Improving Genetic Diagnostic Yield in Familial and Sporadic Cerebral Cavernous Malformations
Abstract number :
2.036
Submission category :
12. Genetics / 12A. Human Studies
Year :
2024
Submission ID :
664
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Michael Hildebrand, PhD – University of Melbourne
Neblina Sikta, BCS – University of Melbourne
Samuel Gooley, MBBS – University of Melbourne
Timothy Green, BSc(Hons) – University of Melbourne
Olivia Hoeper, BSc(Hons) – University of Melbourne
Tom Witkowski, BSc(Hons) – University of Melbourne
Caitlin Bennett, BSc(Hons) – University of Melbourne
David Francis, MS – Victorian Clinical Genetics Services
Kevin Mao, BBiomed Sci – University of Melbourne
Mohammed Awad, MBBS – The Royal Melbourne Hospital
Samuel Roberts-Thomson, MBBS – The Royal Melbourne Hospital
Kristian Bulluss, MBBS – St Vincent's Hospital Melbourne
Jonathan Clark, MBBS – Austin Health
Melanie Bahlo, PhD – The Walter and Eliza Hall Institute of Medical Research
Ingrid Scheffer, MBBS, PhD, FRACP, FRS – University of Melbourne, Austin Hospital and Royal Children's Hospital, Florey and Murdoch Children’s Research Institutes
Piero Perucca, MD PhD – Univeristy of Melbourne
Mark Bennett, PhD – The Walter and Eliza Hall Institute of Medical Research
Samuel Berkovic, MD, FRS – University of Melbourne
Rationale: Cerebral cavernous malformations (CCMs) are vascular lesions in the brain associated with risk of haemorrhages and seizures. While the majority are sporadic and driven by somatic pathogenic variants in PIK3CA and MAP3K3, around 20% are familial cases with germline pathogenic variants in one of three CCM (1/2/3) genes.
Methods: We performed deep phenotyping and genetic analysis of nine multiplex families and ten sporadic individuals with CCM.
Results: We solved all 9 multiplex families identifying germline variants in CCM1 (KRIT1) and CCM2. Of these, one-third (n=3/9) were single or multiple exon deletions or splice site variants, all in KRIT1. In four of these families, we identified second hit somatic PIK3CA variants in two-thirds (n=4/6) of family members tested. Most familial cases had multiple supra- and infra-tentorial CCMs and were more likely to have symptomatic intracerebral haemorrhages. In a high proportion (n=8/10) of sporadic individuals we detected somatic CCM2, PIK3CA or MAP3K3 variants. The sporadic cases all presented with seizures and had a single lesion, which was in the temporal lobe in 8/10 individuals.
Conclusions: All familial cases were solved because we screened for small copy number changes or deep non-coding variants undetectable on standard clinical genetic testing. We expanded on the recently described phenomenon of second hit somatic variants in the CCM tissue of some familial cases. We found a somatic variant in 80% of sporadic cases. Genetic diagnosis provides potential eligibility for precision medicine therapies to treat rapidly growing CCMs, such as the clinically approved mTOR pathway inhibitor Sirolimus.
Funding: National Health and Medical Research Council of Australia
Medical Research Future Fund of Australia
Genetics