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Background: Mendelian disorders are individually rare but collectively common, forming a "long tail" of genetic disease. More than 20 million people worldwide suffer from a disease in this long tail before the age of 25, with minorities and developing countries at highest risk and with the number of carriers far in excess of this figure. Importantly, the Jewish community’s campaign for universal Tay-Sachs screening shows that these incurable diseases can nevertheless be prevented if carrier status is known before conception. A single highly-accurate assay for the long tail of Mendelian disease would allow us to scale this successful campaign up to the general population, thereby improving millions of lives, greatly benefiting minority health, and saving billions of dollars.*Methods and Findings:*We have addressed the need for such an assay by designing the Universal Genetic Test (UNIT), a non-invasive, saliva-based carrier test for more than 100 Mendelian diseases across all major population groups. We exhaustively validated the test with a median of 147 positive and 525 negative samples per variant. By combining probes for risk alleles with family history information, we show that we can achieve extremely high levels of accuracy (median 95% CI [0.99988, 0.]), precision (median 95% CI [0.99993, 0.]), sensitivity (median 95% CI [0.99988, 0.]), and specificity (median 95% CI [0.99643, 1]) at the level of individual mutations. In particular, through a combination of replicated probes and confirmatory testing, we are able to reliably detect rare alleles at q ≈ 1/1000 with positive predictive values above 0.995. To put this in context, this performance for a multiplex assay compares favorably with FDA-approved single-gene carrier tests. Conclusions: The UNIT represents a dramatic reduction in the cost and complexity of large scale population screening. With a single inexpensive assay for a substantial fraction of the global Mendelian disease burden, an end to many preventable genetic diseases is now in sight. Moreover, given that the assay requires only a saliva sample, it is for the first time feasible to contemplate an "at-home carrier test" as a successor to the at-home pregnancy test.*Authors' note:*_Nature Precedings is a preprint server used by scientists to communicate results in advance of the often lengthy publication process. This manuscript is a preprint and has not yet been accepted for publication by a peer-reviewed journal. It is currently undergoing expedited review at a peer-reviewed journal and is posted publicly to allow collegial feedback in advance of publication. Please address technical comments to balajis@stanford.edu_

A Universal Carrier Test for the Long Tail of Mendelian Disease