Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing.
Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is one of the commonest cancer susceptibility syndromes. It is characterized by early onset colon cancer and a variety of extracolonic tumours. Germline mutations in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for this disorder. Identifying an affected individual depends on the tumour histopathology, family history that fulfils the Amsterdam and/or Bethesda criteria, tumour immunohistochemistry, microsatellite instability, and finally molecular analysis of an affected member. It is a laborious, time consuming and expensive procedure, which needs the effort of a multi-disciplinary team. However, once the diagnosis is established and germline defect is identified, other high risk pre-symptomatic carriers could be offered intensive surveillance and management as a preventive measure against cancer development. Here, we present two large highly consanguineous HNPCC-families from Kuwait in whom a founder MSH2 mutation was identified. The relationship between this mutation and cancer expressivity in two large consanguineous families harbouring other genetic defects is discussed. Moreover, we shed light on the challenges pertaining to diagnosis, screening, premarital counselling of couples and prenatal diagnosis of offspring with biallelic MSH2 gene mutation.
Marafie
Makia J
MJ
Kuwait Medical Genetics Centre, Maternity Hospital, 13059 Safat, Kuwait. mj_marafie@yahoo.com
Al-Awadi
Sadiqa
S
Al-Mosawi
Fatemah
F
Elshafey
Alaa
A
Al-Ali
Waleed
W
Al-Mulla
Fahd
F
D000328:Adult; D002648:Child; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007150:Immunohistochemistry; D007730:Kuwait; D008297:Male; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011291:Premarital Examinations
C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein