IMPE2023 Free Communications Puberty and Pituitary (4 abstracts)
Several new candidate genes for self-limited delayed puberty revealed by whole exome sequencing
Raissa Rezende 1 , Evan Schafer 2 , Lena Kaisinger 3 , Naiara Dantas 1 , Nathalia Andrade 1 , Laurana Cellin 1 , Elisangela Quedas 1 , Wen He 2 , John Perry 3,4 , Ana Claudia Latronico Xavier 1,5, , Sasha Howard 6,7 , Yee-Ming Chan 2,8 & Alexander Jorge 1,5
1Unidade de Endocrinologia Genetica (LIM25), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Sao Paulo, Brazil. 2Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, Boston, USA. 3MRC Epidemiology Unit, Wellcome–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom. 4Metabolic Research Laboratory, Wellcome–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom. 5Unidade de Endocrinologia do Desenvolvimento (LIM42), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Sao Paulo, Brazil. 6Centre for Endocrinology, William Harvey Research Institute, Barts and the London FMD, Queen Mary, University of London, London, United Kingdom. 7Department of Paediatric Endocrinology, Royal London Hospital, Barts Health NHS Trust, London, United Kingdom. 8Department of Pediatrics, Harvard Medical School, Boston, USA.
Introduction: Self-limited delayed puberty is defined as the absence of pubertal signs by 13 years in girls and 14 years in boys, but with normal pubertal development starting before 18 years of age. This condition is known for its strong heritability. This study aimed to identify new candidate genes for pubertal delay.
Methods: Fifty-six patients with confirmed self-limited delayed puberty after retrospective evaluation were assessed by whole exome sequencing. We prioritized rare variants (MAF<0.001), classified as loss-of-function (LoF) or missense predicted to be deleterious on in silico analysis. All variants were categorized according to ACMG/AMP criteria. Initially, we analyzed genes previously associated with pubertal delay and/or short stature. We then selected novel candidate genes based on gene function, protein expression, associated phenotypes, GWAS analysis, constraint scores, and clinical plausibility.
Results: Patients had a median height-SDS at the onset of puberty of -2.8±0.6 (95% had short stature). They reached an adult height-SDS of -1.9±0.9, below their midparental target height (-1.4±0.7SDS, P<0.001) and 40% remained short in adult life. The frequency of a positive family history of pubertal delay was 61%, and 30% of parents had height SDS<-2. We found 25 variants of interest in 21 patients, of which 15 were loss-of-function (LoF; stopgain=6, frameshift=5, splicing=4) and 10 were missense. We sorted the genes with variants into three groups. The first group was composed of genes previously associated with pubertal delay (MC3R, LGR4, CCDC141, GHSR), and all variants were of uncertain significance. The second group comprised genes related to phenotypes that explained short stature but not delayed puberty (GDF5, ANKRD11, TYMP, KMT2C, NPR2, SHOX, BRAF). The third group consisted of candidate genes (INHBB, CDK13, CDK16, STXBP5L, OLIG3, TAOK3, TLN1, MYO18A, TMEM108, TRERF1), which harbored LoF variants despite a high constraint score (gnomAD pLI=0.83-1). Within the third group, we elected the INHBB gene as a major candidate because it encodes the beta B subunit of both activin and inhibin and additionally was previously linked to late voice-breaking in males in GWAS. In further analysis, we found 5 female carriers of LoF INHBB variants in the UKBiobank and a nominal association with later age at menarche (P=0.01).
Conclusions: The high frequency of LoF variants in constrained genes drew attention because is unusual compared to previous published cohorts of pubertal delay or idiopathic short stature. Further evaluation with functional analysis is needed to determine whether these variants are indeed causal.
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