Lim Wu Tzen, Nenke Marni, Rawlings Lesley, Wells Amanda, Vakulin Cassandra, Waters Wendy, De Sousa Sunita
Adelaide Medical School, University of Adelaide, Adelaide, Australia.
Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia.
Calcif Tissue Int. 2025 Jun 18;116(1):87. doi: 10.1007/s00223-025-01388-4.
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.
遗传性低磷性佝偻病最常见由X连锁显性PHEX基因变异引起，可导致低磷血症和骨矿化缺陷。我们通过二代测序在一名具有低磷性佝偻病临床特征的男性患者的X染色体上发现了一种新的PHEX基因镶嵌性无义变异——c.1971C＞A，p.(Tyr657X)。由于该变异仅在67%的DNA读数中被发现，我们考虑了性染色体非整倍体的可能性（例如48,XXXY性染色体组成，其中一条X染色体未受影响，即3条X染色体中有2条存在变异，导致变异等位基因频率约为67%），或者是合子后突变，导致部分而非所有细胞中出现PHEX变异。他的母亲临床未受影响，且他没有克氏综合征的特征，因此更倾向于合子后突变而非性染色体非整倍体。我们通过核型研究排除了性染色体非整倍体，结果显示为46,XY核型。因此，由于该事件必定是合子后变异才导致变异等位基因频率降低，他的父母不存在携带该变异的风险。然而，男性的X染色体合子后突变可能会遗传给女性后代（取决于性腺组织的镶嵌状态）。因此，患者的核型结果对于疾病机制的研究和家庭遗传咨询的指导至关重要。
