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Two novel variants of the PHEX gene in patients with X?linked dominant hypophosphatemic rickets and prenatal diagnosis for fetuses in these families.

ABSTRACT: X?linked hypophosphatemic rickets (XLHR; OMIM 307800) is an X?linked dominant disorder caused by mutations in the phosphate?regulating neutral endopeptidase homolog X?linked (PHEX) gene, which is located at Xp22.11. In the present study, two novel variants of the PHEX gene were identified in two unrelated families with XLHR by directly sequencing all 22 exon regions and intron/exon boundaries of the PHEX gene. One missense variant, NM_000444.5: c.1721T>A, was identified in exon 17 of the PHEX gene in Family 1, which led to an amino acid change in the p.Ile574Lys protein. The other splicing variant identified was NM_000444.5: c.591A>G, in exon 5 in Family 2, resulting in a deletion of 77 bp in the 3' site of exon 5 during splicing, which was verified by direct cDNA sequencing of the PHEX gene. According to the results of reverse transcription?quantitative polymerase chain reaction analysis, the affected male with the splicing variant c.591A>G showed normal gene expression of PHEX, whereas the affected female exhibited low gene expression, compared with normal females. Based on these findings, prenatal diagnoses were made for the fetuses with a family history of XLHR using the backup amniotic fluid samples. One fetus without the missense variant was confirmed to be a healthy girl in a follow?up visit 1 month following birth.

SUBMITTER: Liao H

PROVIDER: S-EPMC5810233 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Two novel variants of the PHEX gene in patients with X‑linked dominant hypophosphatemic rickets and prenatal diagnosis for fetuses in these families.

Liao Hong H Zhu Hong-Mei HM Liu Hong-Qian HQ Li Ling-Ping LP Liu Shan-Ling SL Wang He H

International journal of molecular medicine 20180118 4

X‑linked hypophosphatemic rickets (XLHR; OMIM 307800) is an X‑linked dominant disorder caused by mutations in the phosphate‑regulating neutral endopeptidase homolog X‑linked (PHEX) gene, which is located at Xp22.11. In the present study, two novel variants of the PHEX gene were identified in two unrelated families with XLHR by directly sequencing all 22 exon regions and intron/exon boundaries of the PHEX gene. One missense variant, NM_000444.5: c.1721T>A, was identified in exon 17 of the PHEX ge ...[more]

PMID: 29393334

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Project description:BackgroundGenetic Hypophosphatemic Rickets (HR) is a group of diseases characterized by renal phosphate wasting with inappropriately low or normal 1,25-dihydroxyvitamin D3 (1,25(OH)2D) serum levels. The most common form of HR is X-linked dominant HR (XLHR) which is caused by inactivating mutations in the PHEX gene. The purpose of this study was to perform genetic diagnosis in a cohort of patients with clinical diagnosis of HR, to perform genotype-phenotype correlations of those patients and to compare our data with other HR cohort studies.MethodsForty three affected individuals from 36 non related families were analyzed. For the genetic analysis, the PHEX gene was sequenced in all of the patients and in 13 cases the study was complemented by mRNA sequencing and Multiple Ligation Probe Assay. For the genotype-phenotype correlation study, the clinical and biochemical phenotype of the patients was compared with the type of mutation, which was grouped into clearly deleterious or likely causative, using the Mann-Whitney and Fisher's exact test.ResultsMutations in the PHEX gene were identified in all the patients thus confirming an XLHR. Thirty four different mutations were found distributed throughout the gene with higher density at the 3' end. The majority of the mutations were novel (69.4%), most of them resulted in a truncated PHEX protein (83.3%) and were family specific (88.9%). Tubular reabsorption of phosphate (TRP) and 1,25(OH)2D serum levels were significantly lower in patients carrying clearly deleterious mutations than in patients carrying likely causative ones (61.39 ± 19.76 vs. 80.14 ± 8.80%, p = 0.028 and 40.93 ± 30.73 vs. 78.46 ± 36.27 pg/ml, p = 0.013).ConclusionsPHEX gene mutations were found in all the HR cases analyzed, which was in contrast with other cohort studies. Patients with clearly deleterious PHEX mutations had lower TRP and 1,25(OH)2D levels suggesting that the PHEX type of mutation might predict the XLHR phenotype severity.

Dataset Information

Two novel variants of the PHEX gene in patients with X?linked dominant hypophosphatemic rickets and prenatal diagnosis for fetuses in these families.

Publications

Two novel variants of the PHEX gene in patients with X‑linked dominant hypophosphatemic rickets and prenatal diagnosis for fetuses in these families.

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