Abstract
Cerebral cavernous malformations (CCM) are vascular malformations consisting of collections of enlarged capillaries occurring in the brain or spinal cord. These vascular malformations can occur sporadically or susceptibility to develop these can be inherited as an autosomal dominant trait due to mutation in one of three genes. Over a decade ago, we described a 77.6 Kb germline deletion spanning exons 2–10 in the CCM2 gene found in multiple affected individuals from seemingly unrelated families. Segregation analysis using linked, microsatellite markers indicated that this deletion may have arisen at least twice independently. In the ensuing decades, many more CCM patients have been identified with this deletion. In this present study we examined 27 reportedly unrelated affected individuals with this deletion. To investigate the origin of the deletion at base pair level resolution, we sequenced approximately 10 Kb upstream and downstream from the recombination junction on the deleted allele. All patients showed the identical SNP haplotype across this combined 20 Kb interval. In parallel, genealogical records have traced 11 of these individuals to five separate pedigrees dating as far back as the 1600-1700s. These haplotype and genealogical data suggest that these families and the remaining “unrelated” samples converge on a common ancestor due to a founder mutation occurring centuries ago on the North American continent. We also note that another gene, NACAD, is included in this deletion. Although patient self-reporting does not indicate an apparent phenotypic consequence for heterozygous deletion of NACAD, further investigation is warranted for these patients.
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Acknowledgements
We thank the patients who participated in both the genealogical and genetic arms of this study, the patient support group, Angioma Alliance, the CCM2 Exon 2-10 Deletion Families Facebook Group, and our funders: NIH P01-NS092521 (DAM). We also thank Dr. Christine Beck (University of Connecticut Health Center and The Jackson Laboratory for Genomic Medicine) for helpful discussions.
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This work was supported by NIH P01-NS092521 (DAM).
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Gallione, C.J., Detter, M.R., Sheline, A. et al. Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations 2 gene. Hum Genet 141, 1761–1769 (2022). https://doi.org/10.1007/s00439-022-02458-5
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DOI: https://doi.org/10.1007/s00439-022-02458-5