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A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans
1Howard Hughes Medical Institute, Yale University, New Haven, Conn. 06510, USA.
Insights
Genetic analysis reveals that nearly all Hispanic Americans with cerebral cavernous malformation (CCM) inherited the same mutation from a common ancestor. This explains both familial and sporadic cases of this brain vascular disease.
Area of Science:
- Genetics
- Neurology
- Vascular Biology
Background:
- Cerebral cavernous malformation (CCM) is a brain vascular disorder.
- CCM can cause headaches, seizures, and hemorrhage.
- Hispanic Americans exhibit higher CCM prevalence, suggesting a shared genetic origin.
Purpose of the Study:
- Investigate the genetic basis of CCM in Hispanic Americans.
- Determine if familial and sporadic CCM cases share a common ancestral mutation.
Main Methods:
- Compared genetic markers and CCM cases in Hispanic-American families.
- Analyzed marker alleles in familial and sporadic CCM patients.
Main Results:
- Confirmed linkage of CCM to chromosome 7 in all familial cases.
- Identified a shared ancestral mutation for CCM in 14 families and 10 sporadic cases.
- Discovered 33 asymptomatic carriers, highlighting variable disease penetrance.
Conclusions:
- The same ancestral mutation accounts for most familial and sporadic CCM cases in Hispanic Americans.
- Understanding CCM origins aids in diagnosing and managing this vascular disease.
Background:
Cerebral cavernous malformation is a vascular disease of the brain causing headaches, seizures, and cerebral hemorrhage. Familial and sporadic cases are recognized, and a gene causing familial disease has been mapped to chromosome 7. Hispanic Americans have a higher prevalence of cavernous malformation than do other ethnic groups, raising the possibility that affected persons in this population have inherited the same mutation from a common ancestor.
Methods:
We compared the segregation of genetic markers and clinical cases of cavernous malformation in Hispanic-American kindreds with familial disease; we also compared the alleles for markers linked to cavernous malformation in patients with familial and sporadic cases.
Results:
All kindreds with familial disease showed linkage of cavernous malformation to a short segment of chromosome 7 (odds supporting linkage, 4X10(10).1). Forty-seven affected members of 14 kindreds shared identical alleles for up to 15 markers linked to the cavernous-malformation gene, demonstrating that they had inherited the same mutation from a common ancestor. Ten patients with sporadic cases also shared these same alleles, indicating that they too had inherited the same mutation. Thirty-three asymptomatic carriers of the disease gene were identified, demonstrating the variability and age dependence of the development of symptoms and explaining the appearance of apparently sporadic cases.
Conclusions:
Virtually all cases of familial and sporadic cavernous malformation among Hispanic Americans of Mexican descent are due to the inheritance of the same mutation from a common ancestor.
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