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Carriers of autosomal recessive conditions: are they really ‘unaffected?’
  1. Amber Hames1,
  2. Sophia Khan2,
  3. Clara Gilliland3,
  4. Lucy Goldman2,
  5. Hillary WH Lo1,
  6. Kevin Magda2,4,
  7. Justine Keathley2
  1. 1 Department of Family Relations and Applied Nutrition, University of Guelph, Guelph, Southwestern Ontario, Canada
  2. 2 Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Southwestern Ontario, Canada
  3. 3 Department of Food Science, University of Guelph, Guelph, Southwestern Ontario, Canada
  4. 4 Department of Biomedical Sciences, University of Guelph, Guelph, Southwestern Ontario, Canada
  1. Correspondence to Dr Justine Keathley, HHNS, University of Guelph, Guelph, Southwestern Ontario, Canada; jkeathle{at}


Mendel’s Law of Dominance suggests that recessive disease expression requires the inheritance of two mutated alleles as the dominant, wildtype allele suppresses disease presentation leading to the expression of physiological normal phenotypes. However, there is existing evidence that challenges this school of thought. Here, we summarise existing literature evaluating metabolic and health impacts among carriers of autosomal recessive conditions, focusing on phenylketonuria (PKU), classical homocystinuria, galactosemia and Usher syndrome as examples. Our findings suggest that carriers, often described as ‘unaffected’, may actually display attenuated symptoms for the recessive disease they are carrying. For instance, PKU is an inborn error of metabolism characterised by the build-up of plasma phenylalanine attributed to the deficiency of the phenylalanine hydroxylase (PAH) enzyme. While less severe, PKU carriers also exhibit this impaired enzymatic activity, leading to elevated plasma phenylalanine levels, especially after phenylalanine consumption. Related to these metabolic alterations in the PAH pathway, there is early evidence to suggest that PKU carriers may have compromised cognitive and mental health outcomes. Overall, research on the health and metabolic impacts of PKU carriers is sparse, with most studies conducted several decades ago. However, early evidence suggests that intermediate phenotypes among carriers of autosomal recessive conditions are plausible. The illustrated possible intermediate phenotypes observed among carriers necessitates future research to determine possible clinical implications among this population.

  • genetic diseases, inborn
  • genetic carrier screening
  • genetic heterogeneity
  • genetics
  • inborn genetic diseases

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  • Contributors AH, SK, KM, CG, LG, HWHL and JK contributed to literature searching, writing and revising the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.