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Goldilocks principle and recessive disease

European Journal of Human Genetics volume 32, pages 143–145 (2024)Cite this article

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Monogenic disease are often understood as being either recessive, when one pathogenic variant is asymptomatic and two variants are required for symptomatic disease, or dominant, when a single variant is sufficient for the disease to be expressed [1]. However, recessive diseases come in many subtle shades. Among these, a Goldilocks-type situation can arise when the presence of two loss-of-function (LoF) variants is prenatal lethal and Mendelian disease can only be observed in heterozygous individuals with a hypomorphic and a LOF variant. This situation is observed for example in thrombocytopenia-absent radius syndrome caused by compound heterozygosity in RBM8A, involving a LoF variant (frequently a chromosomal microdeletion) and a hypomorphic non coding regulatory variant [2]. This kind of transmission is considered unusual and has been linked to a number of specific features in a recent review [1], such as non-association with consanguinity.

However there is more to be said about the consequences of this kind of inheritance, which is probably not as rare as supposed. Consider the example of recessive diseases linked to aminoacyl-tRNA synthetases (AARSs). Aminoacyl-tRNA synthetases pair tRNAs with cognate amino acids based on the genetic code and are thus essential to life. Six of the 17 cytosolic AARSs have been linked to Charcot-Marie-Tooth disease (by assumed gain-of-function mutation with dominant inheritance) and all 17 cytosolic AARSs have been linked to recessively inherited multiorgan syndrome (RIMOS), probably by loss of function [3].

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Fig. 1: Distribution of allelic profiles for aminoacyl-tRNA synthetase-linked recessively inherited multiorgan syndrome (light grey, “Goldilocks” inheritance), enterocyte-related congenital diarrhoea disorders (medium grey, typical inheritance).
Fig. 2: Theorical distribution of clinical phenotype as a function of total protein function.

Notes

  1. Based on a power calculation with α = 0.05, β = 0.2, and underlying proportions of homozygous patients of 3% for the Goldilocks disease and 50% for the control disease.

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Acknowledgements

The authors thank Dr. Audrey ANZIANI-VENTE for help with data collection.

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No specific funding was received for this study.

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  1. APHM, Timone Enfant, Service de pédiatrie multidisciplinaire, Marseille, France

    Alexandre Fabre

  2. Aix Marseille Univ, INSERM, MMG, Marseille, France

    Alexandre Fabre

  3. Green Grow Scientific, Marseille, France

    Paul Guerry

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Correspondence to Alexandre Fabre.

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Distribution of allelic profiles for aminoacyl-tRNA synthetase-linked recessively inherited multiorgan syndrome and congenital diarrhoea disorders according to gene.

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Fabre, A., Guerry, P. Goldilocks principle and recessive disease. Eur J Hum Genet 32, 143–145 (2024). https://doi.org/10.1038/s41431-023-01458-x

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