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

GABRIELA SANSÓ; ARIEL BERENSTEIN; MARIELA URRUTIA; IGNACIO BERGADA; ROMINA GRINSPON; SEBASTIÁN CASTRO; IZQUIERDO, AGUSTÍN; PAULA ALEJANDRA SCAGLIA; GUILLERMO ALONSO; MARCELO MARTÍ; BRUNELLO, FRANCO; LUCIANA BRENZONI; ESNAOLA AZCOITI, MARÍA; MARÍA GABRIELA ROPELATO; RODOLFO ALBERTO REY

Virtual

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