To the Editor: We thank Drs Sosnay et al.1 for their thoughtful comments. Their commitment to CFTR research continues to add valuable clarity to the clinical and functional consequences of CFTR genetic variation.

We set out to quantitate what we as a genetics community have been aware of for decades: cystic fibrosis carrier screening does not adequately identify reproductive risk among non-European populations. Current “pan-ethnic” carrier screens stipulate as much,2 and yet CFTR is among the most rigorously studied and well-covered disease genes.

New pathogenic variants are currently added to ClinVar on a monthly basis, and affected children continue to be diagnosed with novel variant combinations. Thus, clinically-based pathogenic data sets will always be incomplete. We believe it is our obligation as genetic researchers to acknowledge this complex reality while utilizing the full force of scientific progress to illuminate disease risk in all populations. One crucial step in this direction is the adoption of exome sequencing as the standard for reproductive risk analysis. Exome sequencing provides an opportunity to level the analytic playing field. It eschews the restrictions and population bias inherent in targeted mutation testing. Further, exome sequencing sets the foundation for a sophisticated interpretation of genetic variation and reproductive disease risk.

PolyPhen-2 and PROVEAN are examples of tools that are starting to answer the call for variant interpretation in the absence of clinical data. We champion these efforts to create and improve on existing methods and data sets, which may eventually be used to find clarity in disease potential at stages before diagnosis. We have also developed a publicly accessible resource to assist in this effort.3

In our analysis of CFTR carrier screening, these tools demonstrate important gaps in current approaches to CFTR-related risk. By using them to identify likely disease-contributing variants hidden from current carrier screens, our goal was not to surface variants that should be added to screening panels; instead, we set out to highlight an inherent limitation in the carrier screening framework. These tools, and the innovation they represent, are highly relevant to the development of a more effective response to disease risk identification and management for all patients.

We believe that a combination of tools, incorporated into a dynamic and complex analytic methodology, will be most valuable for determining reproductive risk in novel scenarios. This need has been identified elsewhere, most recently described by Evans et al.4 as an “infrastructure for continuous learning.” As we move together toward a more complete understanding of the human genome, we will achieve better detection of disease risk. However, fulfilling this critical goal also requires new analytic and clinical approaches. We are pursuing improved detection with an alternative methodology that will challenge the way we think about reproductive disease risk.

Disclosure

R.M.L., A.J.S., M.J.S., C.B., B.S., J.L.L., and T.C.P. are currently employees at GenePeeks, Inc. L.M.S. is currently a consultant for GenePeeks, Inc.