The nuclear factor I/X (NFIX) gene encodes a ubiquitously expressed transcription factor whose mutations lead to two allelic disorders characterized by developmental, skeletal, and neural abnormalities, namely, Malan syndrome (MAL) and Marshall–Smith syndrome (MSS).NFIXmutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense‐mediated decay (NMD) leading to NFIX haploinsufficiency, whereasNFIXmutations associated with MSS are clustered in exons 6–10 and escape NMD and result in the production of dominant‐negative mutant NFIX proteins. Thus, differentNFIXmutations have distinct consequences onNFIXexpression. To elucidate thein vivoeffects of MSS‐associatedNFIXexon 7 mutations, we used CRISPR‐Cas9 to generate mouse models with exon 7 deletions that comprised: a frameshift deletion of two nucleotides (NfixDel2); in‐frame deletion of 24 nucleotides (NfixDel24); and deletion of 140 nucleotides (NfixDel140).Nfix+/Del2,Nfix+/Del24,Nfix+/Del140,NfixDel24/Del24, andNfixDel140/Del140mice were viable, normal, and fertile, with no skeletal abnormalities, butNfixDel2/Del2mice had significantly reduced viability (p< 0.002) and died at 2–3 weeks of age.NfixDel2 was not cleared by NMD, andNfixDel2/Del2mice, when compared toNfix+/+andNfix+/Del2mice, had: growth retardation; short stature with kyphosis; reduced skull length; marked porosity of the vertebrae with decreased vertebral and femoral bone mineral content; and reduced caudal vertebrae height and femur length. Plasma biochemistry analysis revealedNfixDel2/Del2mice to have increased total alkaline phosphatase activity but decreased C‐terminal telopeptide and procollagen‐type‐1‐N‐terminal propeptide concentrations compared toNfix+/+andNfix+/Del2mice.NfixDel2/Del2mice were also found to have enlarged cerebral cortices and ventricular areas but smaller dentate gyrus compared toNfix+/+mice. Thus,NfixDel2/Del2mice provide a model for studying thein vivoeffects of NFIX mutants that escape NMD and result in developmental abnormalities of the skeletal and neural tissues that are associated with MSS. © 2023 The Authors.JBMR Pluspublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.