X-linked hypophosphatemia in 4 generations due to an exon 13–15 duplication in PHEX, in the absence of the c.*231A&gt;G variant

Barros, Julio Soto; Sanchez, Sabrina I; Cabral, Kristin; Beggs, Alan H.; Agrawal, Pankaj B.; Genetti, Casie A.; Brownstein, Catherine A.; Carpenter, Thomas O.

doi:10.1016/j.bone.2023.116763

Bone

2023

DOI: 10.1016/j.bone.2023.116763

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X-linked hypophosphatemia in 4 generations due to an exon 13–15 duplication in PHEX, in the absence of the c.*231A>G variant

Julio Soto Barros

Sabrina I Sanchez

Kristin Cabral

et al.

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2024

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Cited by 2 publications

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Familial cases with adult-onset FGF23-related hypophosphatemic osteomalacia -A PHEX 3’-UTR change as a possible cause-

Sawatsubashi,

Takashi,

Endo

et al. 2024

Bone

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Familial cases with adult-onset FGF23-related hypophosphatemic osteomalacia -A PHEX 3’-UTR change as a possible cause-

Sawatsubashi,

Takashi,

Endo

et al. 2024

Bone

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Unusual PHEX variants implicate uncommon genetic mechanisms for X-linked hypophosphatemic rickets

Alzoebie,

Li,

Wang

et al. 2024

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X-linked hypophosphatemic rickets (XLH), the most common form of hereditary rickets, is characterized by renal phosphate wasting and abnormal vitamin D metabolism due to elevated circulating levels of the phosphatonin, FGF23. Dominant inactivating variants of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX) gene are present in patients with XLH, and more than half of affected patients carry de novo variants. We report three families in which affected subjects had highly unusual PHEX pathogenic variants. In one family we identified a previously described deep intronic PHEX variant (c.1768 + 173A > G) in the proband and her affected son. This variant is also near a previously reported PHEX variant (c.1768 + 177_1768 + 180dupGTAA) and is predicted to affect splicing by SpliceAI (delta score 0.95) through creation of a new donor splice site. In a second proband we identified two pathogenic de novo and novel PHEX variants, c.2083delT (p.Ser695Profs*45) and c.2085delC (p.Tyr696Thrfs*44), that were present on different alleles, consistent with mosaicism for three PHEX alleles. The third proband also carried two PHEX variants ((c.755 T > C (p.Phe252Ser) and c.759G > A (p.Met253Ile)), but in this case both variants were present on the same PHEX allele. These studies expand the molecular catalog of pathogenic PHEX variants in XLH and emphasize the importance of deep intronic sequencing and comprehensive family studies. Conventional approaches to genetic diagnosis may not be adequate to identify or characterize the disease-causing variants in the PHEX gene in some patients with likely XLH.

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X-linked hypophosphatemia in 4 generations due to an exon 13–15 duplication in PHEX, in the absence of the c.*231A>G variant

Cited by 2 publications

References 16 publications

Familial cases with adult-onset FGF23-related hypophosphatemic osteomalacia -A PHEX 3’-UTR change as a possible cause-

Familial cases with adult-onset FGF23-related hypophosphatemic osteomalacia -A PHEX 3’-UTR change as a possible cause-

Unusual PHEX variants implicate uncommon genetic mechanisms for X-linked hypophosphatemic rickets

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