We then examined exome data from the additional 25 members of the other 12 families in the study and found another novel frameshift mutation in MKRN3 (p.Ala162Glyfs*14) in Families D and E. A novel missense variant (p.Arg365Ser) was identified in Family C (Fig. 1 and 2). This missense variant is predicted to be “probably damaging” (likely to disrupt protein function) on the basis of a Polymorphism Phenotyping, version 2 (PolyPhen2), score of 1.0 and a Protein Analysis through Evolutionary Relationship (PANTHER) score of 0.95 for the probability of being deleterious. (The range for both scores is 0 to 1.0, with 0 indicating that a change is predicted to be neutral and 1.0 indicating that it is most likely to be deleterious.) We confirmed all variants with the use of Sanger sequencing and tested for cosegregation between the variant and central 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
