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CASP2 biallelic truncating variants: a new case supports the link with lissencephaly/pachygyria and expands the clinical spectrum

European Journal of Human Genetics (2024)Cite this article

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We read with interest the paper recently published by Uctepe et al. [1], presenting seven patients with lissencephaly, neurodevelopmental disorder and biallelic loss-of-function (LOF) variants in the CASP2 gene. Here we describe an additional patient, the first Italian, with pachygyria and neurodevelopmental disorder, carrier of a not previously reported homozygous truncating variant in CASP2. The report of this patient further strengthens the pathogenetic role of CASP2 LOF variants and expands the genotype-phenotype correlation of this newly recognizable syndrome.

CASP2 encodes the Caspase 2 protein, a mediating apoptosis protease, expressed in the human brain, which seems to be involved in the development of the cerebral cortex and cognitive function [1]. The clinical features of our patient almost overlap with the phenotypes reported in patients with LOF biallelic CASP2 variations described to date [1]. For instance, as our patient does, all the patients described present with either cognitive impairment or global developmental delay and the three patients, who underwent brain MRI, show bilateral pachygyria and cortical thickening in the fronto-temporal lobes. On the contrary our patient seems to be the only case with dysmorphic corpus callosum, genitourinary anomalies and severe myopia. To date, no patients described have developed cancer or signs of premature aging, although CASP2 has been described as an oncosuppressor gene [4]. Notably, Dorstyn et al. [5], noted that, in mouse model, loss of caspase-2 leads to defective p53-mediated signaling, decreased trans-activation of p53 target genes upon DNA damage, and that metaphase analyses of casp2−/− mouse fibroblasts, showed an increased aneuploidy rate and decreased telomere length. Caspase 2 is also crucial in regulating necroptosis and autophagy, playing a role as an oncosuppressor [4]. Moreover, caspase-2 knockout mice show signs of premature aging (e.g., bone fragility, reduced body fat and hair growth) and increased risk of developing certain types of tumors [4]. Therefore, although no patient to date has developed signs of premature aging or cancer, we believe and suggest that further international studies, regarding the p53 pathway function, genomic stability including aneuploidy rate and telomere length, should be performed in other patients harboring biallelic CASP2 LOF variants, in order to assess the possible presence of a biological signature of cancer risk and, eventually, to design a preventive clinical management.

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Fig. 1

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The datasets generated and analyzed during the current study which are not shown in the paper are available from the corresponding author on reasonable request.

References

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Acknowledgements

The authors thank the patient and his family for their contribution to this study. This work was also supported by Associazione Malattie Rare “Mauro Baschirotto” OdV, Sezione Umbria.

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Authors and Affiliations

  1. Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara, Ferrara, Italy

    Ilaria Vivaldi

  2. Unit of Medical Genetics, Department Maternal-Infantile, S. Maria della Misericordia Hospital, Perugia, Italy

    Marco Imperi, Maria Giovanna Tedesco, Elisa Vinciarelli & Paolo Prontera

  3. Unit of Medical Genetics, “Mauro Baschirotto” Institute for Rare Diseases-B.I.R.D. Foundation, Vicenza, Italy

    Maria Giovanna Tedesco

  4. Research & Innovation S.R.L. (R&I Genetics), Padova, Italy

    Eleonora Chiarotto & Davide Colavito

  5. Unit of Neurophysiopathology, S. Maria della Misericordia Hospital, Perugia, Italy

    Michela Cecconi & Teresa Anna Cantisani

Authors
  1. Ilaria Vivaldi
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  2. Marco Imperi
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  3. Maria Giovanna Tedesco
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  4. Elisa Vinciarelli
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  7. Michela Cecconi
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  8. Teresa Anna Cantisani
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  9. Paolo Prontera
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Contributions

PP: conceptualization and elaboration of the text, review and editing; IV and PP: writing the manuscript. IV, MI, MGT and PP: clinical evaluation, data analysis, review of the manuscript. MC and TAC: neurological evaluation, Brain MRI interpretation, review of the manuscript. EV, DC and EC: genetic investigation, data analysis, review of the manuscript.

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Correspondence to Paolo Prontera.

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The authors declare no competing interests.

Ethical approval

Ethical approval was not required for the study involving human samples in accordance with the local legislation and institutional requirements because our institution does not require ethical approval for reporting individual cases or case series. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.

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Vivaldi, I., Imperi, M., Tedesco, M.G. et al. CASP2 biallelic truncating variants: a new case supports the link with lissencephaly/pachygyria and expands the clinical spectrum. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01741-5

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