The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families

Area of Science:

• Genetics
• Oncology

Background:

• Lynch syndrome is an inherited disorder that increases the risk of various cancers.
• The MSH2 c.388_389del mutation has been identified in Lynch syndrome families globally.
• Haplotype analysis is crucial for distinguishing founder from recurrent mutations.

Purpose of the Study:

• To investigate the origin of the MSH2 c.388_389del mutation in Portuguese Lynch syndrome families.
• To determine if the mutation is a founder or recurrent event.
• To assess the cost-effectiveness of targeted MSH2 mutation screening in specific populations.

Main Methods:

• Haplotype analysis was performed on 16 Portuguese families and 17 international cases.
• Genetic data was analyzed to identify shared haplotypes and determine mutation origins.
• Comparative analysis of mutation backgrounds in Portuguese and non-Portuguese families.

Main Results:

• A shared haplotype of approximately 10 Mb was identified in 16 Portuguese families, all originating from Northern Portugal, indicating a founder effect.
• Families outside Portugal with the same mutation exhibited diverse haplotype backgrounds, suggesting multiple independent occurrences (de novo mutations).
• The prevalence of this specific MSH2 mutation in Portuguese families suggests it is a significant founder mutation.

Conclusions:

• The MSH2 c.388_389del mutation represents a founder mutation in Portugal with a recent origin, particularly in the northern region.
• The findings support the hypothesis of recurrent de novo occurrences of this mutation in other populations.
• Targeted screening for the MSH2 c.388_389del mutation may be a cost-effective initial step for Lynch syndrome genetic testing in individuals of Portuguese ancestry, especially from Northern Portugal.