Next, we assessed the transcriptome profile by using RNA extracted from whole skin from two individuals in pedigree ED-02. RNA from healthy control skin was obtained from discarded abdominoplasty tissue from plastic surgeons and used as four pooled samples. RNA extraction was performed with the Ambion mirVana miRNA Isolation kit (Invitrogen) according to the manufacturer’s instructions. RNA was amplified with the Illumina TotalPrep RNA Amplification Kit, and subsequent gene-expression profiling was performed with the Illumina array HumanHT-12 v4 Expression BeadChip Kit according to the manufacturer’s instructions. Gene-expression data were then analyzed with GenomeStudio software (Illumina). A prefiltering set was determined for significantly modulated expression (detection p value < 0.01; signal intensity fold change ≥ 2.0) between affected and control skin. A comprehensive functional-enrichment analysis was then performed with (1) the Database for Annotation, Visualization, and Integrated Discovery (v.6.7), based on the Gene Ontology (GO) database (see Web Resources), and (2) the GeneGo Metacore software (Thomson Reuters), a systems-biology analysis tool based on a curated database of human protein-protein and protein-DNA interactions, transcription factors, signaling, and metabolic pathways. Comparison of the affected individuals’ skin with the skin of healthy age- and site-matched control individuals identified 1,457 gene transcripts that were significantly altered: 668 upregulated (≥2-fold change) and 789 downregulated (≤0.5-fold change) transcripts for ED-02 VI-5. For ED-02 VI-3, 1,141 gene transcripts were altered: 466 upregulated and 675 downregulated. Of these changes in gene expression, 359 upregulated and 344 downregulated gene transcripts were common to both affected subjects. Evaluation of the changes in gene expression by functional-enrichment analysis identified several enriched GO pathways, processes, networks, and disease-associated transcripts, some of which are germane to the known functions of GRHL2. The top three upregulated GO pathways were linked to protein-folding maturation, cytoskeleton remodeling, and transcriptional control of lipid biosynthesis (involving genes encoding proopiomelanocortins and mitochondrial enzymes involved in metabolic pathways) (Tables S3–S10). Among the most significantly upregulated GO networks were the signal-transduction pathways and intermediate-filament remodeling (Table S7). Conversely, immune-response signaling; migration-inhibitory-factor-induced cell adhesion, migration, and angiogenesis; and networks of cell-cell and cell-matrix adhesion were downregulated (Table S8).