Thais Kataoka Homma1, Bruna Lucheze Freire1, Rachel Sayuri Honjo Kawahira2, Andrew Dauber3, Mariana Ferreira de Assis Funari4, Antônio Marcondes Lerario5, Mirian Yumie Nishi4, Edoarda Vasco de Albuquerque6, Gabriela de Andrade Vasques6, Paulo Ferrez Collett-Solberg7, Sofia Mizuho Miura Sugayama2, Debora Romeo Bertola2, Chong Ae Kim2, Ivo Jorge Prado Arnhold4, Alexsandra Christianne Malaquias8, Alexander Augusto de Lima Jorge9. 1. Genetic Endocrinology Unit, Laboratory of Cellular and Molecular Endocrinology (LIM25), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Brazil; Development Endocrinology Unit, Laboratory of Hormones and Molecular Genetics (LIM42), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Brazil. 2. Genetic Unit of the Instituto da Criança, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Brazil. 3. Division of Endocrinology, Children's National Health System, USA. 4. Development Endocrinology Unit, Laboratory of Hormones and Molecular Genetics (LIM42), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Brazil. 5. Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, USA. 6. Genetic Endocrinology Unit, Laboratory of Cellular and Molecular Endocrinology (LIM25), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Brazil. 7. Endocrinology Discipline of the Faculdade de Ciência Médicas da Universidade do Estado do Rio de Janeiro - FCM/UERJ, Rio de Janeiro, Brazil. 8. Genetic Endocrinology Unit, Laboratory of Cellular and Molecular Endocrinology (LIM25), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Brazil; Pediatric Endocrinology Unit, Department of Pediatrics, Irmandade da Santa Casa de Misericórdia de São Paulo, Faculdade de Ciências Médicas da Santa Casa de São Paulo, Brazil. 9. Genetic Endocrinology Unit, Laboratory of Cellular and Molecular Endocrinology (LIM25), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Brazil; Development Endocrinology Unit, Laboratory of Hormones and Molecular Genetics (LIM42), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Brazil. Electronic address: alexj@usp.br.
Abstract
OBJECTIVE: To perform a prospective genetic investigation using whole exome sequencing of a group of patients with syndromic short stature born small for gestational age of unknown cause. STUDY DESIGN: For whole exome sequencing analysis, we selected 44 children born small for gestational age with persistent short stature, and additional features, such as dysmorphic face, major malformation, developmental delay, and/or intellectual disability. Seven patients had negative candidate gene testing based on clinical suspicion and 37 patients had syndromic conditions of unknown etiology. RESULTS: Of the 44 patients, 15 (34%) had pathogenic/likely pathogenic variants in genes already associated with growth disturbance: COL2A1 (n = 2), SRCAP (n = 2), AFF4, ACTG1, ANKRD11, BCL11B, BRCA1, CDKN1C, GINS1, INPP5K, KIF11, KMT2A, and POC1A (n = 1 each). Most of the genes found to be deleterious participate in fundamental cellular processes, such as cell replication and DNA repair. CONCLUSIONS: The rarity and heterogeneity of syndromic short stature make the clinical diagnosis difficult. Whole exome sequencing allows the diagnosis of previously undiagnosed patients with syndromic short stature.
OBJECTIVE: To perform a prospective genetic investigation using whole exome sequencing of a group of patients with syndromic short stature born small for gestational age of unknown cause. STUDY DESIGN: For whole exome sequencing analysis, we selected 44 children born small for gestational age with persistent short stature, and additional features, such as dysmorphic face, major malformation, developmental delay, and/or intellectual disability. Seven patients had negative candidate gene testing based on clinical suspicion and 37 patients had syndromic conditions of unknown etiology. RESULTS: Of the 44 patients, 15 (34%) had pathogenic/likely pathogenic variants in genes already associated with growth disturbance: COL2A1 (n = 2), SRCAP (n = 2), AFF4, ACTG1, ANKRD11, BCL11B, BRCA1, CDKN1C, GINS1, INPP5K, KIF11, KMT2A, and POC1A (n = 1 each). Most of the genes found to be deleterious participate in fundamental cellular processes, such as cell replication and DNA repair. CONCLUSIONS: The rarity and heterogeneity of syndromic short stature make the clinical diagnosis difficult. Whole exome sequencing allows the diagnosis of previously undiagnosed patients with syndromic short stature.
