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Detection of the founder effect in Finnish CADASIL families
Kati Mykkänen1, Marja-Liisa Savontaus, Vesa Juvonen
1Department of Medical Genetics, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. kati.mykkanen@utu.fi
Insights
A specific NOTCH3 gene mutation (R133C) causing Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Finland suggests a single founder ancestor. This founder mutation likely originated in the late 17th or early 18th century.
Area of Science:
- Genetics
- Neurology
- Medical Research
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic cerebrovascular disorder.
- It is linked to mutations in the NOTCH3 gene, leading to cognitive decline and dementia.
- A specific mutation, R133C, is prevalent in Finnish CADASIL families.
Purpose of the Study:
- To investigate the genetic origins of CADASIL in Finland.
- To determine if the R133C mutation in Finnish families stems from a common ancestor.
- To estimate the age of the founder mutation.
Main Methods:
- Haplotype analysis of 60 patients from 18 Finnish CADASIL families.
- Utilized 10 microsatellite markers to trace common ancestry.
- Age analysis of the founder mutation.
Main Results:
- A shared haplotype linked to the R133C mutation was identified in all 18 Finnish families.
- This indicates that all families with this mutation descend from a single common ancestor.
- The founder mutation is estimated to have been introduced in the late 1600s or early 1700s.
Conclusions:
- The R133C mutation in Finnish CADASIL families represents a founder effect.
- This finding provides insight into the population genetics of CADASIL.
- The study establishes a historical timeline for the mutation's introduction in Finland.
Abstract:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease characterized by brain infarcts, cognitive decline and dementia. The disease is caused by at least 91 missense mutations, four deletions and one splice site mutation in the NOTCH3 gene, which maps to 19p13.1. In 18 out of the 21 Finnish CADASIL families so far identified, the causative mutation is an arginine to cysteine substitution in position 133 (R133C). Most of the families carrying this mutation originate from the western coast of Finland, thus suggesting a founder effect. No previous reports of a founder effect in CADASIL have been published. We haplotyped 60 patients from these 18 families for 10 microsatellite markers in order to determine whether the families descend from a common ancestor. We found a similar haplotype linked to the mutation in all 18 pedigrees, which indicates a single common ancestor for all the Finnish R133C families. The age analysis of the founder mutation places the introduction of the mutation in the late 1600s or early 1700s.
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