OR37-1 A Novel Genetic Cause of Central Precocious Puberty Identified By Whole Exome Sequencing

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR37-Pediatric Endocrinology: HPG Axis Disorders
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:15 AM
Room 102 (Moscone Center)
Andrew Dauber*1, Ana Paula Abreu2, Delanie B. Macedo3, Vinicius N. Brito3, Priscilla Cukier3, Priscila C. Gagliardi4, Sekoni D. Noel5, Rona S. Carroll5, Joel N Hirschhorn6, Ursula B Kaiser5 and Ana Claudia Latronico3
1Division of Endocrinology, Boston Children's Hospital and Program in Medical and Population Genetics, Broad Institute, Boston, MA, 2Brigham and Women's Hospital and Faculdade de Medicina da Universidade de Sao Paulo, 3Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil., 4Nemours Children's Clinic, Jacksonville, FL, 5Brigham and Women's Hospital and Harvard Medical School, Division of Endocrinology/Diabetes, Boston, MA, 6Division of Endocrinology, Boston Children's Hospital and Program in Medical and Population Genetics, Broad Institute, Harvard Medical School, Boston, MA
Currently, the vast majority of cases of central precocious puberty are idiopathic in origin. Familial cases suggest a genetic etiology but to date the only reported genetic abnormalities associated with central precocious puberty are activating mutations in kisspeptin and its receptor in isolated cases. Understanding the genetic basis of central precocious puberty has significant scientific and public health ramifications, as little is known about what factors initiate puberty and timing of menarche is associated with subsequent disease risks (e.g., breast cancer). We performed whole exome sequencing of 40 individuals belonging to 15 distinct kindreds with familial idiopathic central precocious puberty. The index proband in each family had pubertal onset between ages 5 years 6 months and 6 years 3 months.  All had typical clinical and hormonal features of premature activation of the reproductive axis, including early pubertal signs, such as breast development and pubic hair, advanced linear growth and bone age and elevated basal and/or GnRH-stimulated LH levels.  We first analyzed exome sequence data from a total of 15 individuals in the 3 largest families with pedigrees consistent with a dominant mode of inheritance (affected individuals in multiple generations). We identified heterozygous nonsynonymous variants that were present in affected individuals and not present in unaffected family members. Given the rarity of presentation of familial precocious puberty, we excluded all variants with a minor allele frequency > 0.01% in either the 1000 Genomes database or the NHLBI exome variant server. These criteria identified candidate genes within each family (3 for family 1, 4 for family 2, and 65 for family 3). A shared candidate gene was identified in two of the families. Families 2 and 3 had novel frameshift mutation variants in this gene resulting in premature stop codons. We then examined an additional 25 subjects’ exome data from 12 other families and found another novel frameshift mutation in the candidate gene present in two additional families as well as a novel missense variant present in a third family.  The missense variant is predicted to be probably damaging with a Polyphen2 score of 1.0. All variants were confirmed by Sanger sequencing.  In total, we identified 13 individuals (6 males, 7 females) with central precocious puberty who carried the mutations. Additionally, there is a single report in the medical literature of an individual with a microdeletion overlapping this gene who presented with central precocious puberty. Taken together, these findings provide very strong evidence that loss-of-function mutations in this gene lead to familial central precocious puberty. We have identified a novel genetic cause of central precocious puberty. The gene has no prior link to pubertal biology and will provide new insights into the control of pubertal timing.

Nothing to Disclose: AD, APA, DBM, VNB, PC, PCG, SDN, RSC, JNH, UBK, ACL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Drs. Dauber and Metzger contributed equally to this report. Drs. Kaiser and Latronico are co-Senior authors. NIH Grant 1K23HD073351 awared to AD. NIH Grant F05HD072773-01 and CAPES grant # 3806-11-1 to APA.
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