Genetic analysis of three families with X-linked dominant hypophosphatemic rickets

Xinfu Lin; Yaobin Zhu; Jiewei Luo; Jianbin Huang

doi:10.1515/jpem-2017-0451

Article

Genetic analysis of three families with X-linked dominant hypophosphatemic rickets

Xinfu Lin , Yaobin Zhu , Jiewei Luo and Jianbin Huang

Published/Copyright: June 2, 2018

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 31 Issue 7

Abstract

Background

Hypophosphatemic rickets, including familial hypophosphatemic vitamin D-resistant rickets, which commonly manifests in childhood, is generally hereditary. X-linked dominant hypophosphatemic rickets (XLH, MIM307800), caused by inactivating mutations in the PHEX gene, is the most common form. This study aimed to identify the gene mutations responsible for three cases of XLH and its clinical phenotype.

Methods

We conducted a genetic diagnosis and clinical phenotypic linkage analysis of three pedigrees with XLH. Three probands finally diagnosed as XLH were analyzed by next-generation sequencing (NGS). Sanger sequencing was used for mutation scanning in other family members.

Results

For the three patients with XLH, the age of onset ranged from 1.5 to 2 years and their heights were less than three standard deviations (SDs) below the median. The patients exhibited curved deformities in both lower limbs, hypophosphatemia, elevated serum FGF23 levels and elevated levels of blood alkaline phosphatase, with normal levels of blood parathyroid hormone (PTH) and calcium. X-ray analysis of the limbs and chest revealed characteristic rickets signs. Three candidate pathogenic mutations were identified in PHEX (NM_000444.5): c.433G>T (p.Glu145*, p.E145*) in exon 4, c.1735G>A (p.Gly579Arg, p.G579R) (rs875989883) in exon 17 and c.2245T>C (p.Trp749Arg, p.W749R) in exon 22. The nonsense mutation (p.E145*) in PHEX is novel and is predicted to cause a truncation of the encoded protein, resulting in loss of function.

Conclusions

The novel nonsense mutation (p.E145*) in PHEX is possibly involved in inherited XLH.

Keywords: family pedigree analysis; novel mutation; PHEX; X-link dominant hypophosphatemic rickets

Corresponding author: Jiewei Luo, MD, Provincial Clinical Medical College, Fujian Medical University, Fuzhou, P.R. China; and Department of Traditional Chinese Medicine, Fujian Provincial Hospital, No. 134 DongJie, Fuzhou 350001, P.R. China, Phone: +86-591-88217471

aXinfu Lin and Yaobin Zhu contributed equally to this work.

Author contributions: Xinfu Lin and Jiewei Luo conceived and designed the study and drafted the manuscript. Yaobin Zhu and Jianbin Huang participated in data collection and conducted the statistical analyses. All authors participated in various aspects of the study analysis and interpretation of the data, and in the development of the report. The final version was read and approved by all authors. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This work was supported by Fujian Provincial Natural Science Fund Project (2016J01501) and Financial Scheme for Young Talents training program of the Fujian health industry (Grant #2015-ZQN-ZD-7).
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Received: 2017-10-29

Accepted: 2018-04-23

Published Online: 2018-06-02

Published in Print: 2018-07-26

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Articles in the same Issue

https://doi.org/10.1515/jpem-2017-0451

Keywords for this article

family pedigree analysis; novel mutation; PHEX; X-link dominant hypophosphatemic rickets