Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty.
Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis. Few genetic causes of CPP have been identified, with the most common being mutations in the paternally expressed imprinted gene MKRN3.



To identify the genetic etiology of CPP in a large multigenerational family.



Linkage analysis followed by whole-genome sequencing was performed in a family with five female members with nonsyndromic CPP. Detailed phenotyping was performed at the time of initial diagnosis and long-term follow-up, and circulating levels of Delta-like 1 homolog (DLK1) were measured in affected individuals. Expression of DLK1 was measured in mouse hypothalamus and in kisspeptin-secreting neuronal cell lines in vitro.



Endocrine clinic of an academic medical center.



Patients with familial CPP were studied.



A complex defect of DLK1 (∼14-kb deletion and 269-bp duplication) was identified in this family. This deletion included the 5' untranslated region and the first exon of DLK1, including the translational start site. Only family members who inherited the defect from their father have precocious puberty, consistent with the known imprinting of DLK1. The patients did not demonstrate additional features of the imprinted disorder Temple syndrome except for increased fat mass. Serum DLK1 levels were undetectable in all affected individuals. Dlk1 was expressed in mouse hypothalamus and in kisspeptin neuron-derived cell lines.



We identified a genomic defect in DLK1 associated with isolated familial CPP. MKRN3 and DLK1 are both paternally expressed imprinted genes. These findings suggest a role of genomic imprinting in regulating the timing of human puberty.
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
Andrew
A
Dauber
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-093, Brazil.
Marina
M
Cunha-Silva
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-093, Brazil.
Delanie B
DB
Macedo
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-093, Brazil.
Vinicius N
VN
Brito
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Ana Paula
AP
Abreu
Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts 02115.
Stephanie A
SA
Roberts
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-093, Brazil.
Luciana R
LR
Montenegro
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
Melissa
M
Andrew
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
Andrew
A
Kirby
Center for Autoimmune Genomics and Etiology, Division of Biomedical Informatics and Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
Matthew T
MT
Weirauch
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
Guillaume
G
Labilloy
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-093, Brazil.
Danielle S
DS
Bessa
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Rona S
RS
Carroll
Department of Biological Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331.
Dakota C
DC
Jacobs
Department of Biological Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331.
Patrick E
PE
Chappell
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-093, Brazil.
Berenice B
BB
Mendonca
Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138.
David
D
Haig
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Ursula B
UB
Kaiser
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-093, Brazil.
Ana Claudia
AC
Latronico
D044383:Black People; D001938:Brazil; D002135:Calcium-Binding Proteins; D002648:Child; D005260:Female; D017353:Gene Deletion; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics*; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics*; D000072740:Paternal Inheritance / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011629:Puberty, Precocious / Q000188:drug therapy / Q000235:genetics*; D017422:Sequence Analysis, DNA
D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D007987:Gonadotropin-Releasing Hormone