ESPE2022 Poster Category 1 Growth and Syndromes (85 abstracts)
Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature
Nathalia Andrade 1 , Mariana Funari 1 , Alexsandra Malaquias 2 , Paulo Collett- Solberg 3 , Nathalia Gomes 4 , Renata Scalco 1,2 , Naiara Dantas 1 , Raissa Rezende 1 , Angelica Tiburcio 4 , Micheline Souza 5 , Bruna Freire 1 , Ana Krepischi 1 , Carlos Longui 2 , Antonio Lerario 6 , Ivo Arnhold 1 , Alexander Jorge 1 & Gabriela Vasques 1
1Universidade de Sao Paulo, Sao Paulo, Brazil; 2Irmandade da Santa Casa de Misericordia de Sao Paulo, Sao Paulo, Brazil; 3Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; 4Santa Casa de Belo Horizonte, Belo Horizonte, Brazil; 5Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 6University of Michigan, Ann Arbor, USA
Objective: Most children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene gene analysis in children classified as ISS.
Design and Methods: We selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized target panel sequencing, including all genes already implicated in isolated short stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools.
Results: We identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate development: IHH (n = 4), SHOX (n = 3), FGFR3 (n=2), NPR2 (n = 2), ACAN (n = 2) and COL2A1 (n=1); or involved in the RAS/MAPK pathway: NF1 (n = 2), PTPN11 (n = 1), CBL (n=1) and BRAF (n=1). The diagnostic yield was higher among children with severe short stature (35% vs. 12.2% for height SDS ≤ or > -3; p=0.034). No significant difference in the rate of positive genetic diagnosis was observed regarding familial short stature (with 22.4%, without 9.1%; p=0.129) or presence of mild body disproportion (Present 30.4%, absent 14.1%, p=0.116). None of these patients had clinical findings to guide a candidate gene approach.
Conclusion: A multigene sequencing approach is able to determine a genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification. Additionally, knowing the genetic basis of these patient’s short stature can allow precise genetic counseling, particularly relevant to children harboring variants in the RAS-MAPK pathway and potential to trigger the development of specific treatment protocols including the use of rhGH, and/or puberty modulators in patients with variants in SHOX, IHH, NPR2, and ACAN who already have some preliminary data associated a good short-term response to rhGH treatment and some particularities in relation to their growth pattern.
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