Intra-Familial Clinical Heterogeneity: Absence of Genotype-Phenotype Correlation in Primary Hyperoxaluria Type 1 in Israel

Abstract

Background/Aims: Primary hyperoxaluria type 1 (PH1) is caused by the deficiency of the liver enzyme alanine:glyoxylate aminotransferase which results in increased synthesis and excretion of oxalate. The clinical manifestations of PH1 are heterogeneous with respect to the age of onset and rate of progression. The aim of this study was to investigate possible relationships between a given genotype, the biochemical profile and the clinical phenotype. Methods: We conducted a study of 56 patients from 22 families with PH1 from Israel. The clinical and biochemical data were compiled and the genotype was determined for each family. Results: The prevalent phenotype was of early onset with progression to end-stage renal disease during the first decade of life. Fifteen PH1-causing mutations were detected in 21 families: 10 were first described in this patient population. Marked intra-familial clinical heterogeneity was noted, meaning that there was no correlation between a given genotype and the phenotype. Conclusions: The clinical course of patients with PH1 is not dictated primarily by its genotype. Other genetic and/or environmental factors play a role in determining the ultimate phenotype.

Selected Exonic Sequencing of the AGXT Gene Provides a Genetic Diagnosis in 50% of Patients with Primary Hyperoxaluria Type 1

“…This change has previously been described as a pathological mutation (13,14 ), but in our study this change was actually detected in an unaffected family member and did not track with the disease. Analysis of 76 controls showed that this variant was present in 1 of 158 alleles, an observation consistent with the change being a polymorphism with no pathological significance.…”

“…We detected an additional 6 missense changes that have previously been reported, although not expressed in vitro. These mutations are c.26CϾA (13,14 ) and c.106CϾT (15 ) in exon 1, c.466GϾA (16 ) and c.518GϾA (17 ) in exon 4, and c.697CϾT and c.698GϾA (17 ) in exon 7.…”

Rapid Profiling of Disease Alleles Using a Tunable Reporter of Protein Misfolding

“…In agreement with this prediction, we found that yeast expressing AGT S205P were unable to grow, indicating severe instability ( Figure 4A). We next examined two mutations (R289C, L298P) found in a homozygous form on both alleles (on the minor allele background) in a single PH1 patient (Frishberg et al 2005). AGTmi R289C showed equivalent stability as AGTmi, but stability of AGTmi L298P was greatly impaired, providing strong evidence that the L298P mutation alone is responsible for the disease in this patient ( Figure 4A).…”

Primary hyperoxaluria type 1: update and additional mutation analysis of theAGXTgene

“…While individuals homozygous for the null mutation, c.33dupC, tend to present earlier than c.508G4A, there is considerable overlap and, rather surprisingly, one patient with c.33dupC did not present until over 40 years of age . Another family with a history of early onset disease in five siblings, all of whom died before 3 years of age, was found to have another sibling diagnosed on genetic testing at age 20 years but who was still asymptomatic [Frishberg et al, 2005]. The late presentation of some patients may actually indicate that the prevalence of this disease is underestimated [Van Woerden et al, 2007].…”