OR21-02 Diagnostic Yield Of A Multigene Approach In Children With Short Stature Of Unknown Cause
Authors: De Andrade Nathalia Liberatoscioli Menezes , de Assis Funari Mariana Ferreira , Malaquias Alexsandra , Branco Dantas Naiara Castelo , Rezende Raissa , de Polli Cellin Laurana , Homma Thais Kataoka , Lerario Antonio Marcondes , Arnhold Ivo J , Vasques Gabriela Andrade , Lima Jorge Alexander Augusto 
Published: October 2023

Disclosure: N.L. Menezes De Andrade: None. M.F. Funari: None. A. Malaquias: Speaker; Self; Novo Nordisk. N.C. Dantas: None. R. Rezende: None. L.D. Cellin: None. T.K. Homma: None. A.M. Lerario: None. I.J. Arnhold: None. G.A. Vasques: Employee; Self; Eli Lilly & Company. A.A. Jorge: Advisory Board Member; Self; Novo Nordisk. Consulting Fee; Self; Novo Nordisk. Research Investigator; Self; Novo Nordisk. Speaker; Self; Pfizer Global R&D.

Introduction: The genetic factors are frequently implicated in the growth impairment of short stature (SS) children, whether they are syndromic or apparently healthy. However, the investigation recommended by the consensus fails to establish the etiology in most cases. The difficulty to search for candidate genes increases the importance of using a hypothesis-free approach as whole exome sequencing (WES) for these children. Objective: To determine the diagnostic yield of a multigene gene analysis in a cohort of children with SS of unknown cause. Patients and methods: We enrolled children with syndromic (n= 143) and isolated SS (n=380) of unknown cause after traditional investigation. The genetic analysis was applied to all patients [WES =306, panel = 217, including copy number variants (CNVs) analysis]. A chromosomal microarray analysis was also used for 79 syndromic SS. Results: A genetic defect was identified in 74 and 70 children with syndromic and isolated SS, respectively. Variants associated with syndromic SS were widely distributed in several rare conditions, affecting 63 different genes: COL2A1 in 3 patients; ANKRD11; BCL11B; LTBP3; CHD7; PTPN11; PUF60; SRCAP; STAT5B, GNAS in two patients each; SCN1A; SETD5; PTHLH; GINS1; ZMYM2; TERT; G6PC3; KIF11; SCUBE3; TBC1D32; PDHA1; RPS6KA3; SMARCA4; DNM2; KMT2A ; IHH; BRCA1; NF1; INPP5K; KRAS; FGFR2; DPH1; RPL5; KDM5C; DYRK1A; MVK; FBN1; AFF4; ACTB; POC1A; IGF1R; CREBBP; POLD1; POLR3B; PCNA; CUL7; RUNX2; EXT1; GH1; FGD1; BLM; CHRNG in one patient each. In children with isolated SS, 5 children had more than one causative finding. There were 39 defects associated with the growth plate [SHOX (n=13); NPR2 (n=7); IHH (n=10); ACAN (n=5); FGFR3 (n=3); COL2A1 (n=1)], 6 involved in the GH-IGF-1 axis [GHSR (n=3); IGF1R (n=2); GH1 (n=1)], 9 related to the RAS/MAPK pathway [PTPN11 (n=4); NF1 (n=3); BRAF (n=1); CBL (n=1)]; and 17 other genes [LTBP3 (n=2); THRA (n=2); TYMP; PIK3CA; CDKN1C; ANKRD11; HMGA2; SRCAP; KMT2C; GDF5; OBSL1; MC4R; FBN1; PRKG2; ERF (one patient each)]. Additionally, a pathogenic CNVs were identified in 11 and 3 patients with syndromic and isolated SS, respectively. The diagnostic rate was 51.7% for patients with syndromic features vs 18,4% in patients with isolated SS (p &lt; 0.001). Patients with or without a genetic diagnosis cannot be clinically differentiated into either group. Conclusion: The diagnostic yield of a multigene sequencing approach was three time higher in patients with syndromic SS than those with isolated SS. Nevertheless, the identification of a monogenic condition has a clear impact on patients’ follow-up and treatment for both groups. Maximum of 2,500 characters, including punctuation (not spaces).

Presentation: Saturday, June 17, 2023