title: Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.
abstract: BACKGROUND
  Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively.
  
  
  OBJECTIVE
  The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance.
  
  
  METHODS
  We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait.
  
  
  RESULTS
  Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation.
  
  
  CONCLUSIONS
  Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.
authors.affiliation: Department of Endocrinology and Metabolism, Kobe Children's Hospital, 1-1-1 Takakuradai, Suma-ku, Kobe 654-0081, Japan. gojik@gold.ocn.ne.jp
authors.forename: Katsumi
authors.initials: K
authors.lastname: Goji
authors.forename: Kayo
authors.initials: K
authors.lastname: Ozaki
authors.forename: Ahmad H
authors.initials: AH
authors.lastname: Sadewa
authors.forename: Hisahide
authors.initials: H
authors.lastname: Nishio
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
mesh_terms: D000328:Adult; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics; D004247:DNA / Q000235:genetics; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008666:Metalloendopeptidases / Q000235:genetics*; D009030:Mosaicism; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: C000717427:FGF23 protein, human; D008562:Membrane Glycoproteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D004247:DNA; D008666:Metalloendopeptidases; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human