Microdeletion 4q21 syndrome has been described in about a dozen patients with deletions ranging from 3.2 to 15.1 MB with similar features including the distinctive facial characteristics of broad forehead, hypertelorism, and prominent front teeth, with severe growth delay, developmental delay, and neonatal hypotonia. A 1.37 MB minimal critical region has been described that accounts for this shared phenotype and includes five known genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1. We report on two new patients found through single nucleotide polymorphism (SNP) microarray testing that expand the reported phenotype. Patient 1 has a novel deletion of 2.0 MB, the smallest reported deletion, which involves only a partial deletion of the minimal critical region, including the genes HNRNPD, HNRPDL, and ENOPH1. She shares much of the typical phenotype including moderate developmental delay, unusual facial features, small hands and feet, but not any growth delay or neonatal hypotonia. This patient allows further genotype–phenotype correlation of the genes in the minimal critical region, and supports that heterozygous loss of PRKG2 leads to the growth delay. Patient 2 has a novel 3.4 MB deletion that includes the entire critical region, and has typical features, but also presented with cleft palate and Pierre Robin sequence, which have not been previously described. A gene reported to be associated with inherited cleft palate, SCD5, is in the deleted region in this patient, which suggests it may be playing a role in palate formation. Taken together, these patients allow for an expansion of the microdeletion 4q21 syndrome and provide candidate genes for particular features of the phenotype. © 2013 Wiley Periodicals, Inc.