{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T23:04:23Z","timestamp":1772579063944,"version":"3.50.1"},"reference-count":38,"publisher":"The Endocrine Society","issue":"2","license":[{"start":{"date-parts":[[2017,11,17]],"date-time":"2017-11-17T00:00:00Z","timestamp":1510876800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["102745"],"award-info":[{"award-number":["102745"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000833","name":"Rosetrees Trust","doi-asserted-by":"publisher","award":["M222"],"award-info":[{"award-number":["M222"]}],"id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/L002671\/1"],"award-info":[{"award-number":["BB\/L002671\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective\/Main Outcome Measures<\/jats:title>\n                  <jats:p>We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design\/Patients<\/jats:title>\n                  <jats:p>We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity\u2013associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+\/\u2212 mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+\/\u2212 mice displayed a significantly delayed timing of pubertal onset (P &amp;lt; 0.05).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/jc.2017-02147","type":"journal-article","created":{"date-parts":[[2017,11,16]],"date-time":"2017-11-16T19:01:40Z","timestamp":1510858900000},"page":"649-659","source":"Crossref","is-referenced-by-count":35,"title":["Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty"],"prefix":"10.1210","volume":"103","author":[{"given":"Sasha R","family":"Howard","sequence":"first","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonardo","family":"Guasti","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariel","family":"Poliandri","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"David","sequence":"additional","affiliation":[{"name":"Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia P","family":"Cabrera","sequence":"additional","affiliation":[{"name":"Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"},{"name":"National Institute for Health Research Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R","family":"Barnes","sequence":"additional","affiliation":[{"name":"Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"},{"name":"National Institute for Health Research Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karoliina","family":"Wehkalampi","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"O\u2019Rahilly","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine E","family":"Aiken","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom"},{"name":"National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony P","family":"Coll","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcella","family":"Ma","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debra","family":"Rimmington","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-MRC Institute of 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