ESPE2023 Free Communications Pituitary, neuroendocrinology and puberty 2 (6 abstracts)
Genetic evaluation in children with self-limited pubertal delay discloses new candidate genes
Raissa Rezende 1 , Evan Schafer 2 , Lena Kaisinger 3 , Wen He 2 , Nathalia Andrade 1 , Naiara Dantas 1 , Laurana Cellin 1 , Elisangela Quedas 1 , John Perry 3 , Sasha Howard 4,5 , Ana Claudia Latronico 1 , Yee-Ming Chan 2,6 & Alexander Jorge 1
1Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil. 2Boston Children’s Hospital, Boston, USA. 3University of Cambridge, Cambridge, United Kingdom. 4Queen Mary University of London, London, United Kingdom. 5Royal London Hospital, London, United Kingdom. 6Harvard Medical School, Boston, USA
Introduction: Age at pubertal onset is a markedly inherited trait. The most common cause of pubertal delay, self-limited pubertal delay, is defined by the absence of secondary sexual characteristics after 13 years in girls and 14 years in boys, with progression before age 18. This study aimed to detect novel candidate genes for self-limited pubertal delay.
Methods: Eighty-one patients with confirmed self-limited delayed puberty after retrospective appraisal were evaluated by whole exome sequencing. We prioritized variants with MAF<0.001, classified as loss-of-function (LoF) or missense predicted to be deleterious on in silico analysis. Variants of interest were classified by the ACMG/AMP criteria. Genes previously associated with pubertal delay and/or short stature were assessed first. Candidate genes were chosen according to gene function, protein expression, associated phenotypes, GWAS analysis, constraint scores, and clinical plausibility.
Results: Patients had a mean height-SDS at the onset of puberty of -3.0±0.5 (95% had short stature). They reached an adult height-SDS of -1.4±0.8, below their mid-parental target height (-0.8±0.7 SDS, 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 28 variants of interest in 23 patients, of which 18 were LoF (stopgain=8, frameshift=5, splicing=5) and 10 were missense. We categorized the genes with variants into three groups. The first one was constituted of genes 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, MAP3K4, BAG6, DROSHA), which harbored LoF variants despite a high constraint score (pLI=0.83-1 from gnomAD). Within the third group, INHBB was the major candidate because it encodes the beta B subunit of activin and inhibin and 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 it is unusual compared to previously published cohorts. We hypothesize that carriers of deleterious variants in such genes have their reproductive capacity limited from the perspective of evolutionary genetics.
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