Dataset Information

[Novel PHEX gene mutations in patients with X-linked hypophosphatemic rickets: an analysis of 2 cases].

ABSTRACT: OBJECTIVE:To investigate PHEX gene mutations in 2 patients with X-linked hypophosphatemic rickets (XLH) and their families and to clarify the genetic etiology. METHODS:A retrospective analysis was performed for the clinical data of two patients with XLH. High-throughput sequencing was used to detect the PHEX gene, a pathogenic gene of XLH. PCR-Sanger sequencing was used to verify the distribution of mutations in families. RESULTS:Both patients had novel mutations in the PHEX gene; one patient had a frameshift mutation, c.931dupC, which caused early termination of translation and produced the truncated protein p.Gln311Profs*13; the other patient had a splice site mutation, IVS14+1G>A, which caused the skipping of exon 15 and produced an incomplete amino acid chain. Their parents had normal gene phenotypes. CONCLUSIONS:c.931dupC and IVS14+1G>A are two novel mutations of the PHEX gene and might be the new pathogenic mutations of XLH.

SUBMITTER: Ran Q

PROVIDER: S-EPMC7389139 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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[Novel PHEX gene mutations in patients with X-linked hypophosphatemic rickets: an analysis of 2 cases].

Ran Qing Q Xiong Feng F Zhu Min M Deng Lei-Li LL Lei Pei-Yun PY Luo Yan-Hong YH Zeng Yan Y Zhu Gao-Hui GH Song Cui C

Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 20170501 5

<h4>Objective</h4>To investigate PHEX gene mutations in 2 patients with X-linked hypophosphatemic rickets (XLH) and their families and to clarify the genetic etiology.<h4>Methods</h4>A retrospective analysis was performed for the clinical data of two patients with XLH. High-throughput sequencing was used to detect the PHEX gene, a pathogenic gene of XLH. PCR-Sanger sequencing was used to verify the distribution of mutations in families.<h4>Results</h4>Both patients had novel mutations in the PHE ...[more]

PMID: 28506344

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Project description:ObjectiveHypophosphatemic rickets (HR) is a heterogeneous genetic phosphate wasting disorder. The disease is most commonly caused by mutations in the PHEX gene located on the X-chromosome or by mutations in CLCN5, DMP1, ENPP1, FGF23, and SLC34A3. The aims of this study were to perform molecular diagnostics for four patients with HR of Indian origin (two independent families) and to describe their clinical features.MethodsWe performed whole exome sequencing (WES) for the affected mother of two boys who also displayed the typical features of HR, including bone malformations and phosphate wasting. B-lymphoblast cell lines were established by EBV transformation and subsequent RT-PCR to investigate an uncommon splice site variant found by WES. An in silico analysis was done to obtain accurate nucleotide frequency occurrences of consensus splice positions other than the canonical sites of all human exons. Additionally, we applied direct Sanger sequencing for all exons and exon/intron boundaries of the PHEX gene for an affected girl from an independent second Indian family.ResultsWES revealed a novel PHEX splice acceptor mutation in intron 9 (c.1080-3C>A) in a family with 3 affected individuals with HR. The effect on splicing of this mutation was further investigated by RT-PCR using RNA obtained from a patient's EBV-transformed lymphoblast cell line. RT-PCR revealed an aberrant splice transcript skipping exons 10-14 which was not observed in control samples, confirming the diagnosis of X-linked dominant hypophosphatemia (XLH). The in silico analysis of all human splice sites adjacent to all 327,293 exons across 81,814 transcripts among 20,345 human genes revealed that cytosine is, with 64.3%, the most frequent nucleobase at the minus 3 splice acceptor position, followed by thymidine with 28.7%, adenine with 6.3%, and guanine with 0.8%. We generated frequency tables and pictograms for the extended donor and acceptor splice consensus regions by analyzing all human exons. Direct Sanger sequencing of all PHEX exons in a sporadic case with HR from the Indian subcontinent revealed an additional novel PHEX mutation (c.1211_1215delACAAAinsTTTACAT, p.Asp404Valfs*5, de novo) located in exon 11.ConclusionsMutation analyses revealed two novel mutations and helped to confirm the clinical diagnoses of XLH in two families from India. WES helped to analyze all genes implicated in the underlying disease complex. Mutations at splice positions other than the canonical key sites need further functional investigation to support the assertion of pathogenicity.

Dataset Information

[Novel PHEX gene mutations in patients with X-linked hypophosphatemic rickets: an analysis of 2 cases].

Publications

[Novel PHEX gene mutations in patients with X-linked hypophosphatemic rickets: an analysis of 2 cases].

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