Selected AGXT gene mutations analysis provides a genetic diagnosis in 28% of Tunisian patients with primary hyperoxaluria

Abstract

BackgroundPrimary hyperoxaluria type I (PH1) is a rare genetic disorder characterized by allelic and clinical heterogeneity. Four mutations (G170R, 33_34insC, I244T and F152I) account for more than 50% of PH1 alleles and form the basis for diagnostic genetic screening for PH1. We aimed to analyze the prevalence of these specific mutations causing PH1, and to provide an accurate tool for diagnosis of presymptomatic patients as well as for prenatal diagnosis in the affected families.MethodsPolymerase chain reaction/Restriction Fragment Length Polymorphism, were used to detect the four mutations in the AGXT gene in DNA samples from 57 patients belonging to 40 families.ResultsTwo mutations causing PH1 were detected in 24 patients (42.1%), with a predominance of the I244T mutation (68% of patients) and 33_34insC (in the remaining 32%). In 92% of cases, mutated alleles were in homozygous state.The presented clinical features were similar for the two mutations. The age of onset was heterogeneous with a higher frequency of the pediatric age. In 58.3% of cases, the presentation corresponded to advanced renal disease which occurred early (< 5 years) in the two mutations. In adolescents, only the I244T mutation was detected (41.1%). I244T and 33_34insC mutations were observed in adult patients, with 17.6% and 12.5% respectively.ConclusionLimited mutation analysis can provide a useful first line investigation for PH1. I244T and 33_34insC presented 28.2% of identified mutations causing disease in our cohort. This identification could provide an accurate tool for prenatal diagnosis in the affected families, for genetic counselling and for detection of presymptomatic individuals.

Primary Hyperoxaluria Type 1 in 18 Children: Genotyping and Outcome

“…Thus, the PH1 consanguinity rate in this study was 100%. There are many similar reports from different Middle East countries that showed elevated PH1 rates associated with increased consanguinity [ 12 – 15 ]. Mbarek et al reported on 57 patients with PH1 from 40 different families.…”

“…Mbarek et al reported on 57 patients with PH1 from 40 different families. In their cohort, more than one family member was affected and the reported consanguinity rate was 75% [ 15 ]. In our study, all patients diagnosed with PH1 were <5 years old and the median age at initial PH1 symptom onset was 7 months.…”

Mutational Analysis of Agxt in Tunisian Population with Primary Hyperoxaluria Type 1

“…The molecular investigation of AGXT in previous studies proved that four mutations, p.Phe152Ile, p.Gly170Arg, p.Ile244Thr, and p.Lys12Glnfs*156, represent more than 50% of PH1 alleles and represent the basis of genetic screening for PH1 (Monico et al., ; Williams & Rumsby, ). However, direct testing for these mutations in a previous Tunisian study made a diagnosis of PH1 in only 28% of patients (Mbarek et al., ). The identification of the AGXT mutations causing PH1 in Tunisia is important for heterozygote detection and prenatal diagnosis in affected families.…”

Common mutation underlying primary hyperoxaluria type1 in three Indian children

“…[9] Screening for the three most common mutations, c.33_34insC, c.508G>A, and c.731T > C, enables a molecular diagnosis in 34.5% cases. [10] These mutations, along with one third of the other documented mutations, are located in exons 1, 4 and 7, suggesting that these exons may be hot spots for screening. [10] A recent report on 57 patients from Tunisia revealed that screening for I244T (exon 7) and 33_34insC (exon 1) accounted for 28.2% of mutations causing disease in their cohort.…”

“…[10] These mutations, along with one third of the other documented mutations, are located in exons 1, 4 and 7, suggesting that these exons may be hot spots for screening. [10] A recent report on 57 patients from Tunisia revealed that screening for I244T (exon 7) and 33_34insC (exon 1) accounted for 28.2% of mutations causing disease in their cohort. [11] However, since the mutational hotspots reported are few and population-specific, molecular diagnosis requires sequencing of the entire AGXT gene.…”