A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets

Yang, Misun; Kim, Jinsup; Yang, Aram; Jang, Ja‐Hyun; Jeon, Tae Yeon; Cho, Sung Yoon; Jin, Dong‐Kyu

doi:10.6065/apem.2018.23.4.229

Cited by 8 publications

(9 citation statements)

References 18 publications

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“…XLHR is a dominant disease, and the somatic mosaicism also shows clinical symptoms but mildly, which reminds us to investigate the disease-causing variant using other tissue samples. To date, four somatic mosaicism male patients with XLHR have been reported (21,27,28,29), and our in-house study also identifies two XLHR mosaic boys carrying heterozygous PHEX pathogenic variants.…”

Section: Discussionsupporting

confidence: 53%

‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

Lin

Cai

et al. 2020

European Journal of Endocrinology

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Objective X-linked hypophosphatemic rickets (XLHR) is the most common form of inherited rickets caused by pathogenic variants of PHEX gene with an X-linked dominant inheritance pattern. Precise molecular diagnosis of pathogenic variant will benefit the genetic counseling and prenatal diagnosis for the family with XLHR. Here, we presented an ‘isolated’ germline mosaicism in the phenotypically normal father of a girl with XLHR. Methods and results For the initial molecular screen of PHEX gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples respectively. Sanger sequencing found a ‘de novo’ novel heterozygous variant, c.1666C>T(p.Q556X), at the PHEX gene in the proband, but not in her phenotypically healthy parents. Due to an occasional abnormality of his serum phosphate previously, further examinations for the father were taken to exclude the possibility of paternal mosaicism. Eight samples from different tissues were analyzed for PHEX gene by Sanger sequencing. Surprisingly, one ‘isolated’ germline mosaicism was detected only in his sperm with an estimated frequency of 26.67%. The mosaic allele was identical to the c.1666C>T(p.Q556X) variant in the proband. Conclusions This is the first case of ‘isolated’ germline mosaicism with pathogenic PHEX variant. Our study provides accurate diagnosis and valuable counseling for this family. This report also alerts clinicians and geneticists to exclude the possibility of the isolated germline mosaicism and prevent intrafamilial recurrences of inherited diseases.

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Section: Discussionsupporting

confidence: 53%

‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

Lin

Cai

et al. 2020

European Journal of Endocrinology

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“…The mosaic mutation in PHEX appears to be rare. Indeed, there have been only three cases with novel mosaic mutations in PHEX reported in males [11][12][13]. Table 3 summarizes the clinical features of these cases.…”

Section: Discussionmentioning

confidence: 99%

A mosaic mutation of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (<i>PHEX</i>) in X-linked hypophosphatemic rickets with mild bone phenotypes

et al. 2021

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“…2). Since mosaic mutations are difficult to detect by Sanger sequencing, their description in PHEX is rare in the literature ( 22 , 23 , 24 ). Therefore, the identification of this mosaic mutation demonstrated the high sensitivity of the developed NGS panel.…”

Section: Discussionmentioning

confidence: 99%

Validation of a next-generation sequencing (NGS) panel to improve the diagnosis of X-linked hypophosphataemia (XLH) and other genetic disorders of renal phosphate wasting

Thiele

Werner

Stubbe

et al. 2020

European Journal of Endocrinology

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Background: Hypophosphataemic rickets (HR) comprise a clinically and genetically heterogeneous group of conditions, defined by renal-tubular phosphate wasting and consecutive loss of bone mineralisation. X-linked hypophosphataemia (XLH) is the most common form, caused by inactivating dominant mutations in PHEX, a gene encompassing 22 exons located at Xp22.1. XLH is treatable by anti-Fibroblast Growth Factor 23 antibody, while for other forms of HR such a therapy may not be indicated. Therefore, a genetic differentiation of HR is recommended. Objective: To develop and validate a next generation sequencing panel for HR with special focus on PHEX. Design and Methods: We designed an AmpliSeq gene panel for the IonTorrent PGM next generation platform for PHEX and ten other HR-related genes. For validation of PHEX sequencing 50 DNA-samples from XLH-patients, in whom 42 different mutations in PHEX and one structural variation have been proven before, were blinded, anonymised and investigated with the NGS panel. In addition, we analyzed one known homozygous DMP1 mutation and two samples of HR-patients, where no pathogenic PHEX mutation had been detected by conventional sequencing. Results: The panel detected all 42 pathogenic missense/nonsense/splice-site/indel PHEX-mutations and in one the known homozygous DMP1 mutation. In the remaining two patients, we revealed a somatic mosaicism of a PHEX mutation in one; as well as two variations in DMP1 and a very rare compound heterozygous variation in ENPP1 in the second patient. Conclusions: This NGS panel is a reliable tool with high sensitivity and specificity for diagnosis of XLH and related forms of HR.

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A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets

Cited by 8 publications

References 18 publications

‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

A mosaic mutation of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (<i>PHEX</i>) in X-linked hypophosphatemic rickets with mild bone phenotypes

Validation of a next-generation sequencing (NGS) panel to improve the diagnosis of X-linked hypophosphataemia (XLH) and other genetic disorders of renal phosphate wasting

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