Is CFTR 621+3 A>G a cystic fibrosis causing mutation?

Area of Science:

• Genetics
• Molecular Biology
• Medical Research

Background:

• The CFTR gene variant 621+3 A>G was previously associated with severe cystic fibrosis.
• This variant was reported to negatively impact CFTR mRNA splicing.

Purpose of the Study:

• To investigate the pathogenicity of the CFTR gene variant 621+3 A>G.
• To evaluate the variant's role in cystic fibrosis and related conditions.

Main Methods:

• Analysis of allelic frequency in the Italian population.
• In vitro splicing assay using a hybrid minigene in HeLa cells.
• Genotyping of an individual with the 621+3 A>G variant and the Q552X mutation.

Main Results:

• The allelic frequency of 621+3 A>G in the Italian population (0.4%) is inconsistent with a significant role in cystic fibrosis.
• In vitro splicing assays showed minimal impact on CFTR mRNA splicing, comparable to the CFTR intron 8 5T variant.
• An asymptomatic individual carrying the 621+3 A>G variant in trans with Q552X suggests non-pathogenicity.

Conclusions:

• The CFTR 621+3 A>G variant is unlikely to be pathogenic for cystic fibrosis.
• This finding is crucial for genetic counseling, especially as the variant is included in population screening.
• Further research is warranted to explore potential roles in congenital bilateral absence of vas deferens or atypical cystic fibrosis.