Abstract
Disclosure: L.D. Cellin: None. N.L. Andrade: None. A.C. Malaquias: None. R.C. Rezende: None. G.J. Kim: None. P.V. Atique: None. C.C. Luz: None. G.A. Vasques: None. V. Souza: None. E. Quedas: None. P.F. Collett-Solberg: None. S.R. Rauber Antonini: None. C. Longui: None. R.D. Scalco: None. A.A. Jorge: Novo Nordisk.
Introduction: Most children evaluated for short stature are classified as having idiopathic short stature (ISS) due to the absence of clinical or laboratory findings that suggest a specific underlying cause. In this context, genetic testing has emerged as a valuable diagnostic tool. Objective: To assess the diagnostic yield of whole exome sequencing (WES) and identify novel genes implicated in short stature among children diagnosed with ISS. Patients and Methods: From 2021 to 2024, we prospectively enrolled 233 children with ISS (defined as normal birth weight, height SDS < -2, normal neurodevelopment, adequate nutrition, and the absence of malformations, dysmorphisms, endocrine, or chronic diseases). Genetic evaluation involved WES to analyze single nucleotide variants (SNVs) and copy number variations (CNVs). Segregation analysis was performed in family members for positive cases, and identified variants were classified according to ACMG criteria. Results: We identified 30 pathogenic (P) or likely pathogenic (LP) variants, including 11 loss-of-function (LoF) mutations. These variants were categorized into three groups: 1. Genes/pathways previously associated with ISS: Growth plate-related genes [e.g., SHOX (4x), IHH (4x), FGFR3 (2x), COL2A1 (2x), FBN1, and ACAN] and the RAS-MAPK pathway [e.g., NF1, PTPN11 (2x), and BRAF]; 2. Genes associated with skeletal dysplasia: Variants potentially explaining a milder phenotype [e.g., LTBP3 (2x), PTHLH, ERF, POLR1A, and RPL13]; 3. Genes linked to complex growth disorders: [e.g., CSNK2A1 (2x), SPTBN1, PMM2, and ZNF292], including one variant in THRA. All variants were heterozygous except one case in PMM2, which was compound heterozygous. Patient phenotype reassessment confirmed the absence of typical features associated with these genes. In at least 50% of cases, the genetic diagnosis influenced treatment and/or follow-up strategies. Variants of uncertain significance (VUS) were identified in 28 cases, with at least 4 showing evidence of pathogenicity (VUSp). Notably, three patients carried LoF variants in SMAD6, a gene not previously associated with growth disorders. Burden analysis, including comparisons with internal and public databases, and familial segregation studies suggest that SMAD6 represents a novel gene implicated in ISS. Conclusion: Our findings reveal that a significant proportion of children classified as having ISS have an identifiable monogenic cause of growth disturbance, with a diagnostic yield of 12.9% (95% CI: 8.6%–17.2%). A gene panel restricted to those traditionally associated with ISS would yield a maximum diagnostic rate of 7.3%, underscoring the advantages of hypothesis-free approaches such as WES or WGS. Furthermore, we expanded the genetic landscape of ISS by implicating SMAD6 LoF variants as a potential novel cause of this condition.
Presentation: Saturday, July 12, 2025