Global genetic prevalence estimates of primary hyperoxaluria are greater than previously reported.

Background: Primary hyperoxaluria (PH), a rare autosomal recessive disease of oxalate accumulation in the kidneys, is caused by biallelic pathogenic changes in three known genes: (PH1), (PH2) and (PH3).

Methods: To better understand the overall risk of developing clinical PH, we manually curated and classified PH genetic variants and calculated the estimated genetic prevalence overall and in five ethnic subpopulations using allelic frequencies from the population Genome Aggregation Database (gnomAD version 2.1.1).

Results: Of the 651 identified PH variants, 273 were found in gnomAD 2.1.1 on the day of download and after reclassification, 208 were determined pathogenic (P) or likely pathogenic (LP) ( = 94;  = 46; and  = 68) and a further 65 were classified as rare variants of uncertain significance (VUS). Using P and LP only, estimated carrier frequency was 1:229 for PH1, 1:465 for PH2 and 1:151 for PH3, while genetic prevalence was 1:209 357 for PH1, 1:863 028 for PH2 and 1:90 834 for PH3 (i.e. nearly 5, 1 and 11 per 1 million individuals, respectively). The highest carrier frequencies for pathogenic variants were in East Asians (1 in 146) and the European non-Finnish population (1 in 187); for , South Asians (1 in 313) and the European non-Finnish population (1 in 413); and for , Ashkenazi Jewish (1 in 38) and East Asians (1 in 100). The estimated risk of developing PH was ≈1:59 017.

Conclusions: This careful benchmarking exercise indicates that a significant number of individuals at risk for PH symptoms remain undiagnosed. Since these numbers exceed known diagnosed cases of PH, improved screening and diagnosis of this underestimated disease is necessary.