Molecular Genetics of 1α-Hydroxylase Deficiency in the Saudi Population

TL;DR

This study identifies unique genetic mutations in Saudi patients with 1α-hydroxylase deficiency, highlighting a possible founder mutation and several novel variants.

Contribution

The study reports six novel CYP27B1 mutations in Saudi Arabia, including two previously unreported in other populations.

Findings

Ten CYP27B1 mutations were identified in Saudi patients, including four novel mutations.

The most common mutation, p.(Arg429Pro), was found in 51.7% of patients.

Two previously reported mutations are unique to Saudi Arabia and not found in other populations.

Abstract

The aim of this study was to characterize the molecular genetics of 1α-hydroxylase deficiency in the highly consanguineous population of Saudi Arabia, hypothesizing that the results will show a unique CYP27B1 genotype.

We collected data on a large cohort of patients diagnosed with 1α-hydroxylase deficiency from different parts of the country. These patients underwent molecular testing for CYP27B1 mutations.

A cohort of 45 patients from 29 unrelated families was studied. In 13 families (29 patients), more than one affected sibling was included (2-4 siblings) while the other 16 families had only a single patient per family. The patients included 24 females and 21 males with median age at time of presentation of 1 year and a current median age of 10 years. The clinical, biochemical and radiological profile was typical of 1α-hydroxylase deficiency. Molecular testing showed 10 mutations of different types in the 29 families. Four mutations were novel (p.(Trp257LeufsTer76), p.(Glu101Gln), p.(Gly398Ser), and p.(Arg206Cys)) while the other 6 mutations were previously described (p.(arg429Pro), p.(Phe443Profs*24), p.(Gln135Ter), p. (Gly102Glu), p.(Gln504Ter), and c.589 + 1G > A). Two of the previously reported mutations were from Saudi patients and have never been reported from other populations, increasing the number of novel/previously novel mutations to 6 of 10 mutations (60%). The most common mutation was c.1286G > C, p.(Arg429Pro) occurring in 22 patients from 15 unrelated families (51.7%).

The molecular genetics of 1α-hydroxylase deficiency in Saudi Arabia is unique with several novel mutations of different types and a possible founder mutation.

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