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Biallelic variants in genes previously associated with dominant inheritance: CACNA1A, RET and SLC20A2

European Journal of Human Genetics volume 29, pages 1520–1526 (2021)Cite this article

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A Comment to this article was published on 09 September 2021

Abstract

A subset of families with co-dominant or recessive inheritance has been described in several genes previously associated with dominant inheritance. Those recessive families displayed similar, more severe, or even completely different phenotypes to their dominant counterparts. We report the first patients harboring homozygous disease-related variants in three genes that were previously associated with dominant inheritance: a loss-of-function variant in the CACNA1A gene and two missense variants in the RET and SLC20A2 genes, respectively. All patients presented with a more severe clinical phenotype than the corresponding typical dominant form. We suggest that co-dominant or recessive inheritance for these three genes could explain the phenotypic differences from those documented in their cognate dominant phenotypes. Our results reinforce that geneticists should be aware of the possible different forms of inheritance in genes when WES variant interpretation is performed. We also evidence the need to refine phenotypes and inheritance patterns associated with genes in order to avoid failures during WES analysis and thus, raising the WES diagnostic capacity in the benefit of patients.

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Fig. 1: Family 1: CACNA1A gene.
Fig. 2: Family 2: RET gene.
Fig. 3: Family 3: SLC20A2 gene.

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Acknowledgements

The authors would like to thank all the clinical staff from the University Hospital 12 de Octubre, who made this study possible. Grant number PI17/1067 to MIAB from the Spanish “Instituto de Salud Carlos III” (ISCIII). Grant number PI18/01374 to MAM from the Spanish “Instituto de Salud Carlos III” (ISCIII) and European Regional Development Fund (ERDF; FEDER).

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Authors and Affiliations

  1. Genetics Department, University Hospital 12 de Octubre, Madrid, Spain

    A. Arteche-López, MI. Álvarez-Mora, MT. Sánchez Calvin, JM. Lezana Rosales, C. Palma Milla, M. J. Gómez Rodríguez, I. Gomez Manjón, A. Juarez Rufián, P. Ramos Gómez, O. Sierra Tomillo, I. Hidalgo Mayoral, R. Pérez de la Fuente, JF. Quesada-Espinosa & M. Moreno-García

  2. Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona and Fundació Clínic per la Recerca Biomèdica, Barcelona, Spain

    MI. Álvarez-Mora

  3. Mitochondrial and Neurometabolic Diseases Lab. Biochemistry Department, ‘12 de Octubre’ Research Institute (imas12), Madrid, Spain

    A. Blázquez & Miguel A. Martin

  4. Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain

    A. Blázquez & Miguel A. Martin

  5. Neurology Department, University Hospital 12 de Octubre, Madrid, Spain

    IJ. Posada Rodríguez

  6. Pediatrics Department, Immunodeficiency Unit, University Hospital 12 de Octubre, Madrid, Spain

    LI. González Granado

  7. Complutense University School of Medicine. Madrid, Spain and ‘12 de Octubre’ Research Institute (imas12), Madrid, Spain

    LI. González Granado

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  1. A. Arteche-López
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Arteche-López, A., Álvarez-Mora, M., Sánchez Calvin, M. et al. Biallelic variants in genes previously associated with dominant inheritance: CACNA1A, RET and SLC20A2. Eur J Hum Genet 29, 1520–1526 (2021). https://doi.org/10.1038/s41431-021-00919-5

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