Abstract A major challenge in the field of genomic precision medicine is the observation that genotype does not always predict phenotype in Mendelian disorders. This phenotype variation is thought to be caused in part by common variants and variants with subtle effects, but the potential deterministic roles of such modifier alleles have not been rigorously or systematically studied in clinical settings. Toward the long-term goal of deciphering the genetic basis of incomplete penetrance and variable expressivity in human monogenic diseases, this proposal aims to study patients with recurrent genomic disorders in whom identical genomic rearrangements manifest disease phenotypes in an incompletely penetrant manner. The overall objective of this proposed project is to formulate a generalizable approach using cohorts of patients with recurrent large genomic deletions that can identify and characterize clinically significant disease-modifying variants. The central hypothesis is that patients with recurrent large genomic deletions offer an effective genomic background to identify disease-modifying alleles that serve as reliable predictors of disease outcome in individual patients. This central hypothesis will be tested by defining the genetic determinants of specific phenotype presentations at two genomic loci: early onset diabetes at 17q12 and abnormal head size at 1q21.1. Large-scale patient resources will be gathered based on molecular information made available by clinical diagnostics. Recruited patients will be analyzed at the molecular level by whole genome sequencing. Phenotype–genotype correlation analysis will be performed to identify candidate modifier alleles under different disease-modifying models based on preliminary data from each disease locus. Functional validation of selected disease-modifying alleles will be performed using patient- derived induced pluripotent stem cells. The innovation of this study lies in the assembly of rare personal genomes with identical copy number variants from clinical diagnostic databases to enable a human subject “enhancer screen.” The proposed research is significant because it is expected to identify clinically important alleles in recurrent deletion loci whose presence or absence can be used for precise diagnosis, counseling and management for patients with genetic disorders. The research strategy utilized herein could be generalized to other phenotypes or genomic loci, and the general mechanisms discovered will be directly applicable to understanding incomplete penetrance and variable expressivity in human diseases.