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Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify  Necdin  ( Ndn ) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of  Ndn  results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate  15q dupΔNdn  mice with a normalized copy number of  Ndn  by excising its one copy from Dup15q mice using a CRISPR-Cas9 system.  15q dupΔNdn  mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory-inhibitory balance similar to wild type animals. Our study provides an insight into the role of  Ndn  in paternal 15q duplication and a mouse model of paternal Dup15q syndrome.

Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications