SAT-195 Exome Sequencing of Patients with Syndromic Tall Stature Reveals Novel Candidate Genes

Abstract Disclosure: G.J. Kim: None. E.V. de Albuquerque Albuquerque: None. R.C. Rezende: None. L.D. Cellin: None. L.S. de Santana: None. A.M. Lerario: None. V. de Souza: None. R.D. Scalco: None. A.A. Jorge: Novo Nordisk. Background: Monogenic causes of syndromic tall stature result in a recognizable pattern of clinical characteristics that include dysmorphisms, malformations, and/or neurodevelopmental disorders. Thus far, few articles have been published regarding the diagnosis of syndromic tall stature by genetic testing. The purpose of this study was to use whole exome sequencing (WES) to evaluate a cohort of patients with syndromic tall stature, with the aim of describing genetic causes of and new candidate genes for tall stature. Methods: We included 37 patients referred to a single, tertiary academic center specialized in growth disorders for the evaluation of tall stature from January 2017 to February 2024. Patients included both novel cases and cases being reanalyzed. Trio analysis was performed for four patients, and WES was performed for only the index cases for the remaining patients. Variants were prioritized based on minor allele frequency, prediction to be loss-of-function, inheritance pattern compatibility, and prior reports. Copy number variations (CNVs) were further prioritized based on involved protein-coding genes displaying haploinsufficiency. If diagnosis of a known tall stature disorder could not be achieved, analysis for candidate genes was performed, taking into account the above criteria as well as GWAS catalog associations with height and weight phenotypes, DECIPHER catalog listings of overlapping CNVs, medical literature on our candidate genes, recurrence of rare variants with similar phenotypes, and animal models consistent with the proposed phenotype. Results: Of the 37 patients included in this study, genetic diagnosis was achieved in 11 patients, for a diagnostic yield of 29.7%. Pathogenic or likely pathogenic variants were identified in FBN1 (3x), PTEN, NSD1, SUZ12, CDH8, and DEPDC5, with some of these results having been previously described in other papers. One patient carried significant variants in two genes, FBN2 and COL5A1. Furthermore, we identified two patients with pathogenic deletions confirmed by chromosomal microarray analysis. Through analysis of the gene content compromised by these deletions, description of other cases with overlapping CNVs, biological plausibility, and data from the literature, two candidate genes for tall stature were identified: PTCH1 and SST. Additionally, three genes (KDM4A, RAP1GAP2 and GRB10) were identified via WES based on gene constraints, recurrence in our cohort (KDM4A), biological plausibility, and additional cases in literature (GRB10). Conclusions: These findings indicate a diagnostic yield of syndromic tall stature by WES that is comparable to those found in studies of other syndromic growth disorders. We also present five new candidate genes for tall stature. Further work is required to continue characterizing the impact of these genes on adult height, as well as to describe novel candidate genes for height. Presentation: Saturday, July 12, 2025