Challenging the dogma of the healthy heterozygote: Implications for newborn screening policies and practices

Philip M. Farrell, Elinor Langfelder-Schwind, Michael H. Farrell

Research output: Contribution to journalReview articlepeer-review

14 Scopus citations


Heterozygous (carrier) status for an autosomal recessive condition is traditionally considered to lack significance for an individual's health, but this assumption has been challenged by a growing body of evidence. Carriers of several autosomal recessive disorders and some X-linked diseases are potentially at risk for the pathology manifest in homozygotes. This minireview provides an overview of the literature regarding health risks to carriers of two common autosomal recessive conditions on the Recommended Uniform Screening Panel: sickle cell disease [sickle cell trait (SCT)] and cystic fibrosis (CF). We also consider and comment on bioethical and policy implications for newborn blood screening (NBS). Health risks for heterozygotes, while relatively low for individuals, are often influenced by intrinsic (e.g., other genomic variants or co-morbidities) and extrinsic (environmental) factors, which present opportunities for personalized genomic medicine and risk counseling. They create a special challenge, however, for developing screening/follow-up policies and for genetic counseling, particularly after identification and reporting of heterozygote status through NBS. Although more research is needed, this minireview of the SCT and CF literature to date leads us to propose that blanket terms such as “healthy heterozygotes” or “unaffected carriers” should be superseded in communications about NBS results, in favor of a more nuanced paradigm of setting expectations for health outcomes with “genotype-to-risk.” In the molecular era of NBS, it remains clear that public health needs to become better prepared for the full range of applied genetics.

Original languageEnglish (US)
Pages (from-to)8-19
Number of pages12
JournalMolecular Genetics and Metabolism
Issue number1-2
Early online dateAug 21 2021
StatePublished - Sep 7 2021

Bibliographical note

Funding Information:
We thank Michael Welsh (University of Iowa) for inspiration, guidance, and encouragement; William Gahl (National Institutes of Health) for sharing valuable perspectives and information on genetic disorders potentially affecting carriers; Philip Polgreen (University of Iowa) for assistance with literature searches and interpretation of complex articles; Carlo Castellani (IRCCS Istituto Giannina Gaslini, Genoa ITALY) for reviewing our manuscript critically and suggesting revisions; Gregory Rice (University of Wisconsin) for help identifying autosomal recessive metabolic disorders with heterozygote manifestations; Joseph Farrell (University of Iowa) for literature and advice on interpreting Mendel's experiments; David Allen (University of Wisconsin) and Kyriakie Sarafoglou (University of Minnesota) for recommending and clarifying reports on congenital adrenal hyperplasia; Karen Raraigh (Johns Hopkins University) Amy Gaviglio (Centers for Disease Control and Prevention) and Sumedha Ghate (HSHS St. Vincent Hospital, Green Bay) for information and advice regarding heterozygote manifestations and counseling options as well as editorial review and revisions by Sumedha Ghate; and Mia Schiff (Icahn School of Medicine at Mount Sinai) who provided assistance with the literature search on heterozygotes with disease manifestations for Table 1. Philip Farrell gratefully acknowledges the support of The Legacy of Angels Foundation.

Publisher Copyright:
© 2021 Elsevier Inc.


  • Autosomal recessive
  • Carrier
  • Cystic fibrosis
  • Heterozygote
  • Sickle cell trait

PubMed: MeSH publication types

  • Review
  • Journal Article


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