Bruna L Freire1,2, Thais K Homma1,2, Mariana F A Funari2, Antônio M Lerario3, Gabriela A Vasques1,2, Alexsandra C Malaquias1,4, Ivo J P Arnhold2, Alexander A L Jorge1,2. 1. Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo CEP, Brazil. 2. Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo CEP, Brazil. 3. Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan. 4. Unidade de Endocrinologia Pediátrica, Departamento de Pediatria, Irmandade da Santa Casa de Misericórdia de São Paulo, Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, Brazil.
Abstract
CONTEXT: Patients born small for gestational age (SGA) who present with persistent short stature could have an underlying genetic etiology that will account for prenatal and postnatal growth impairment. We applied a unique massive parallel sequencing approach in cohort of patients with exclusively nonsyndromic SGA to simultaneously interrogate for clinically substantial genetic variants. OBJECTIVE: To perform a genetic investigation of children with isolated short stature born SGA. DESIGN: Screening by exome (n = 16) or targeted gene panel (n = 39) sequencing. SETTING: Tertiary referral center for growth disorders. PATIENTS AND METHODS: We selected 55 patients born SGA with persistent short stature without an identified cause of short stature. MAIN OUTCOME MEASURES: Frequency of pathogenic findings. RESULTS: We identified heterozygous pathogenic or likely pathogenic genetic variants in 8 of 55 patients, all in genes already associated with growth disorders. Four of the genes are associated with growth plate development, IHH (n = 2), NPR2 (n = 2), SHOX (n = 1), and ACAN (n = 1), and two are involved in the RAS/MAPK pathway, PTPN11 (n = 1) and NF1 (n = 1). None of these patients had clinical findings that allowed for a clinical diagnosis. Seven patients were SGA only for length and one was SGA for both length and weight. CONCLUSION: These genomic approaches identified pathogenic or likely pathogenic genetic variants in 8 of 55 patients (15%). Six of the eight patients carried variants in genes associated with growth plate development, indicating that mild forms of skeletal dysplasia could be a cause of growth disorders in this group of patients.
CONTEXT: Patients born small for gestational age (SGA) who present with persistent short stature could have an underlying genetic etiology that will account for prenatal and postnatal growth impairment. We applied a unique massive parallel sequencing approach in cohort of patients with exclusively nonsyndromic SGA to simultaneously interrogate for clinically substantial genetic variants. OBJECTIVE: To perform a genetic investigation of children with isolated short stature born SGA. DESIGN: Screening by exome (n = 16) or targeted gene panel (n = 39) sequencing. SETTING: Tertiary referral center for growth disorders. PATIENTS AND METHODS: We selected 55 patients born SGA with persistent short stature without an identified cause of short stature. MAIN OUTCOME MEASURES: Frequency of pathogenic findings. RESULTS: We identified heterozygous pathogenic or likely pathogenic genetic variants in 8 of 55 patients, all in genes already associated with growth disorders. Four of the genes are associated with growth plate development, IHH (n = 2), NPR2 (n = 2), SHOX (n = 1), and ACAN (n = 1), and two are involved in the RAS/MAPK pathway, PTPN11 (n = 1) and NF1 (n = 1). None of these patients had clinical findings that allowed for a clinical diagnosis. Seven patients were SGA only for length and one was SGA for both length and weight. CONCLUSION: These genomic approaches identified pathogenic or likely pathogenic genetic variants in 8 of 55 patients (15%). Six of the eight patients carried variants in genes associated with growth plate development, indicating that mild forms of skeletal dysplasia could be a cause of growth disorders in this group of patients.
Authors: Paulo F Collett-Solberg; Geoffrey Ambler; Philippe F Backeljauw; Martin Bidlingmaier; Beverly M K Biller; Margaret C S Boguszewski; Pik To Cheung; Catherine Seut Yhoke Choong; Laurie E Cohen; Pinchas Cohen; Andrew Dauber; Cheri L Deal; Chunxiu Gong; Yukihiro Hasegawa; Andrew R Hoffman; Paul L Hofman; Reiko Horikawa; Alexander A L Jorge; Anders Juul; Peter Kamenický; Vaman Khadilkar; John J Kopchick; Berit Kriström; Maria de Lurdes A Lopes; Xiaoping Luo; Bradley S Miller; Madhusmita Misra; Irene Netchine; Sally Radovick; Michael B Ranke; Alan D Rogol; Ron G Rosenfeld; Paul Saenger; Jan M Wit; Joachim Woelfle Journal: Horm Res Paediatr Date: 2019-09-12 Impact factor: 2.852
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: Catherine Tcheandjieu; Matthew Aguirre; Stefan Gustafsson; Priyanka Saha; Praneetha Potiny; Melissa Haendel; Erik Ingelsson; Manuel A Rivas; James R Priest Journal: PLoS Genet Date: 2020-11-23 Impact factor: 5.917