Supplementary Material for: Clustered structural variants involving PHEX 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.