ESPEYB17 4. Growth and Growth Factors Important for clinical practice (5 abstracts)
4.2. Genetic disorders in prenatal onset syndromic short stature identified by exome sequencing
Homma TK , Freire BL , Honjo Kawahira RS , Dauber A , Funari MFA , Lerario AM , Nishi MY , Albuquerque EV , Vasques GA , Collett-Solberg PF , Miura Sugayama SM , Bertola DR , Kim CA , Arnhold IJP , Malaquias AC & Jorge AAL
Genetic Endocrinology Unit, Laboratory of Cellular and Molecular Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil alexj@usp.br
To read the full abstract: J Pediatr. 2019 Dec;215:192–198.
Identifying the diagnosis in children with syndromic short stature and those with recognized genetic growth disorders is often challenging, as they may share many clinical features (1)(2). The candidate gene approach has many limitations in unveiling the genetic cause. Therefore, whole exome sequencing (WES) has been proposed to improve the diagnostic rate in children with short stature of unknown etiology, including both idiopathic short stature (ISS) and SGA (3). In this study, 44 children with the following inclusion criteria were selected for WES analysis: available DNA samples, consent by the patient and family, a syndromic condition without an initial clinical diagnosis and a negative result on candidate gene testing based on clinical suspicion. Among these 44 patients, 40 had already been investigated by a genetic test before enrollment, mainly chromosomal microarray analysis, multiplex ligation-dependent probe amplification for Silver-Russell syndrome, or targeted gene panel sequencing, including genes frequently associated with growth disorders.
Positive genetic results on WES were found in 15 of 44 patients (34%): 11 had pathogenic and 4 likely-pathogenic gene variants. All variants were not present in local and public genetic databases and the detected genes are involved in fundamental cellular process and pathways: ACTG1, AFF4, ANKRD11, BCL11B, BRCA1, CDKN1C, GINS1, INPP5K, KIF11, KMT2A, POC1A, COLA2A1 and SRCAP. Although the majority of patients did not have a definite diagnosis even after WES, the authors concluded that the WES approach should be considered as the first line investigation in children with syndromic short stature without initial clinical, laboratory and radiological diagnosis. This WES based approach seems to be more cost-effective and less time consuming in patients selected on clinical grounds, instead of the conventional step-by-step diagnostic work-up. Genetic characterization is important not only for identifying the diagnosis and informing genetic counseling, but also to avoid potentially harmful growth promoting therapies in children who harbor cancer-susceptibility genetic mutations.
References:
1. Freire BL, Homma TK, Funari MFA, Lerario AM, Vasques GA, Malaquias AC, Arnhold IJP, Jorge AAL. Multigene Sequencing Analysis of Children Born Small for Gestational Age With Isolated Short Stature. J Clin Endocrinol Metab. 2019 Jun 1;104(6):2023–2030.
2. Hauer NN, Popp B, Schoeller E, Schuhmann S, Heath KE, Hisado-Oliva A, et al. Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature. Genet Med 2018;20:630–8.
3. Homma TK, Krepischi ACV, Furuya TK, Honjo RS, Malaquias AC, Bertola DR, et al. Recurrent copy number variants associated with syndromic short stature ofunknown cause.HormRes Paediatr 2018;89:13–21.
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ESPE Yearbook of Paediatric Endocrinology
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