Authors: Danielle Christine Maria van der Kaay; Anne Rochtus; Gerhard Binder; Ingo Kurth; Dirk Prawitt; Irène Netchine; Gudmundur Johannsson; Anita C S Hokken-Koelega; Miriam Elbracht; Thomas Eggermann Journal: Endocr Connect Date: 2022-10-10 Impact factor: 3.221
Authors: Mary E McQuaid; Kashif Ahmed; Stephanie Tran; Justine Rousseau; Ranad Shaheen; Kristin D Kernohan; Kyoko E Yuki; Prerna Grover; Ema S Dreseris; Sameen Ahmed; Lucie Dupuis; Jennifer Stimec; Mary Shago; Zuhair N Al-Hassnan; Roch Tremblay; Philipp G Maass; Michael D Wilson; Eyal Grunebaum; Kym M Boycott; François-Michel Boisvert; Sateesh Maddirevula; Eissa A Faqeih; Fahad Almanjomi; Zaheer Ullah Khan; Fowzan S Alkuraya; Philippe M Campeau; Peter Kannu; Eric I Campos; Hugo Wurtele Journal: JCI Insight Date: 2022-05-23
Authors: Sarah E Sheppard; Ian M Campbell; Margaret H Harr; Nina Gold; Dong Li; Hans T Bjornsson; Julie S Cohen; Jill A Fahrner; Ali Fatemi; Jacqueline R Harris; Catherine Nowak; Cathy A Stevens; Katheryn Grand; Margaret Au; John M Graham; Pedro A Sanchez-Lara; Miguel Del Campo; Marilyn C Jones; Omar Abdul-Rahman; Fowzan S Alkuraya; Jennifer A Bassetti; Katherine Bergstrom; Elizabeth Bhoj; Sarah Dugan; Julie D Kaplan; Nada Derar; Karen W Gripp; Natalie Hauser; A Micheil Innes; Beth Keena; Neslida Kodra; Rebecca Miller; Beverly Nelson; Malgorzata J Nowaczyk; Zuhair Rahbeeni; Shay Ben-Shachar; Joseph T Shieh; Anne Slavotinek; Andrew K Sobering; Mary-Alice Abbott; Dawn C Allain; Louise Amlie-Wolf; Ping Yee Billie Au; Emma Bedoukian; Geoffrey Beek; James Barry; Janet Berg; Jonathan A Bernstein; Cheryl Cytrynbaum; Brian Hon-Yin Chung; Sarah Donoghue; Naghmeh Dorrani; Alison Eaton; Josue A Flores-Daboub; Holly Dubbs; Carolyn A Felix; Chin-To Fong; Jasmine Lee Fong Fung; Balram Gangaram; Amy Goldstein; Rotem Greenberg; Thoa K Ha; Joseph Hersh; Kosuke Izumi; Staci Kallish; Elijah Kravets; Pui-Yan Kwok; Rebekah K Jobling; Amy E Knight Johnson; Jessica Kushner; Bo Hoon Lee; Brooke Levin; Kristin Lindstrom; Kandamurugu Manickam; Rebecca Mardach; Elizabeth McCormick; D Ross McLeod; Frank D Mentch; Kelly Minks; Colleen Muraresku; Stanley F Nelson; Patrizia Porazzi; Pavel N Pichurin; Nina N Powell-Hamilton; Zoe Powis; Alyssa Ritter; Caleb Rogers; Luis Rohena; Carey Ronspies; Audrey Schroeder; Zornitza Stark; Lois Starr; Joan Stoler; Pim Suwannarat; Milen Velinov; Rosanna Weksberg; Yael Wilnai; Neda Zadeh; Dina J Zand; Marni J Falk; Hakon Hakonarson; Elaine H Zackai; Fabiola Quintero-Rivera Journal: Am J Med Genet A Date: 2021-03-30 Impact factor: 2.578