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The pathogenesis of most human diseases, and the consequence of mutation of 80 percent of human genes, is unknown. By developing and implementing robust exome sequencing, Lifton has provided evidence that loss of nearly every gene will have large effect on the risk of specific traits. These findings expand the scope of human genetics, provide insight into pathophysiology, and define new targets for risk determination, prevention, and therapy.

The prevention and treatment of human disease rests upon understanding disease mechanisms. Despite extensive efforts, the pathogenesis of most diseases remains poorly understood. Genomic approaches provide a means to establish causal relationships between genotypes and phenotypes by enabling the determination of the mechanisms that link them and identifying new targets for prevention, treatment, and diagnosis. The Mendelian era identified the consequence of mutation of only 3,000 of the 20,000 human genes. The conservation of human genes among vertebrates suggests the vast majority of the remainder will have large effects when mutated.

To explore this possibility, Lifton developed rapid and inexpensive exome sequencing and new analytic approaches, enabling large-scale discovery of rare mutations with large effects on human traits. His lab has identified hundreds of new disease genes causing known or previously undescribed diseases. These include de novo mutation of large numbers of genes that cause congenital diseases, including malformations of the heart, the fusion of skull bones that prevent normal brain growth (craniosynostosis), and autism. Unexpectedly, mutations in chromatin modifiers are major contributors to both congenital heart disease and autism, explaining the frequent co-occurrence of these traits.

The lab has also developed methods to identify genes with incomplete penetrance, including new telomere maintenance genes for pulmonary fibrosis (e.g., PARN) that require inhalational exposure for disease expression; and rare mutations in SMAD6 that have low penetrance for craniosynostosis without the presence of a common BMP2 risk allele.

Similarly, the lab has been able to dissect a number of previously unsolved problems, including mutations that cause a variety of primary cancers and determinants of metastatic disease; and single mutations that cause hormone-producing tumors and diverse skin diseases.

In the case of hypertension, the most frequent global cause of death, Lifton has shown that mutations that cause extremely high or low blood pressure act by modulating renal salt reabsorption, providing the scientific basis for global efforts to reduce cardiovascular mortality by altering salt balance. Recent studies have shown that adrenal tumors that constitutively produce aldosterone—a common cause of severe hypertension—arise from single somatic mutations in a potassium ion channel that causes cell proliferation and hormone production. Chemical screens have identified macrolides that selectively inhibit mutant channels, providing new opportunities for the diagnosis and treatment of these tumors. Genetic studies also identified a new physiologic pathway regulating the balance between salt reabsorption and potassium ion secretion. Biochemical studies have revealed the mechanisms that regulate this balance, which explains how increased dietary potassium lowers blood pressure.

These results collectively demonstrate a path to determine the consequence of mutation of every gene in the human genome, showing that much more genomic discovery lies ahead than behind.