Constructing and interpreting a large-scale variant effect map for an ultrarare disease gene: Comprehensive prediction of the functional impact of PSAT1 genotypes

• DOI: 10.1371/journal.pgen.1010972
• Publication Date: 2023-10-09T17:32:05Z
• Authors: Michael J. Xie; Gareth A. Cromie; Katherine Owens; Martin S. Timour; Michelle Tang; J. Nathan Kutz; Ayman W. El-Hattab; Richard N. McLaug...; Aimée M. Dudley
• Keywords: Compound heterozygosity

Reduced activity of the enzymes encoded by PHGDH, PSAT1, and PSPH causes a set ultrarare, autosomal recessive diseases known as serine biosynthesis defects. These present in broad phenotypic spectrum: at severe end is Neu-Laxova syndrome, intermediate range are infantile defects with neurological manifestations growth deficiency, mild childhood disease intellectual disability. However, L-serine supplementation, especially if started early, can ameliorate some cases even prevent symptoms. Therefore, knowledge pathogenic variants improve clinical outcomes. Here, we use yeast-based assay to individually measure functional impact 1,914 SNV-accessible amino acid substitutions PSAT. Results our agree well interpretations protein structure-function relationships, supporting inclusion data evidence part ACMG variant interpretation guidelines. We existing ClinVar variants, alleles reported literature homozygotes primAD database define ranges that could aid for up 98% tested variants. In addition measuring individual yeast haploid cells, also pairwise combinations PSAT1 recapitulate human genotypes, including compound heterozygotes, diploids. from diploid successfully distinguish genotypes affected individuals those healthy carriers severity. Finally, linear model uses allele measurements predict biallelic function ~1.8 million corresponding potential genotypes. Taken together, work provides an example how large-scale assays systems be powerfully applied study ultrarare diseases.