precocious puberty in an additional 8 members from Families A through E who did not undergo exome sequencing. MKRN3 is an imprinted gene that is expressed only from the paternal allele.27 All affected family members inherited their mutations from their fathers, indicating perfect segregation in accordance with the imprinted mode of inheritance. The one heterozygous carrier known to have inherited his mutation from his mother (Patient II-1 in Family A) was unaffected, as expected. The remaining 10 families did not have any detectable rare coding variants in MKRN3. The prevalence of truncating variants (4 variants, 3 of which were unique, in 15 families) is much greater than that seen in population-based databases (5 variants, 4 unique, in approximately 6500 persons in the exome variant server) (P<5.0×10−8 for the prevalence of all variants, and P<2.6×10−6 for the prevalence of unique variants). Furthermore, the segregation with precocious puberty in the precise manner predicted for this imprinted gene provides additional strong and independent evidence that the MKRN3 frameshift mutations identified lead to precocious puberty in these families.
