We selected for our study 15 probands with central precocious puberty and their affected and unaffected family members (Fig. 1; and Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Whole-exome sequencing was performed for 40 members of these families, 32 with central precocious puberty (27 females and 5 males) and 8 with normal pubertal timing (5 females and 3 males). Central precocious puberty was diagnosed on the basis of clinical signs of progressive pubertal development before the age of 8 years in girls and 9 years in boys; pubertal basal luteinizing hormone levels, GnRH-stimulated luteinizing hormone levels, or both; advanced bone age (determined with the use of the Greulich and Pyle method21), and normal results on magnetic resonance imaging of the central nervous system (Table 1, and Table S1 in the Supplementary Appendix). The ancestries of the families with MKRN3 defects were established by means of verbal report to clinical investigators (Table 1). The protocol was approved by the ethics committee of Sao Paulo University. Written informed consent was obtained from all
