Title: Genetic and clinical characteristics of the patients with Vitamin D Dependent Rickets Type 1A
Abstract: Objective: Vitamin D dependent rickets type 1A (VDDR1A) is an autosomal recessive disorder caused by mutations in the 25OHD 1α-hydroxylase gene (CYB27B1).As it may be confused with nutritional rickets and hypophosphatemic rickets, genetic analysis is important for making a correct diagnosis.Methods: We analysed genomic DNA from 11 patients from 8 different Turkish families.The patients were recruited for our studies if they presented with diagnosis of vitamin D dependent rickets. Results:The mean age at diagnosis was 13.1 ±7.4 months.Seven patients had mild hypocalcemia at presentation while 4 patients had normal calcium levels.All patients underwent CYP27B1 gene analysis; The most prevalent mutation was the c.195 + 2T>G splice donor site mutation, affecting 5 out of 11 patients with VDDR1A.Two patients from the fourth family was compound heterozygous for c.195 +2T>G and c.195 +2 T>A in intron 1.Two patients from different families were homozygous for a previously reported duplication mutation in exon 8 (1319_1325dupCCCACCC, Phe443Profs*24).One patient had homozygous splice site mutation in intron 7 (c.1215+2T>A).And one patient had homozygous mutation in exon 9 (c.1474C>T).Conclusion: Intron 1 mutation was the most common mutation as in the previous studies, and all patients carrying that mutation were from same city of origin suggesting a "founder" or a "common ancestor" effect.VDDR1A should be definitely considered when a patient with signs of rickets has a normal 25-OH level or when there is unresponsiveness to vitamin D treatment. What is already known on this topic?Although vitamin D dependent rickets type 1A (VDDR1A) is a rare disease, it is relatively more common in Turkey.Intron-1 mutations have been reported only from Turkey so far.Intron-1 mutations have been reported to be associated with milder clinical findings.Clinical and laboratory findings can overlap with other types of rickets.Serum 1, 25-dihydroxyvitamin D (-OH2 D) levels are usually known to be low with VDDR1A. What this study adds?In this study, we have observed that the patients with intron-1 mutations can present with clinical findings of variable severity.We have also emphasized that the concentrations of 1, 25-OH 2 D levels could be in inappropriately normal ranges in patients with VDDR1A and can lead to diagnostic confusion.