Clustered Structural Variants Involving <italic>PHEX</italic> at Xp22 in a Female Patient with X-Linked Hypophosphatemia.

INTRODUCTION

X chromosomal structural changes involving PHEX result in X-linked hypophosphatemia (XLH). However, their underlying mechanisms were poorly determined. Moreover, X chromosome inactivation (XCI) statuses in female patients with XLH remain to be studied.

CASE PRESENTATION: We conducted systematic genomic analyses for a woman with XLH and detected a 3.2 Mb tandem duplication at Xp22.33, a 1.9 Mb tandem duplication at Xp22.31, and a 0.8 Mb deletion involving PHEX at Xp22.11 on the paternally derived chromosome. The fusion junctions contained templated insertions and short nucleotide additions indicative of non-homologous end joining (NHEJ) or alternative NHEJ. The patient had random XCI.

CONCLUSION

This study provides evidence that PHEX haploinsufficiency leads to typical XLH in women with random XCI and that a 5.9 Mb rearrangement on Xp22 permits random XCI. Our results, together with previous findings, imply that clustered structural changes due to NHEJ/alternative NHEJ are a unique type of human genomic rearrangements.