Next-generation sequencing in the diagnosis of hypogonadotrophic hypogonadism and potential oligogenic mechanisms: difficulties for establishing the definitive aetiology

SEBASTIAN CASTRO; FRANCO GINO BRUNELLO; GABRIELA SANSO; AGUSTIN IZQUIERDO; LUCIANA BRENZONI; ARIEL BERENSTEIN; PAULA SCAGLIA; MARIA ESNAOLA AZCOITI; MARIELA URRUTIA; GUILLERMO ALONSO; MARIA GABRIELA ROPELATO; IGNACIO BERGADÁ; MARCELO MARTI; RODOLFO REY; ROMINA GRINSPON

Congreso; Latin American Society for Pediatric Endocrinology (SLEP) / Mexican Society of Pediatric Endocrinology; 2020

Introduction: The genetic defects of hypogonadotrophic hypogonadism(HH) are known in approximately 30% of cases.Objective and justification of the presentation of the case(s):Next-generation sequencing (NGS) showed that there may bevariantsin multiple genes of the same pathway, suggesting anoligogenicaetiology for HH.Case Description: An 8-year-old boy consulted for cryptorchidism,micro-orchidism and micropenis. At 13 years he was diagnosedwith HH by a GnRH test (LH peak: 2 IU/L). Another 14-month-old male consulted for cryptorchidism and micropenis.At 13 years, he was diagnosed with HH by a GnRH test (LH peak:2.8 IU/L). The remaining hormonal axes were preserved, notablythe corticotropic axis. To confirm the aetiology, NGS was performedusing the TruSight One capture kit on a NextSeq 500. Filtersrelated to variant frequency ( 10X, GQ> 60) were applied. Variantswere classified according to ACMG criteria (P: Pathogenic,VUS: variant of unknown significance). Genomic EvolutionaryRate Profiling (GERP) rejected substitution (RS) score was calculated.In case 1, the previously reported variant PROK2: p.Ile55fswas prioritised (alt/ref alleles: 25/41, ACMG: P, GnomAD: