Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update.

Area of Science:

• Genetics
• Genomic Medicine
• Molecular Biology

Background:

• Standardizing gene-disease associations is crucial for classifying genetic variants in Mendelian disorders.
• Observing pathogenic variants independently in unrelated individuals with similar phenotypes provides key evidence.
• Autozygosity can reveal rare homozygous pathogenic variants, aiding in the study of tentative gene-disease links.

Purpose of the Study:

• To identify and characterize homozygous pathogenic variants in genes with tentative associations to Mendelian diseases.
• To leverage autozygosity to uncover rare homozygous variants that are difficult to find otherwise.
• To strengthen evidence for gene-disease associations by finding homozygous variants in compatible phenotypes.

Main Methods:

• Exploiting autozygosity to generate homozygous pathogenic variants.
• Selecting variants based on criteria such as truncating nature, founder status with segregation data, or functional assays.
• Validating a specific variant (DUT) using a yeast model system.

Main Results:

• Reported 20 homozygous variants in 18 genes (ADAMTS18, ARNT2, ASTN1, C3, DMBX1, DUT, GABRB3, GM2A, KIF12, LOXL3, NUP160, PTRHD1, RAP1GDS1, RHOBTB2, SIGMAR1, SPAST, TENM3, WASHC5).
• These variants meet criteria for pathogenic/likely pathogenic classification if gene-disease links were confirmed.
• Functional validation was performed for the DUT gene variant using a yeast model.

Conclusions:

• The identified homozygous variants support previously reported disease associations for the studied genes.
• These findings represent a significant step towards confirming tentative gene-disease links.
• The study highlights the utility of autozygosity in discovering rare homozygous variants for genetic disease research.