OR03-03 Whole Exome Sequencing (WES) in a Large Prospective Cohort of Idiopathic Short Stature (ISS): New Genes Implicated in the ISS Phenotype
Notice bibliographique
Résumé
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
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».