Potentially pathogenic variants identified by next generation sequencing in patients with short stature of unknown origin.

SANGUINETI, NORA; SCAGLIA, PAULA; KESELMAN, ANA; CASALI, BÁRBARA; BRASLAVSKY, DEBORA; GUTIERREZ, MARIANA; LAURA RAMIREZ; LANDI, ESTEFANÍA; ROPELATO, MARIA GABRIELA; BALLERINI, MARIA GABRIELA; PENNISI, PATRICIA; MARTIN, AYELEN; VAZQUEZ, MARTIN; CASSINELLI, HAMILTON; DOMENE, SABINA; ARIEL BERENSTEIN; IZQUIERDO, AGUSTIN; DEL REY, GRACIELA; VILLEGAS, F; ARMANDO, ROMINA; AZCOITI, MARÍA ESNAOLA; ARBERAS, CLAUDIA; DOMENE, HORACIO; JASPER, HECTOR; ARNHOLD, I; VASQUES, GABRIELA; JORGE, ALEXANDER; REY, RODOLFO; BERGADA, IGNACIO

Merida

Congreso; Sociedad Latinoamericana de Endocrinologia Pediatrica; 2020

Introduction: Short stature is a common condition of great concern to patients and their families. Underlying etiology often remains elusive due to clinical and genetic heterogeneity.Objective: To identify the genetic etiology in children with short stature of unknown origin. Methods: We included 10 patients with severe short stature (height 97th centile. Six also had at least one short stature parent. Dysmorphias were present in 6 patients, 5 of them associated neurodevelopmental delay. Serum IGF-1 level was elevated in 4 cases and normal-low in 6.  Potentially relevant variants (4 pathogenic or likely pathogenic and 4 VUS, according to ACMG criteria) were detected in 8 patients within genes with a known impact on growth: IGF1, ACAN, STAT5B, FBN1, RRAS2, NPR2, FLNB, COL2A1. In vitro studies and/or segregation analysis gave strong evidence to assume the cause of short stature in 4/10 patients.CGH+SNP microarray identified a 0.7Mb copy number gain in Xq25-q26 in a boy which could explain his neurodevelopmental delay and autism; and in a patient with consanguinity, a large region of homozygosity in chr12 guided the study of IGF1 gene.Conclusion: The use of genomic technologies in this selected group of severe short stature patients had a 40% diagnostic yield and helped to explain the genetic etiology of other clinical features. In addition they contributed to expand the phenotype for already known gene defects. Further studies will be needed to assign a pathogenic role or to rule out the other variants.