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DAG1 haploinsufficiency is associated with sporadic and familial isolated or pauci-symptomatic hyperCKemia

European Journal of Human Genetics volume 32, pages 342–349 (2024)Cite this article

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Abstract

DAG1 encodes for dystroglycan, a key component of the dystrophin-glycoprotein complex (DGC) with a pivotal role in skeletal muscle function and maintenance. Biallelic loss-of-function DAG1 variants cause severe muscular dystrophy and muscle-eye-brain disease. A possible contribution of DAG1 deficiency to milder muscular phenotypes has been suggested. We investigated the genetic background of twelve subjects with persistent mild-to-severe hyperCKemia to dissect the role of DAG1 in this condition. Genetic testing was performed through exome sequencing (ES) or custom NGS panels including various genes involved in a spectrum of muscular disorders. Histopathological and Western blot analyses were performed on muscle biopsy samples obtained from three patients. We identified seven novel heterozygous truncating variants in DAG1 segregating with isolated or pauci-symptomatic hyperCKemia in all families. The variants were rare and predicted to lead to nonsense-mediated mRNA decay or the formation of a truncated transcript. In four cases, DAG1 variants were inherited from similarly affected parents. Histopathological analysis revealed a decreased expression of dystroglycan subunits and Western blot confirmed a significantly reduced expression of beta-dystroglycan in muscle samples. This study supports the pathogenic role of DAG1 haploinsufficiency in isolated or pauci-symptomatic hyperCKemia, with implications for clinical management and genetic counseling.

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Fig. 1: Summary of genetic findings in heterozygous DAG1 patients.
Fig. 2: Immunohistochemical findings in heterozygous DAG1 patients.

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Data availability

All data described in this study are provided within the article and Supplementary Material. Raw sequencing data and de-identified clinical data are available from the corresponding authors upon request.

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Acknowledgements

We would like to thank the patients and their families for their consent and valuable support to our work.

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No specific funding.

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Author notes

  1. These authors contributed equally: Monica Traverso, Serena Baratto.

Authors and Affiliations

  1. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy

    Monica Traverso & Antonio Falace

  2. Centre of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa, Italy

    Serena Baratto, Chiara Panicucci, Sara Casalini & Claudio Bruno

  3. Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy

    Michele Iacomino, Marco Di Duca, Federico Zara & Marcello Scala

  4. IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Marina Grandis

  5. Department of Precision Medicine, University “Luigi Vanvitelli”, Naples, Italy

    Annalaura Torella, Esther Picillo, Maria Elena Onore, Luisa Politano & Vincenzo Nigro

  6. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy

    Annalaura Torella, Esther Picillo, Maria Elena Onore, Luisa Politano & Vincenzo Nigro

  7. Department of Medical Genetics and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    A. Micheil Innes

  8. Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    A. Micheil Innes

  9. IRCCS San Camillo Hospital, Venice, Italy

    Rita Barresi

  10. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy

    Claudio Bruno, Federico Zara, Chiara Fiorillo & Marcello Scala

  11. Child Neuropsychiatry Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy

    Chiara Fiorillo

Authors
  1. Monica Traverso
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  2. Serena Baratto
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  7. Marina Grandis
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  9. Annalaura Torella
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  10. Esther Picillo
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Contributions

Conceptualization: MS. Data curation: MT, SB, MS. Formal analysis: MT, SB, MDD, CP, MI, SC, MG, FZ, RB, AF, AT, EP, LP, VN, MI, CB, CF, MS. Methodology: MT, SB, MS. Writing—original draft: MT, SB, MS. Writing—review & editing: CB, CF, MS. Supervision: FZ and MS.

Corresponding authors

Correspondence to Federico Zara, Chiara Fiorillo or Marcello Scala.

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Competing interests

The authors have no competing interests.

Ethics declaration

This study adheres to the principles in the Declaration of Helsinki. The study was reviewed by IRCCS Istituto Giannina Gaslini Review Board (IRB) (Comitato Etico della Regione Liguria, protocol 163/2018) protocol. Written informed consent was obtained from all participants including consent for publication of photographs as required by the IRB. Consent forms are archived and available upon request.

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Traverso, M., Baratto, S., Iacomino, M. et al. DAG1 haploinsufficiency is associated with sporadic and familial isolated or pauci-symptomatic hyperCKemia. Eur J Hum Genet 32, 342–349 (2024). https://doi.org/10.1038/s41431-023-01516-4

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