Single-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in Cerebral Cavernous Malformations

Andrew K. Ressler (), Daniel A. Snellings, Romuald Girard, Carol J. Gallione, Rhonda Lightle, Andrew S. Allen, Issam A. Awad and Douglas A. Marchuk ()
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Andrew K. Ressler: Duke University School of Medicine
Daniel A. Snellings: Duke University School of Medicine
Romuald Girard: The University of Chicago Medicine and Biological Sciences
Carol J. Gallione: Duke University School of Medicine
Rhonda Lightle: The University of Chicago Medicine and Biological Sciences
Andrew S. Allen: Duke University
Issam A. Awad: The University of Chicago Medicine and Biological Sciences
Douglas A. Marchuk: Duke University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: Abstract Cerebral Cavernous Malformations (CCMs) are vascular malformations of the central nervous system which can lead to moderate to severe neurological phenotypes in patients. A majority of CCM lesions are driven by a cancer-like three-hit mutational mechanism, including a somatic, activating mutation in the oncogene PIK3CA, as well as biallelic loss-of-function mutations in a CCM gene. However, standard sequencing approaches often fail to yield a full complement of pathogenic mutations in many CCMs. We suggest this reality reflects the limited sensitivity to identify low-frequency variants and the presence of mutations undetectable with bulk short-read sequencing. Here we report a single-nucleus DNA-sequencing approach that leverages the underlying biology of CCMs to identify lesions with somatic loss-of-heterozygosity, a class of such hidden mutations. We identify an alternative genetic mechanism for CCM pathogenesis and establish a method that can be repurposed to investigate the genetic underpinning of other disorders with multiple somatic mutations.

Date: 2023
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DOI: 10.1038/s41467-023-42908-w

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