High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families.
Lynch syndrome is one of the most common autosomal dominantly inherited cancer syndromes. Mutations in MLH1, MSH2, MSH6, and PMS2 account for greater than 98% of reported mutations in Lynch syndrome families. It has been reported that large genomic deletions in MLH1 and MSH2 are a frequent cause of Lynch syndrome in certain populations. Using a multimodal approach, we have identified mutations in MLH1, MSH2, and MSH6 in French Canadian families fulfilling the Amsterdam criteria for Lynch syndrome and who displayed abnormal staining for at least one of the Lynch syndrome proteins. Mutations were identified in 28 of our 29 French Canadian probands (97%). A total of 18 distinct mutations (nine in MLH1, seven in MSH2, two in MSH6) were identified, of which six (33%) were genomic exon deletions. Another four (22%) resulted in exon deletions in cDNA alone. Three (17%) are novel mutations. Five of these 18 mutations were detected in more than one distinct family (four in MLH1, one in MSH2) and haplotype analysis suggests the possibility of founder effects. Fifteen of the 29 (52%) families carried one of these five putative founder mutations. These findings may simplify genetic testing for Lynch syndrome in French Canadians.
Chong
George
G
Departments of Medical Genetics and Oncology, Cancer Prevention Centre, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
Jarry
Jonathan
J
Marcus
Victoria
V
Thiffault
Isabelle
I
Winocour
Sebastian
S
Monczak
Yury
Y
Drouin
Régen
R
Latreille
Jean
J
Australie
Karlene
K
Bapat
Bharati
B
Gordon
Philip H
PH
Giguère
Yves
Y
Gologan
Adrian
A
Galiatsatos
Polymnia
P
Jass
Jeremy R
JR
Wong
Nora
N
Zaor
Sonya
S
Palma
Laura
L
Kasprzak
Lidia
L
Tischkowitz
Marc
M
Foulkes
William D
WD
D001483:Base Sequence; D015139:Blotting, Southern; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D017931:DNA Primers; D018076:DNA, Complementary; D005091:Exons; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D011792:Quebec
D017931:DNA Primers; D018076:DNA, Complementary