Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency

Hrafnhildur L. Runólfsdóttir, John A. Sayer, Olafur S. Indridason, Viðar Örn Eðvarðsson, Brynjar O. Jensson, Gudny A. Arnadottir, Sigurjon A. Gudjonsson, Run Fridriksdottir, Hildigunnur Katrinardottir, Daniel Gudbjartsson, Unnur Thorsteinsdottir, Patrick Sulem, Kari Stefansson, Runólfur Pálsson*

*Corresponding author for this work

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Adenine phosphoribosyltransferase deficiency is a rare, autosomal recessive disorder of purine metabolism that causes nephrolithiasis and progressive chronic kidney disease. The small number of reported cases indicates an extremely low prevalence, although it has been suggested that missed diagnoses may play a role. We assessed the prevalence of APRT deficiency based on the frequency of causally-related APRT sequence variants in a diverse set of large genomic databases. A thorough search was carried out for all APRT variants that have been confirmed as pathogenic under recessive mode of inheritance, and the frequency of the identified variants examined in six population genomic databases: the deCODE genetics database, the UK Biobank, the 100,000 Genomes Project, the Genome Aggregation Database, the Human Genetic Variation Database and the Korean Variant Archive. The estimated frequency of homozygous genotypes was calculated using the Hardy-Weinberg equation. Sixty-two pathogenic APRT variants were identified, including six novel variants. Most common were the missense variants c.407T>C (p.(Met136Thr)) in Japan and c.194A>T (p.(Asp65Val)) in Iceland, as well as the splice-site variant c.400 + 2dup (p.(Ala108Glufs*3)) in the European population. Twenty-nine variants were detected in at least one of the six genomic databases. The highest cumulative minor allele frequency (cMAF) of pathogenic variants outside of Japan and Iceland was observed in the Irish population (0.2%), though no APRT deficiency cases have been reported in Ireland. The large number of cases in Japan and Iceland is consistent with a founder effect in these populations. There is no evidence for widespread underdiagnosis based on the current analysis.

Original languageEnglish
Pages (from-to)1061-1070
Number of pages10
JournalEuropean Journal of Human Genetics
Issue number7
Publication statusPublished - 11 Mar 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to European Society of Human Genetics.

This study was supported by the Rare Kidney Stone Consortium (U54DK083908), a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research. The Rare Kidney Stone Consortium is funded through collaboration between NCATS and National Institute of Diabetes and Digestive and Kidney Diseases. This work was also funded by the Landspitali University Hospital Research Fund (B-2016-006).

Other keywords

  • Adenine phosphoribosyltransferase deficiency
  • Alleles
  • Metabolism, Inborn Errors
  • Urolithiasis


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