OR17-5 Clinical and Genetic Features of Constitutional Delay of Growth and Puberty

Abstract

Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. It has a strong family history, however, its genetic basis is still poorly understood. Objective: To characterize the clinical and genetic features of a CDGP cohort. Methods: 59 unrelated probands with CDGP were selected. They underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel (NextSeq 500 next-generation sequencing, Illumina Inc) designed to capture 36 known and candidate genes implicated with delayed puberty. Results: All CDGP patients had spontaneous pubertal development or it was induced by a transient sexual steroid replacement. Male predominance (81%), short stature (91%) associated with delayed bone age and positive family history (59%) were the major clinical features of this cohort. Genetic analyses revealed 16 rare heterozygous predicted to be deleterious variants in 15 CDGP patients (25%) in 8 distinct genes (HS6ST1, IGSF10, GHSR, CHD7, SEMA3A, IL17RD, SPRY4 and WDR11). IGSF10 and GHSR were the most prevalent affected genes in this group (3 variants in 4 patients each one). The vast majority of variants were missense. We identified a stop-gain variant, likely pathogenic, in HS6ST1 gene (p.Cys27X) in a male proband with no family history of delayed puberty. 5% of the subjects had oligogenicity (variants in more than one gene). Conclusions: The classic phenotype of CDGP has as clinical features short stature in the prepubertal period, higher prevalence in males and more than a half of the individuals had a positive family history. Genetic heterogeneity was demonstrated in typical CDGP phenotype.