In this family, we identified one female patient (P85, subject III-D, Fig. 5) who carried a maternally inherited SHANK3 deletion of 67 kb, removing exons 1–8 of the isoform A. In addition, she also carried a 104 kb deletion of NRXN1 at 2p16.3 (exons 3–5 of the Alpha 2 isoform and exons 3–4 of the Alpha 1 isoform) and a 255 kb duplication on chromosome Xp22.31 including the Kallman syndrome gene KAL1. This proband was a member of a multiplex family that illustrates the heterogeneous clinical severity and the presence of multiple hits in the genome of the patients. The gene discussed is SHANK3; the disease is Kallmann syndrome.