New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan...

Area of Science:

• Genetics
• Medical Genetics
• Rare Diseases

Background:

• Marfan syndrome (MFS) is a rare, autosomal dominant connective tissue disorder.
• Over 1000 variants linked to MFS, but their pathogenicity is questionable due to limited control groups.
• Investigating false-positive variants is crucial for accurate MFS diagnosis and genetic counseling.

Purpose of the Study:

• To assess the pathogenicity of previously reported Marfan syndrome variants.
• To determine if reported MFS variants are false positives by comparing their frequency in a control population.
• To re-evaluate genotype-prevalence correlations in Marfan syndrome.

Main Methods:

• Utilized four in silico prediction tools (SIFT, Polyphen-2, Grantham score, conservation across species) to evaluate variant pathogenicity.
• Screened 6494 individuals from the Exome Sequencing Project (ESP) for 891 previously reported MFS-associated variants.
• Compared the frequency of MFS variants in the ESP with their predicted pathogenicity using computational tools.

Main Results:

• Identified 23 MFS variants in the ESP, indicating a genotype prevalence of 1:65.
• A more conservative analysis revealed 10 variants in 82 individuals, yielding a genotype prevalence of 1:79.
• Variants not found in the ESP were significantly more likely to be predicted as pathogenic by multiple tools (p < 3.5 x 10^-15).

Conclusions:

• The study identified a higher genotype prevalence for Marfan syndrome than suggested by phenotypic prevalence.
• The high frequency of certain variants in the general population suggests they are not the sole monogenic cause of MFS.
• Caution is advised when using previously reported MFS variants for disease stratification and genetic diagnosis.