Diagnostic yield of a multigene approach in children with short stature of unknown cause: It is time to remove the term idiopathic!

Nathalia Andrade; Mariana Funari; Alexsandra Malaquias; Naiara Dantas; Raissa Rezende; Laurana Cellin; Thais Homma; Bruna Lucheze; Antonio Lerario; Ivo Arnhold; Gabriela Vasques; Alexander Jorge

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=125) and isolated SS (n=376) of unknown cause after traditional investigation. The genetic analysis was applied to all patients [WES=285, panel = 217, including copy number variants (CNVs) analysis]. A chromosomal microarray analysis was also used for 77 syndromic SS. Results: A genetic defect was identified in 67 and 66 children with syndromic and isolated SS, respectively. Variants associated with syndromic SS were widely distributed in several rare conditions, affecting 47 different genes: COL2A1 in 3 patients; ANKRD11; BCL11B; LTBP3; CHD7; PTPN11; PUF60; SRCAP; STAT5B in two patients each; SCN1A; SETD5; PTHLH; GINS1; ZMYM2; GNAS; TERT; G6PC3; KIF11; SCUBE3; TBC1D32; PDHA1; RPS6KA3; SMARCA4; DNM2; KMT2A; IHH; BRCA1; GNAS; NF1; INPP5K; KRAS; FGFR2; DPH1; RPL5; KDM5C; DYRK1A; MVK; FBN1; AFF4; ACTB; POC1A; IGF1R; CREBBP; POLD1; POLR3B; PCNA; CUL7 in one patient each. In children with isolated SS, 5 children had more than one causative finding. There were 36 defects associated with the growth plate [SHOX (n=13); NPR2 (n=7); IHH (n=10); ACAN (n=5); FGFR3 (n=3); COL2A1 (n=1)], 8 involved in the GH-IGF-1 axis [GHSR (n=3); IGF1R (n=2)], 8 related to the RAS/MAPK pathway [PTPN11 (n=4); NF1 (n=3); BRAF (n=1); CBL (n=1)]; and 14 other genes [LTBP3 (n=2); TYMP; PIK3CA; CDKN1C; ANKRD11; THRA; HMGA2; SRCAP; KMT2C; GDF5; OBSL1; MC4R; FBN1 (one patient each)]. Additionally, a pathogenic CNVs were identified in 10 and 2 patients with syndromic and isolated SS, respectively. The diagnostic rate was 53.6% for patients with syndromic features vs 17.5% in patients with isolated SS (P< 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.

IMPE Abstracts

FC4.3