Our study combined high-quality genome sequencing and RNA-seq data for a 17 member, three-generation family, enabling us to investigate the role and interpretability of rare noncoding variants. In contrast to low-pass approaches, high-quality full-coverage genome sequencing and patterns of Mendelian segregation provided the ability to more confidently identify and genotype rare variants within the family. More importantly, the large number of children provided us with the ability to detect eQTLs caused by rare variants specific to the family. In contrast, the power of a design that includes many small families or trios would be reduced by the overall heterogeneity of causal rare variants in each family. A further advantage is that with matched cell type and population, we were able to compare family eQTLs to population eQTLs reported by the Geuvadis Consortium.18 We identified genes that exhibit larger eQTL effect sizes in the family than in the population and demonstrated that these family-specific eQTLs are enriched with rare regulatory variants, influence more evolutionarily constrained and central genes, and are potential contributors to risk of complex disease.