Congenital disorders

Goldilocks principle and recessive disease

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22
Sep

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.

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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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  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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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 (2023). https://doi.org/10.1038/s41431-023-01458-x

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  • Received: 31 August 2023

  • Accepted: 04 September 2023

  • Published: 22 September 2023

  • DOI: https://doi.org/10.1038/s41431-023-01458-x

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