltophilia.

Case details: This case series describes an in-depth examination of three cases involving immunocompromised pediatric patients with S. maltophilia infections. Each case exhibited a distinct clinical presentation, encompassing infection of …

Patients With Advanced Cancer And Their Spouses Parenting Minor Children: The Role Of The Relationship Context In Parenting Concerns, Kathrin Milbury, Sujin Ann-Yi, Morgan Jones, Yisheng Li, Meagan Whisenant, Sania Yousuf, Victoria Necroto, Mariana Chavez Mac Gregor, Eduardo Bruera

Faculty, Staff and Student Publications

Objective: Patients with advanced cancer who parent minor children report parenting concerns and increased psychological distress. This cross-sectional study seeks to understand parenting-related issues in patients and spousal caregivers from a relationship perspective.

Methods: Patients with a metastatic solid malignancy and their spouses independently completed cross-sectional assessments of psychological distress (Hospital Anxiety and Depression Scale), parenting concerns (Parenting Concern Questionnaire) and efficacy (Cancer-Related Parenting Self-Efficacy Scale), and relationship measures (DAS-7, Couples' Illness Communication Scale, and Family Relationship Index).

Results: Of the 51 patients (57% female, 49% NHW, mean age 42 years) and spouses (43% female, 43% NHW, mean age of …

Polygenic Risk Scores, Radiation Treatment Exposures And Subsequent Cancer Risk In Childhood Cancer Survivors, Todd M Gibson, Danielle M Karyadi, Stephen W Hartley, Michael A Arnold, Amy Berrington De Gonzalez, Miriam R Conces, Rebecca M Howell, Vidushi Kapoor, Wendy M Leisenring, Joseph P Neglia, Joshua N Sampson, Lucie M Turcotte, Stephen J Chanock, Gregory T Armstrong, Lindsay M Morton

Faculty, Staff and Student Publications

Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), …