Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

Abstract

Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.

Keywords: genetic renal disease; kidney stones; molecular genetics.

Figure 1.

Genotypic and allelic breakdown varies considerably between the different PH types in the mutation resolved 267 pedigrees. (A) Genotypic breakdown by PH type showing patients with two truncating alleles (nonsense, splice, and frameshifting InDels [insertion, duplication, deletion, or insertion+deletion]), two nontruncating alleles (missense and inframe InDels), or a truncating plus a nontruncating allele. Number in parentheses represents number of families with that genotype. (B) Allelic analysis by PH type of different mutation types. Common alleles of each PH type plus their frequencies are also highlighted. AGXT p.G170R was found homozygously (hom) in 29 families and heterozygously (het) in 75 families, GRHPR c.103delG (hom, 5 families; het, 5 families), HOGA1 c.700+5G>T (hom, 8 families; het, 12 families), HOGA1 p.E315del (hom, 7 families; het, 7 families).

Figure 2.

Renal Survival plots showing (A) poorer renal survival for PH1 patients followed by PH2, and (B) better renal survival for PH1 patients with two MiR alleles. (A) Kaplan-Meier renal survival plot of the PH1, PH2, PH3, and NMD cohorts. (B) Kaplan-Meier renal survival plot of PH1 patients categorized as having two MiR alleles (homozygous, or compound heterozygous; AGXT p.G41R, p.F152I, p.G170R, p.I244T, 89 patients), one MiR allele in combination with a non-MiR allele (97 patients), or two alleles of which neither was a MiR allele (no MiR, 81 patients). Tables below Kaplan-Meier plots show survival estimates with number of patients at risk in parentheses.

Figure 3.

Renal survival plots showing that only homozygous p.G170R patients but not homozygotes of other MiR genotypes had a renal survival advantage. Kaplan-Meier renal survival plot plus survival estimate table for PH1 patients homozygous for p.G170R (34 patients), homozygous or compound heterozygous for another MiR allele (p.G41R, p.F152I, p.I244T, 19 patients), or having no MiR allele (81 patients). Pairwise comparisons show greater renal survival in patients homozygous for AGXT p.G170R but not the other MiR alleles compared with patients without a MiR allele (Hom p.G170R versus no MiR; P<0.0001 [P<0.001], Hom other MiR versus no MiR P=0.27 [P=0.35], Hom p.G170R versus Hom other MiR P=0.04 [P=0.05]). P values in square brackets are adjusted for the effect of pyridoxine treatment, reducing the overall significance but upholding the survival advantage of AGXT p.G170R homozygotes.

Figure 4.

Carrier frequencies of common PH alleles found in the NHLBI ESP account for significant racial differences. Depiction of the most common PH alleles separated by EA and AA CF. AGXT p.G170R (CF in EAs, 0.23%) and p.R289H (CF in AAs, 0.35%) account for 45.1% and 68.8% of the total PH1 CF, respectively. Similarly, GRHPR c.103delG accounts for 75.3% and 63.4% of the total EA or AA PH2 CF, respectively, and HOGA1 c.700+5G>T accounts for 78.4% and 100% of the total EA or AA PH3 CF, respectively.