Multigene Sequencing Analysis of Children Born Small for Gestational Age With Isolated Short Stature

Author(s)

Freire, Bruna L. ^{[1, 2]} ; Homma, Thais K. ^{[1, 2]} ; Funari, Mariana F. A. ^[2] ; Lerario, Antonio M. ^[3] ; Vasques, Gabriela A. ^{[1, 2]} ; Malaquias, Alexsandra C. ^{[1, 4]} ; Arnhold, Ivo J. P. ^[2] ; Jorge, Alexander A. L. ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Fac Med, Lab Endocrinol Celular & Mol LIM25, Disciplina Endocrinol, Unidade Endocrinol Genet, Ave Dr Arnaldo, 455 5 Andar Sala 5340, BR-01246903 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Lab Hormonios & Genet Mol LIM42, Unidade Endocrinol Desenvolvimento, Hosp Clin, BR-01246903 Sao Paulo - Brazil

^[3] Univ Michigan, Div Metab Endocrinol & Diabet, Dept Internal Med, Ann Arbor, MI 48109 - USA

^[4] Fac Ciencias Med Santa Casa Sao Paulo, Irmandade Santa Casa Misericordia Sao Paulo, Dept Pediat, Unidade Endocrinol Pediat, BR-01221020 Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 104, n. 6, p. 2023-2030, JUN 2019.
• Web of Science Citations: 7

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. (AU)

• FAPESP's process: 15/26980-7 - Genetic causes of prenatal onset growth disorder
• Grantee: Thais Kataoka Homma
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Research Projects - Thematic Grants