Developing a primer for communicating about penetrance, expressivity, and genotype-phenotype correlation of R117H and...

Variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which causes cystic fibrosis, have become increasingly well-characterized in recent decades. However, clinicians remain challenged by CFTR variants that result in variable expressivity and reduced penetrance, including the variant R117H (c.350G>A) and the intron 9 poly-thymidine (poly-T) and poly-thymidine-guanosine (TG) tracts, highlighting a knowledge gap that impacts the delivery of accurate information to patients and families. To address this gap, we developed an educational resource that provides descriptive likelihoods of specific phenotypes that may result from genotypes including R117H and the poly-T and TG tracts. Development of the resource was grounded in an extensive literature review, clinical expertise, and publicly available CFTR variant databases, with feedback incorporated from CF clinicians, genetic counselors, and CF content experts. Genotypes were determined to have very low, low, moderate, high, or very high likelihood of resulting in CF, CFTR-related disorder (CFTR-RD), no symptoms, or the designation of CFTR-related metabolic syndrome/CF-screen positive, inconclusive diagnosis (CRMS/CFSPID) following CF newborn screening. The resource described in this report is intended to help clinicians navigate the uncertainty surrounding potential diagnostic scenarios to present accurate assessments to patients and families, a critical component of CF genetic testing and counseling.