Response to Biesecker et al.

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To the Editor: We read with interest the perspective by Biesecker et al. proposing a dyadic approach to the naming of Mendelian disorders.¹ We share the authors’ consternation regarding challenges inherent in naming of diagnostic entities in clinical genomics, especially given the recent explosion of new conditions. Progress has been made on standardizing the use of gene symbols² and the assessment of likelihood of variant pathogenicity;³ however, the genetics community has yet to reach consensus on an approach to naming of genetic disorders.

Biesecker et al. stated that naming of Mendelian conditions needs to “accurately reflect biologic reality while supporting clinicians in the diagnosis and treatment of genetic disorders” and proposed that the disease name be a dyad that includes molecular etiology (a gene symbol) and phenotype name (e.g., CFTR-related cystic fibrosis).¹ While seemingly a logical approach, it raises several potential issues.⁴

First, variants cause disease, not genes.⁵ The dyadic approach implies that the gene itself, rather than a pathogenic variant in a gene, is responsible for causing disease. While this distinction is usually apparent to geneticists, it is often confusing to other care providers, families, and the general public.

Second, our understanding of molecular etiology of Mendelian conditions is not static. Current etiologic focus is on pathogenic variants in causative genes; the future is likely to include regulatory noncoding variant information, genetic modifiers, combinations of coding and noncoding variation at a locus (i.e., compound inheritance),⁶ and the environment. Other factors (e.g., diet, drugs, other genes) have already been documented to alter Mendelian phenotypes; improved understanding of factors that contribute to variable expressivity of phenotypes is expected in the future. Allowing flexibility in disease naming recognizes that knowledge regarding molecular etiology and complexity will continue to evolve.

Third, the genetic underpinnings of susceptibility to, or cause of, disease is changing. Although Mendelian disease traits are predominantly single-gene disorders, the role for tissue mosaicism, multi-locus pathogenic variation, complex genomic changes such as structural variants, and mutational burden are becoming better appreciated.^7,8 The dyadic approach could confuse rather than illuminate the genomics and complicate management, treatment, and recurrence risk implications.

Fourth, the dyadic approach increases disease name complexity. For historical perspective and heuristic illustrative purposes, for over 25 years, one form of “cataloging” Mendelian conditions (i.e., Online Mendelian Inheritance in Man [OMIM], see web resources) has split phenotypes by their molecular basis (e.g., Noonan syndrome 1–13) and organized similar phenotypes caused by different genes into phenotypic series. Using the dyadic approach, Noonan syndrome 10 would become LZTR1-related-Noonan syndrome, cumbersome terminology for most clinicians and families. While clinicians and scientists who are deeply embedded in a group of genes or disorders might find it easy to remember gene symbols, other clinicians and families who live with these phenotypes will most likely find it easier to remember a disease name and number; moreover, all stakeholders have ready internet access to a clinical knowledgebase that connects diseases and genes. Adding a potentially unstable gene symbol provides no other information to most clinicians and researchers and risks compromise of the cadence of clinical and scientific dialog.

Fifth, the dyadic approach is distinctly different from disease naming in other branches of medicine. Names of most medical conditions do not include etiology as part of their nomenclature, partly because etiology is often unknown at clinical presentation when differential diagnoses are generated. Naming genetic conditions in a manner distinct from that used for nongenetic diseases could separate Mendelian disorders from the rest of the medical community, which could hinder both diagnosis and timely delivery of appropriate patient care and could appear to endorse a form of “genetic exceptionalism.” Further, not all patients will receive a molecular diagnosis; sometimes molecular testing cannot be performed or does not identify a pathogenic variant in an established causative gene. Even the example given by Biesecker et al.—“CFTR-related cystic fibrosis”—will not prove demonstrable in patients diagnosed solely on the basis of phenotypic features and sweat chloride testing; disease-causing variants in CFTR might not always be documented.⁹

Sixth, adoption of the dyadic approach could create dismay for some families; identification of a molecular diagnosis might lead to an apparent diagnostic “change,” presenting undue challenges for families who found a supportive community on the basis of phenotype name. Indeed, using a dyadic approach for naming conditions that might change over time or demonstrate incomplete penetrance might create uncertainty among families affected by these diagnoses and their primary care providers.

Thus, it appears that the dyadic approach fails at both goals set by Biesecker et al.—to reflect biologic reality and to support clinicians in the diagnosis and treatment of genetic disorders. The dyadic approach does not reflect biologic reality given that knowledge about molecular etiology continues to evolve. A naming system needs to retain flexibility so future advances can be readily incorporated. Names using the dyadic approach are more complex not only for clinicians but also for the families they serve. The dyadic approach also alienates Mendelian disorders from the rest of medical practice by naming them differently. We suggest the dyadic approach is conceptually flawed, increases complexity, and could obfuscate clinical reality and hinder worldwide sharing of knowledge about Mendelian disorders. We look forward to working with our colleagues in the genetics community to reach consensus on a naming approach.

Web resources

• OMIM, https://www.omim.org