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Abstract: SA-PO402

Estimation of Adenine Phosphoribosyltransferase Deficiency Prevalence Using Public Whole-Exome Sequencing Data

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Runolfsdottir, Hrafnhildur L., University of Iceland, Reykjavik, Iceland
  • Sayer, John Andrew, Newcastle University, Newcastle, United Kingdom
  • Indridason, Olafur S., Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland
  • Edvardsson, Vidar O., Landspital - The National University Hospital of Iceland, Reykjavik, Iceland
  • Sulem, Patrick, deCODE genetics, Reykjavik, Iceland
  • Palsson, Runolfur, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland

Group or Team Name

  • Rare Kidney Stone Consortium
Background

Adenine phosphoribosyltransferase deficiency (APRTd) is a rare, hereditary cause of recurrent kidney stones and progressive chronic kidney disease (CKD). While treatment with allopurinol or febuxostat is effective, a delay in diagnosis frequently results in adverse outcomes. The small number of reported cases in countries other than France, Iceland and Japan suggests an extremely low prevalence, although missed diagnoses may significantly affect prevalence estimates. We assessed the prevalence of APRTd based on the frequency of mutated APRT alleles in public genomic databases.

Methods

Four databases containing genome sequencing data, the Genome Aggregation Database (gnomAD, n=141,353), the NHLBI GO Exome Sequencing Project (n=6503), the 100,000 Genomes Project (n=62,000) and the deCODE Genetics database (n=35,000) were searched for 64 reported APRT mutations and other potentially pathogenic variants. Minor allele frequencies (MAF) <0.01% were identified. The estimated prevalence of homozygous genotypes was calculated using the Hardy-Weinberg principle.

Results

A total of 30 disease-causing mutations with MAF <0.01% were detected in all databases. The variants with the highest allele counts are shown in Table 1. The p.Arg89Gln mutation was found to have a heterozygous frequency of 0.4087(%) in the South Asian population (n=1.3 billion), yielding an estimated 17.201 homozygotes, and a heterozygous frequency of 0.03714 (%) in the UK population (n=66 million) with an estimated 910 homozygotes. In the US, the p.Phe174 deletion had a heterozygous frequency of 0.3271 (%) in the European-American population (n=223 million), yielding an estimated 2408 homozygotes.

Conclusion

The data suggest a greater prevalence of APRTd in the Asian, UK and US populations than is reported in the literature. Based on these findings, APRTd appears to be a seriously underrecognized cause of kidney stones and CKD.

Table 1.
DatabaseVariantMutant Allele FrequencyCarrier frequency (1 in*)Estimated prevalence (1 in*)
NHLBI, European-Americanp.Phe174del0.3271%15392,844
100.000 Genomes Project, UKp.Arg89Gln0.3714%13572,496
gnomAD,
South Asia
p.Arg89Gln0.4087%12359,864
gnomAD,
East Asia
p.Ala116Thr0.2307%217187,941
deCODE Genetics, Icelandp.Asp65Val1.2%426874

Funding

  • NIDDK Support