Two de novo mosaic variants within the same site of PHEX gene in a girl with X-linked hypophosphatemic rickets

Calcif Tissue Int. 2022 Feb;110(2):266-271. doi: 10.1007/s00223-021-00909-1

PMID: 34487203

Yunting Lin, Wen Zhang, Xinjiang Huang, Ling Su, Yanna Cai, Cuili Liang, Min Rao, Li Liu, Chunhua Zeng

Highlights: This is the first time two different mosaic variants of the PHEX gene have been found in an XLH individual.

Abstract

Background: X-linked hypophosphatemic rickets (XLH) is the most common form of hypophosphatemic rickets, which is caused by the deficiencies of PHEX gene with an X-linked dominant inheritance pattern. As at least several thousands of XLH patients have been diagnosed, only several males and fewer females with mosaicism of PHEX gene were found.

Objective and Methods: In this publication, an XLH girl with two de novo mosaic variants within the same site of PHEX gene was reported. To rapidly screen all of the causative genes of hypophosphatemic rickets and rule out other diseases, DNA samples were initially analysed using whole exome sequencing (WES).

Results: Interestingly, two different pathogenic mosaic variants, a known c.1809G > A(p.W603*) variant and a novel c.1809G > T(p.W603C) variant within the same site of PHEX gene, were identified in the proband by WES. Subsequent Sanger sequencing confirmed the presence and de novo pattern of these two mosaic variants in the proband, which were absent in her healthy parents. This is the first case to report two different mosaic variants of PHEX gene in an XLH individual. The XLH patient has a de novo mosaic genotype of c.1809 = /G > T/G > A in PHEX gene.

Conclusion: The study adds an unusual mosaicism case for XLH and expands the mutational event and spectrum of PHEX gene. According to the study, clinicians and geneticists to be cautious about mosaicism and detection methods.

Keywords: Mosaicism, PHEX gene, Sanger sequencing, Whole exome sequencing, X-linked hypophosphatemic rickets