ESPE2021 Free Communications Growth Disorders (6 abstracts)
Prospective genetic analysis by a targeted gene panel of a cohort of patients classified as idiopathic short stature (ISS)
Nathalia Andrade 1 , Mariana Funari 1 , Antonio Lerario 2 , Alexsandra Malaquias 3 , Paulo Solberg 4 , Nathalia Lisboa 5 , Micheline Rayol 6 , Naiara Dantas 1 , Raíssa Rezende 1 , Bruna Lucheze 1 , Elisangela Quedas 1 , Ana Krepischi 1 , Ivo Arnhold 1 , Gabriela Vasques 1 & Alexander Jorge 1
1Universidade de São Paulo, São Paulo, Brazil.;2University of Michigan, Ann Arbor, USA.;3Santa Casa de Misericórida de São Paulo, São Paulo, Brazil.;4Faculdade de Ciências Médicas da Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.;5Santa Casa de Belo Horizonte, Belo Horizonte, Brazil.;6Universidade Federal do Rio de Janeiro, Volta Redonda, Brazil
Introduction: The majority of children with short stature are classified as ISS by the absence of findings that could elucidate the cause of their growth impairment. Several monogenic defects have already been identified in children with ISS, but the candidate gene approach is not feasible when there are no specific findings to guide a specific genetic test.
Objective: To evaluate the diagnostic yield of a targeted gene panel in children with ISS.
Methods: We prospectively analyzed 44 children with ISS. We included healthy children with adequate birth weight, height SDS<-2, normal development, and without positive results in clinical, laboratory and radiological evaluation. They were submitted to multigene sequencing analysis containing 90 genes related to growth disorders. We analyzed small variants and copy number variations (CNVs) by standard bioinformatics procedure. Rare variants with potential to be pathogenic were segregated into the family and classified according to the ACMG/AMP criteria.
Results: Forty-four children (24 boys) at the age of 7.2±3.0y were evaluated. They have a height SDS of -2.4±0.6; BMI SDS of -0.3±1.0 and SH/H SDS of 0.6 ±1.2. Mild body disproportion was observed in 20.5% (SH: H SDS: 2.3±0.5). Twenty patients (45.5%) had familial short stature. In total, 9 heterozygous pathogenic/likely pathogenic (P/LP) variants were identified in 9 patients. Among them, 5 variants are located in genes related to growth plate: IHH (n = 2), ACAN (n = 1), FGFR3 (n = 1), COL2A1 (n = 1), 1 variant is in one gene associated with the GH-IGF1 axis: GHSR (n = 1) and 3 variants are in genes related to the RASopathies: CBL (n = 1), NF1 (n = 1) and PTPN11 (n = 1). Additionally, we identified 4 heterozygous pathogenic CNVs: 3 deletions in SHOX and 1 complex rearrangement in ACAN. Most of these P/LP variants were inherited from a short parent (n = 6) whereas 3 were de novo. Six further variants were classified as uncertain significance and are still under investigation. It is noteworthy that 5 patients have more than one genetic variant that could contribute to the patient short stature.
Conclusion: We were able to identify a genetic cause of ISS in 9/44 patients (20.5%). This diagnostic yield is remarkable in a group of children whose the regular evaluation was unable to determine the cause of growth impairment. The multigene sequencing analysis approach to ISS is useful to determine the cause of short stature with an additional perspective of guiding treatment and clinical follow-up.
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