The frequent BRCA1 mutation 1135insA has multiple origins: a haplotype study in different populations.
BACKGROUND
Analysis of the chromosomal background upon which a mutation occurs can be used to reconstruct the origins of specific disease-causing mutations. The relatively common BRCA1 mutation, 1135insA, has been previously identified as a Norwegian founder mutation. We performed haplotype analysis of individuals from breast and ovarian cancer families from four different ethnic backgrounds who had been identified as carriers of the BRCA1: 1135insA mutation.


METHODS
Four microsatellite markers (D17S855, D17S1322, D17S1323 and D17S1325) located within or near the BRCA1 gene were genotyped in mutation carriers from 6 families of French Canadian, Italian and Dutch descent. Haplotypes were inferred from the genotype data and compared between these families and with the previously reported Norwegian founder haplotype.


RESULTS
The 1135insA mutation was found to occur on three distinct haplotype backgrounds. The families from Norway shared a distinct haplotype while the families of French Canadian, Italian, and Dutch descent were found to occur on one of two additional, distinct backgrounds.


CONCLUSIONS
Our results indicate that while the Norwegian haplotype including 1135insA represents an ancient Norwegian mutation, the same mutation has occurred independently in the other populations examined. In centres where targeted mutation testing is performed, exclusively or prior to gene sequencing, our findings suggest that this recurring mutation should be included in targeted mutation panels, irrespective of the ethnic origin of the persons tested.
Rudkin
Teresa M
TM
Department of Human Genetics, McGill University, Montreal, Canada. teresa@mrs.mni.mcgill.ca
Hamel
Nancy
N
Galvez
Maria
M
Hogervorst
Frans
F
Gille
Johan J P
JJ
Møller
Pål
P
Apold
Jaran
J
Foulkes
William D
WD
D001943:Breast Neoplasms / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics; D002170:Canada; D003718:Denmark; D005192:Family Health; D005260:Female; D018703:Founder Effect; D019398:Genes, BRCA1; D006239:Haplotypes; D006801:Humans; D007558:Italy; D017720:Molecular Epidemiology; D009154:Mutation; D009664:Norway; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics