Potentially pathogenic variants identified by nextgeneration sequencing in patients with short stature of unknown origin

SANGUINETI, NORA; SCAGLIA, PAULA; KESELMAN, ANA; BRASLAVSKY, DEBORA; CASALI, BARBARA; BALLERINI, MARÍA G; ESNAOLA AZCOITI, MARÍA ; ARMANDO, ROMINA; VILLEGAS, FLORENCIA; FERNANDEZ, MARPIA DEL CARMEN; CORREA, LOURDEZ; MARTIN, AYELEN; RAMIREZ, LAURA; LANDI, ESTEFANÍA; IZQUIERDO, AGUSTIN; ROSENBROCK, SOLANGE; DEL REY, GRACIELA; DOMENÉ, SABINA; PENNISI, PATRICIA; JASPER, HÉCTOR; ARBERAS, CLAUDIA; ROPELATO, MARÍA G; REY, RODOLFO A; BERGADÁ IGNACIO

Buenos Aires

Congreso; 11th International Meeting of Paediatric Endocrinology (IMPE); 2023

Introduction: Short Stature (SS), defined as height below -2 SD,is a common reason for referral to pediatric endocrinologists.Genetic factors determine ~80% of adult height. Lately, next-generationsequencing (NGS) has led to the discovery of anincreasing number of novel monogenic causes for SS.Objective: The aim of this work was to identify the genetic etiologyof SS of unknown origin (SSUO) in children.Methods: Patients with SSUO were included. They had undergoneextensive prior clinical and endocrinological workup toexclude systemic diseases, growth hormone deficiency, knownskeletal dysplasias and syndromic diseases. Whole-exome sequencingor gene panels were performed in those patients. Identifiedvariants were prioritized according to their potential pathogenicimpact based on type of variant, population frequency, relevanceof the affected gene related to growth, presumed inheritance pattern,segregation analysis, and in vitro functional studies; and wereclassified according to ACMG criteria. CGH+SNP array was performedin patients with dysmorphic features and/or neurodevelopmentaldelay; or when no diagnosis was achieved after NGSstudies. The study was approved by the institutional Ethics ReviewBoard.Results: Thirty children from a SS cohort study (n=216) metthe inclusion criteria as SSUO. We prioritized 21 variants in 20 outof 30 patients (66%): 10 pathogenic, 10 likely pathogenic and1 VUS. Seven of them had been previously reported in literatureand 14 were novel. Two variants were found in components ofGH-IGF-1 axis (IGF1, STAT5B), 4 in components of cartilageextracellular matrix (FBN1, COL2A1, ACAN), 4 in paracrine factorsof the growth plate (NPR2, LRP5, FGFR3), 2 in componentsof intracellular pathways (MAP2K1, KMT2D), 6 in components offundamental cellular processes (PIK3R1, SRCAP, ARID1B,POC1A, HDAC8, EP300) and 3 in other genes related to syndromicSS (ARCN1, CSNK2A1, SIN3A). Also, a heterozygous deletionencompassing 3 exons of HMGA2 gene was identified by WES(and confirmed by MLPA) in one patient with Silver-Russellsyndrome-like phenotype. Microarray was performed in 20patients, with a diagnostic yield of 10%. A heterozygous pathogenic3.5 Mb-deletion in 2p11.2 was detected in one patient and a0.76 Mb-duplication in Xq25q26.1 in another, explaining theirclinical features.Conclusions: We identified pathogenic and likely pathogenicvariants in 66% of the patients, a high diagnostic yield when thecohort is carefully selected, and the patients present features suggestiveof a genetic cause for SS. This study supports the utility ofhigh-throughput molecular techniques for the etiological diagnosisof SSUO.