Familial hypercholesterolemia (FH) remains underdiagnosed despite widespread cholesterol screening. Exome sequencing and electronic health record (EHR) data of 50,726 individuals were used to assess the prevalence and clinical impact of FH-associated genomic variants in the Geisinger Health System. The estimated FH prevalence was 1:256 in unselected participants and 1:118 in participants ascertained via the cardiac catheterization laboratory. FH variant carriers had significantly increased risk of coronary artery disease. Only 24% of carriers met EHR-based presequencing criteria for probable or definite FH diagnosis. Active statin use was identified in 58% of carriers; 46% of statin-treated carriers had a low-density lipoprotein cholesterol level below 100 mg/dl. Thus, we find that genomic screening can prompt the diagnosis of FH patients, most of whom are receiving inadequate lipid-lowering therapy.

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Key Points Question Can population-level genomic screening identify those at risk for disease? Findings In this cross-sectional study of an unselected population cohort of 50 726 adults who underwent exome sequencing, pathogenic and likely pathogenic BRCA1 and BRCA2 variants were found in a higher proportion of patients than was previously reported. Meaning Current methods to identify BRCA1/2 variant carriers may not be sufficient as a screening tool; population genomic screening for hereditary breast and ovarian cancer may better identify patients at high risk and provide an intervention opportunity to reduce mortality and morbidity.

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.