Open AccessSUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes
Author(s) -
Ana Cantón,
Ana Cristina Victorino Krepischi,
Luciana Ribeiro Montenegro,
Silvia Souza da Costa,
Carla Rosenberg,
Carolina Ramos,
Aline Guimarães de Faria,
Carlos Eduardo Seraphim,
Flávia Rezende Tinano,
Rachel Sayuri Honjo Kawahira,
Chong Kim,
Francis Edouard de Zegher,
Mariana Ferreira de Assis Funari,
Alexander Jorge,
Berenice Bilharinho Mendonça,
Vinícius Nahime Brito,
Ana Claudia Latrônico
Publication year - 2020
Publication title -
journal of the endocrine society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.046
H-Index - 20
ISSN - 2472-1972
DOI - 10.1210/jendso/bvaa046.822
Subject(s) - phenotype , genetics , exome sequencing , precocious puberty , candidate gene , biology , snp array , microarray , medicine , genetic heterogeneity , gene , bioinformatics , single nucleotide polymorphism , genotype , gene expression , hormone
Background: Central precocious puberty (CPP) is mostly described as an isolated entity. Few studies have shown an association of CPP with complex cases or genetic syndromes, but without making inferences on molecular causalities. Objective: To genetically investigate a cohort of patients with CPP associated with complex phenotypes using high throughput methodologies. Patients and methods: From a large cohort of patients with idiopathic CPP followed at a university hospital outpatient clinic, thirty-eight patients were selected for high throughput genetic investigation for presenting at least 3 additional clinical features and conditions, characterizing complex phenotypes. All had normal brain MRI. Pathogenic allelic variants in CPP known genes were initially excluded. All patients were submitted to genomic microarray (SNP or CGH arrays). A subset of patients was also submitted to whole-exome sequencing (11 cases) or target panel sequencing (18 cases). Results: Among the group of 38 patients (35 girls, 4 boys; 21 sporadic, 17 familial), mean age at puberty onset was 5.8 ±2.1 and 8.3 ±3.0 yr in girls and boys, respectively. The more prevalent clinical features described included metabolic, growth and neurocognitive phenotypes; less prevalent features included dysmorphic features and congenital anomalies. Pathogenic or probably pathogenic genetic defects were identified in 9 cases: 5 sporadic (all identified as de novo) and 4 familial. Defects in sporadic cases were as follows: three cases with 7q11.23 deletion (Williams syndrome); one girl with ventricular arrhythmia presenting a rare 1p31.3 duplication, involving NFIA gene coding a transcription factor of NFI family with hypothalamic expression; and one girl with imperforate anus and learning difficulties with rare frameshift variants in AREL1 gene (p.Ser229Aspfs*3) coding an ubiquitin ligase, and TNRC6B gene (p.Gly665Leufs*35) coding a regulator of translational inhibition. In the four familial cases, the genetic defects segregated with CPP in a dominant inheritance mode. Three cases from unrelated families presented growth phenotypes and Xp22.33 deletions, including SHOX gene and other elements. One boy with maternal familial CPP and autism had two rare potentially pathogenic variants: a frameshift deletion in MKKS gene (p.Phe144Leufs*14); and a missense variant (p.Pro267Leu) in UGT2B4 gene. Interestingly, the later gene encodes a protein involved in estrogen hydroxylation and is associated to menarche timing in GWAS. Conclusion: Novel genetic defects were identified in 23% cases of CPP associated with complex phenotypes. Three chromosomal regions represented loci potentially implicated in CPP: Xp22.33, 7q11.23 and 1p31.3. Five genes were identified as candidate genes associated with CPP: NFIA, AREL1, TNRC6B, MKKS and UGT2B4.