Predicting the functional effect of compound heterozygous genotypes from large scale variant effect maps.

Area of Science:

• Biochemistry
• Genetics
• Rare Diseases

Background:

• Pathogenic variants in PHGDH, PSAT1, and PSPH cause serine biosynthesis defects, a group of rare autosomal recessive diseases.
• These defects present a spectrum of phenotypes, from lethal Neu-Laxova syndrome to intellectual disability, with early L-serine supplementation showing therapeutic potential.

Approach:

• A yeast-based assay was developed to assess the functional impact of 1,914 SNV-accessible amino acid substitutions in human PSAT1.
• The assay was scaled to evaluate individual variants in haploid yeast and pairwise allele combinations in diploid yeast, mimicking human genotypes.

Key Points:

• Assay results for individual variants align with clinical interpretations and structural data, supporting their use as functional evidence.
• Diploid assays effectively differentiate patient genotypes from healthy carriers and correlate with disease severity.
• A predictive model accurately estimates biallelic function from haploid measurements for millions of potential genotypes.

Conclusions:

• Large-scale functional assays in model systems offer a powerful approach for studying rare diseases like serine biosynthesis defects.
• This work provides a scalable method for variant interpretation and predicting disease outcomes.