Potentially pathogenic variants Identified by next- generation sequencing in patients with short stature of unknown origin

ANA KESELMAN; MARIANA GUTIÉRREZ; MARÍA GABRIELA ROPELATO; MARTIN, AYELEN; DEL REY, GRACIELA; VILLEGAS, FLORENCIA; ESNAOLA AZCOITI, MARÍA; HÉCTOR JASPER; ALEXANDER AL JORGE; NORA SANGUINETI; BÁRBARA CASALI; LAURA RAMÍREZ URREA; MARÍA GABRIELA BALLERINI; CASSINELLI, HAMILTON; ARIEL BERENSTEIN; ARMANDO, ROMINA; ARBERAS, CLAUDIA; IVO JORGE PRADO ARNHOLD; RODOLFO A. REY; PAULA ALEJANDRA SCAGLIA; DEBORA BRASLAVSKY; ESTEFANIA LANDI; PENNISI, PATRICIA; DOMENÉ, SABINA; IZQUIERDO, AGUSTÍN; FERNÁNDEZ, MARÍA DEL CARMEN; HORACIO DOMENÉ; GABRIELA A VASQUES; BERGADÁ, IGNACIO

Merida

Congreso; XXIX Congreso de la Sociedad Latinoamericana de Endocrinología Pediátrica; 2020

Introduction: Short stature is a common condition of greatconcern to patients and their families. Underlying etiology oftenremains elusive due to clinical and genetic heterogeneity.Objective: To identify the genetic etiology in children withshort stature of unknown origin.Material and methods: We included 10 patients with severeshort stature (height below -2.5 SDS) of unknown origin who hadundergone extensive prior clinical and endocrinological workupto exclude GH deficiency, systemic diseases and known skeletaldysplasias. Eight patients were studied by whole-exome and, 2 byclinical-exome sequencing. In 5 with dysmorphias, CGH SNPmicroarray-180K was initially performed. Identified variants wereprioritized according to their potential pathogenic impact basedon type of variant, population frequency, relevance of the affectedgene related to growth, presumed inheritance pattern, segregationanalysis, and, when available, in vitro functional studies. All patientsand their parents signed an informed consent and the protocolwas approved by institutional review board.Results: Among the 10 selected patients (7 males), 5 were smallfor gestational age. Median age at presentation was 1.96 years old(0.66 to 3.3) and height was −4.6 SDS (−6.7 to −2.8). Eight patientspresented proportionate short stature while 2 had sitting height/height ratio >97th centile. Six also had at least one short statureparent. Dysmorphias were present in 6 patients, 5 of them associatedneurodevelopmental delay. Serum IGF-1 level was elevated in4 cases and normal-low in 6. Potentially relevant variants (4 pathogenicor likely pathogenic and 4 VUS, according to ACMG criteria) were detected in 8 patients within genes with a knownimpact on growth: IGF1, ACAN, STAT5B, FBN1, RRAS2, NPR2,FLNB, COL2A1. In vitro studies and/or segregation analysis gavestrong evidence to assume the cause of short stature in 4/10 patients.CGH SNP microarray identified a 0.7Mb copy number gainin Xq25-q26 in a boy which could explain his neurodevelopmentaldelay and autism; and in a patient with consanguinity, a large regionof homozygosity in chr12 guided the study of IGF1 gene.Conclusions: The use of genomic technologies in this selectedgroup of severe short stature patients had a 40% diagnostic yieldand helped to explain the genetic etiology of other clinical features.In addition, they contributed to expand the phenotype for alreadyknown gene defects. Further studies will be needed to assign apathogenic role or to rule out the other variants.