ArticleThe Journal of clinical endocrinology and metabolism2015
Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency.
Abstract read
In one paragraph
Article in The Journal of clinical endocrinology and metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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0cells of the map it votes in
15citing papers in PubMed
3.4field-weighted citation impact, top 8% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
15 citing papers in PubMed, 25 citations in OpenAlex.
- Genetic landscape of a neonatal hypogonadotropic hypogonadism series: Novel variants and phenotypic spectrum.Journal of neuroendocrinology · 2026Article
- The Spectrum of Disease-Associated Alleles in Countries with a Predominantly Slavic Population.International journal of molecular sciences · 2024Review
- High Population Frequency ofJournal of the Endocrine Society · 2024Article
- Applications of genomic research in pediatric endocrine diseases.Clinical and experimental pediatrics · 2023Article
- Gonadotropin-Releasing Hormone Receptor (GnRHR) and Hypogonadotropic Hypogonadism.International journal of molecular sciences · 2023Review
- GNRHR-related central hypogonadism with spontaneous recovery - case report.Italian journal of pediatrics · 2022Article
- From Steroid and Drug Metabolism to Glycobiology, Using Sulfotransferase Structures to Understand and Tailor Function.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
- Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty.European journal of endocrinology · 2021Article
- A pathogenic variant in CHEK2 shows a founder effect in Portuguese Roma patients with thyroid cancer.Endocrine · 2021Article
- A partial loss-of-function variant inTranslational andrology and urology · 2021Article
- Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History.The Journal of clinical endocrinology and metabolism · 2019Article
- Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism.Journal of clinical medicine · 2019Article
- Modeling mutant/wild-type interactions to ascertain pathogenicity of PROKR2 missense variants in patients with isolated GnRH deficiency.Human molecular genetics · 2018Article
- Article
- Mutations in gonadotropin-releasing hormone signaling pathway in two nIHH patients with successful pregnancy outcomes.Reproductive biology and endocrinology : RB&E · 2016Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
18 authors at 5 institutions in 7 countries.
Jin-Ho ChoiHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Ravikumar BalasubramanianHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Phil H LeeHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Natalie D ShawHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Janet E HallHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Lacey PlummerHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Cassandra L BuckHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Marie-Laure KottlerHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Katarzyna JarzabekHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Sławomir WołczynskiHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Richard QuintonHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Ana Claudia LatronicoHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Catherine DodeHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Tsutomu OgataHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Hyung-Goo KimHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Lawrence C LaymanHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
James F GusellaHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
William F CrowleyHarvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Center for Human Genetics · USHarvard University Press · USAugusta University Health · USHamamatsu University · JPUniversité de Caen Normandie · FR
Funding
RAPID GENE DISCOVERYP01GM061354 · NIGMS · BRIGHAM AND WOMEN'S HOSPITAL · PI MORTON, CYNTHIA CASSON · 2001 to 2019
$24.3MThe Genetic Determinants of Human GNRH DeficiencyU54HD028138 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI CROWLEY, WILLIAM FRANCIS · 2000 to 2013
$19.9MTHE NEUROENDOCRINE CONTROL OF REPRODUCTION IN THE HUMANR01HD015788 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI CROWLEY, WILLIAM FRANCIS · 1985 to 2012
$4.6MGenetics of Delayed Puberty.R01HD033004 · NICHD · MEDICAL COLLEGE OF GEORGIA (MCG) · PI LAYMAN, LAWRENCE C · 2003 to 2014
$3.1MBiologic Roles of Novel Axonal Guidance Genes in Isolated GnRH DeficiencyK23HD077043 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI BALASUBRAMANIAN, RAVIKUMAR · 2014 to 2018
$759kGENETICS OF DELAYED PUBERTYR29HD033004 · NICHD · UNIVERSITY OF CHICAGO · PI LAYMAN, LAWRENCE C · 1997 to 2001
$213kNICHD NIH HHS HD33004NICHD NIH HHS K23 HD077043NICHD NIH HHS R01 HD015788NICHD NIH HHS R01 HD033004NICHD NIH HHS R01 HD15788NICHD NIH HHS R29 HD033004NICHD NIH HHS U54 HD028138NICHD NIH HHS U54HD028138NIGMS NIH HHS P01 GM061354PHS HHS K23HDHD077043
Abstract
contextLoss of function (LoF) mutations in more than 20 genes are now known to cause isolated GnRH deficiency (IGD) in humans. Most causal IGD mutations are typically private, ie, limited to a single individual/pedigree. However, somewhat paradoxically, four IGD genes (GNRH1, TAC3, PROKR2, and GNRHR) have been shown to harbor LoF founder mutations that are shared by multiple unrelated individuals. It is not known whether similar founder mutations occur in other IGD genes.
objectiveThe objective of the study was to determine whether shared deleterious mutations in IGD-associated genes represent founder alleles.
settingThis study was an international collaboration among academic medical centers.
methodsIGD patients with shared mutations, defined as those documented in three or more unrelated probands in 14 IGD-associated genes, were identified from various academic institutions, the Human Gene Mutation Database, and literature reports by other international investigators. Haplotypes of single-nucleotide polymorphisms and short tandem repeats surrounding the mutations were constructed to assess genetic ancestry.
resultsA total of eight founder mutations in five genes, GNRHR (Q106R, R262Q, R139H), TACR3 (W275X), PROKR2 (R85H), FGFR1 (R250Q, G687R), and HS6ST1 (R382W) were identified. Most founder alleles were present at low frequency in the general population. The estimated age of these mutant alleles ranged from 1925 to 5600 years and corresponded to the time of rapid human population expansion.
conclusionsWe have expanded the spectrum of founder alleles associated with IGD to a total of eight founder mutations. In contrast to the approximately 9000-year-old PROKR2 founder allele that may confer a heterozygote advantage, the rest of the founder alleles are relatively more recent in origin, in keeping with the timing of recent human population expansion and any selective heterozygote advantage of these alleles requires further evaluation.
Indexed as
MutationAllelesGonadotropin-Releasing HormoneHaplotypesHumansHypothalamic DiseasesNeurokinin BPedigreeReceptors, G-Protein-CoupledReceptors, LHRHReceptors, PeptideGonadotropin-Releasing HormoneNeurokinin BPROKR2 protein, humanReceptors, G-Protein-CoupledReceptors, LHRHReceptors, PeptideTAC3 protein, human
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