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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, Douglas A. Marchuk
Nature Communications Nov 2023

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.



Solid Tumor

Institution Type


Indication / Modality

Cerebral Cavernous Malformation

Goal of Study

Clinical Profiling

Key Genes


PAD Project


Analytes Assessed

SNV, InDels, LOH

Sample Prep

Nuclei Prep



Proof Point Demonstrated

Co-occurrence, Clonality