Author response for "Hypomorphic alleles pose challenges in rare disease genomic variant interpretation"

Under the classical genetic model for Mendelian disorders, one or more rare pathogenic variants within a single locus act separately or in conjunction to cause a disease phenotype. In contrast, complex traits are modeled as the interactions of common or rare variants at multiple sites that when combined push the genetic liability past a threshold whereupon disease manifests. Recent research has blurred the lines between these two models. We direct attention to the role of common variants in Mendelian disease through two case examples. A key assumption of the Mendelian model is that causal variants underlying severe disease are rare due to mutation–selection balance. This applies to pathogenic variants with a clear gain or loss of function and does not speak to those variants that more subtly affect gene function; such variants could lead to quantitative changes in gene function within the established normal range and are not disease causing per se. However, when such variants are paired with pathogenic mutations in trans, the activity of that gene could be reduced beyond the normal range leading to disease. Here, we report two subjects who met clinical criteria for autosomal recessive disorders but whose clinical genetic testing did not reveal a molecular diagnosis. Further research revealed that each patient harbored a variant that ordinarily would not be considered as causal due to its relatively high frequency. Case 1 A patient presented at 9 years of age with hepatic steatosis, elevated transaminases, and low ceruloplasmin, 15–19 mg/dL (normal range 20–40 mg/dL). A liver biopsy and subsequent testing showed a tissue copper level of 367 mcg/g (normal range 20–50 mcg/g), confirming the diagnosis of Wilson's disease. Initial sequencing of the