OR17-2 Comprehensive Genetic Investigation of Patients with Central Precocious Puberty Associated with Complex Phenotypes

Abstract Background: Idiopathic central precocious puberty (CPP) is mostly described as an isolated entity. A few studies have shown its association with clinical syndromes and rare cases of chromosomal abnormalities. Objective: To clinically characterize and to genetically investigate a cohort of patients with CPP associated with complex phenotypes. Patients and methods: Two hundred patients with idiopathic CPP were retrospectively evaluated, including phenotypic, metabolic and hormonal characterization. Thirty-two of them presented at least 3 other clinical features and conditions, characterizing complex phenotypes. Genomic microarray was performed in all sporadic and index cases, and MLPA and whole-exome sequencing were performed in a subset of cases. Results: In the group of 32 idiopathic CPP patients with complex phenotypes (28 girls, 4 boys; 16 sporadic, 16 familial), mean age at puberty onset was 6.2 yr (±1.9) for girls and 8 yr (±0.1) for boys. There was a wide phenotypic spectrum. The more prevalent clinical features described included metabolic, neurocognitive and growth phenotypes; less prevalent features included dysmorphic features and congenital anomalies. Genetic investigation resulted as follows: 3 sporadic cases with maternal uniparental disomy of chromosome 14 (Temple syndrome), with disruption at the imprinted locus of DLK1; 1 sporadic patient with a 7q11.23 deletion (Williams syndrome); 7 patients from 3 unrelated families with Xp22.33 deletions, including SHOX, upstream regulatory regions, and 3 other coding-genes. Moreover, whole-exome sequencing analysis revealed candidate pathogenic variants in 2 CPP cases. One girl with sporadic CPP associated with imperforate anus and learning difficulties presented rare frameshift variants in a dominant de novo mode in 2 genes: AREL1 (14:75142990; p.S229fs) coding an ubiquitin ligase; and TNRC6B (22:40662223-40662224; p.S663fs) coding a molecule with a role in RNA-mediated gene silencing. Both genes are expressed in hypothalamus. In addition, one boy with maternal familial CPP and autism had 2 rare potentially pathogenic variants in a dominant autosomal inheritance mode: a frameshift deletion in MKKS (20:10393728-10393731; p.F144fs) coding a protein with a role in cytokinesis; and a missense variant (4:70359481; p.P267L) in UGT2B4, coding a protein involved in estrogen hydroxylation and related to menarche timing in genome-wide association studies. Conclusion: CPP might be associated with additional clinical conditions, characterizing complex phenotypes. Two chromosomal regions, Xp22.33 and 7q11.23, represent novel candidate loci implicated in CPP. In addition, distinct novel genetic abnormalities were identified in CPP patients with complex phenotypes.