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

• Published in: The journal of clinical endocrinology and metabolism 2019-06, Vol.104 (6), p.2023-2030
• Main Authors: Freire, Bruna L, Homma, Thais K, Funari, Mariana F A, Lerario, Antônio M, Vasques, Gabriela A, Malaquias, Alexsandra C, Arnhold, Ivo J P, Jorge, Alexander A L
• Format: Article
• Language: English
• Subjects: Body Height - genetics; Body Weight - genetics; Bone dysplasia; Child; Child, Preschool; Children; Dysplasia; Etiology; Female; Genetic diversity; Genetic Markers - genetics; Gestational age; Growth disorders; Growth Disorders - diagnosis; Growth Disorders - genetics; Growth plate; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Infant, Small for Gestational Age - growth & development; Male; MAP kinase; Sequence analysis; Skeleton; Small for gestational age; Whole Exome Sequencing
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2018-01971

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. In the present study, molecular investigation, using massive parallel sequencing, showed effectiveness in diagnosing one in seven patients with prenatal short stature of unknown etiology.