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

CASTRO S; BRUNELLO FG; SANSÓ GE; IZQUIERDO A; BRENZONI L; BERENSTEIN A; SCAGLIA P; AZCOITI ME; URRUTIA M,; ALONSO G; ROPELATO MG; BERGADÁ I; MARTÍ M; REY RA; GRINSPON RP

Virtual

Congreso; XXIX Reunión Sociedad Latinoamericana Endocrinología Pediátrica; 2021

The genetic defects of hypogonadotrophic hypogonadism (HH) are known in approximately 30% of cases. Next-generation sequencing (NGS) showed that there may be variants in multiple genes of the same pathway, suggesting an oligogenic aetiology for HH.An 8-year-old boy consulted for cryptorchidism, micro-orchidism and micropenis. At 13 years he was diagnosed with 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, notably the corticotropic axis.To confirm the aetiology, NGS was performed using the TruSight One capture kit on a NextSeq 500. Filters related to variant frequency ( 10X, GQ> 60) were applied. Variants were classified according to ACMG criteria (P: Pathogenic, VUS: variant of unknown significance). Genomic Evolutionary Rate Profiling (GERP) rejected substitution (RS) score was calculated.In case 1, the previously reported variant PROK2: p.Ile55fs was prioritised (alt/ref alleles: 25/41, ACMG: P, GnomAD: