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<p>Hereditary hypophosphatemic rickets, most commonly caused by X-linked dominant <i>PHEX</i> variants, leads to hypophosphatemia and bone mineralization defects. We identified a novel mosaic nonsense variant in the <i>PHEX</i> gene on the X chromosome by next-generation sequencing—c.1971C &gt; A, p.(Tyr657X)—–in a man with clinical features of hypophosphatemic rickets. As the variant was only found in 67% of DNA reads, we considered the possibility of sex chromosome aneuploidy (e.g. a 48,XXXY sex chromosome complement with an unaffected X chromosome i.e. variant on 2 of 3 X chromosomes producing a variant allele frequency of approx. 67%) or a postzygotic mutation resulting in the <i>PHEX</i> variant in some but not all cells. His mother was clinically unaffected, and he did not have features of Klinefelter’s syndrome, favouring postzygotic mutation over sex chromosome aneuploidy. We excluded sex chromosome aneuploidy through karyotype studies showing a 46,XY status. As the event must therefore be a postzygotic variant to produce the reduced variant allele frequency, his parents are not at risk of having the variant. However, X chromosome postzygotic mutations in men may be inherited by female offspring (depending on the mosaic status of gonadal tissue). The patient’s karyotype result was thus integral in the investigation of disease mechanism and in guiding family genetic counselling. </p>

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A Mosaic PHEX Variant in Hypophosphatemic Rickets: Distinguishing Postzygotic Mutation from Sex Chromosome Aneuploidy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月18日

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  • Wu Tzen Lim,
  • Marni Nenke,
  • Lesley Rawlings,
  • Amanda Wells,
  • Cassandra Vakulin,
  • Wendy Waters,
  • Sunita De Sousa

摘要

Hereditary hypophosphatemic rickets, most commonly caused by X-linked dominant PHEX variants, leads to hypophosphatemia and bone mineralization defects. We identified a novel mosaic nonsense variant in the PHEX gene on the X chromosome by next-generation sequencing—c.1971C > A, p.(Tyr657X)—–in a man with clinical features of hypophosphatemic rickets. As the variant was only found in 67% of DNA reads, we considered the possibility of sex chromosome aneuploidy (e.g. a 48,XXXY sex chromosome complement with an unaffected X chromosome i.e. variant on 2 of 3 X chromosomes producing a variant allele frequency of approx. 67%) or a postzygotic mutation resulting in the PHEX variant in some but not all cells. His mother was clinically unaffected, and he did not have features of Klinefelter’s syndrome, favouring postzygotic mutation over sex chromosome aneuploidy. We excluded sex chromosome aneuploidy through karyotype studies showing a 46,XY status. As the event must therefore be a postzygotic variant to produce the reduced variant allele frequency, his parents are not at risk of having the variant. However, X chromosome postzygotic mutations in men may be inherited by female offspring (depending on the mosaic status of gonadal tissue). The patient’s karyotype result was thus integral in the investigation of disease mechanism and in guiding family genetic counselling.