title: Establishing an algorithm for molecular genetic diagnostics in 127 families with juvenile nephronophthisis.
abstract: BACKGROUND
  Juvenile nephronophthisis (NPH1), an autosomal recessive cystic disease of the kidney, represents the most common genetic cause of end-stage renal disease in the first two decades of life. On the basis of identification of the gene (NPHP1) defective in NPH1 and the presence of homozygous deletions of NPHP1 in the majority of NPH1 patients, molecular genetic diagnosis for NPH1 is now possible. Molecular genetic testing offers the only method for definite diagnosis of NPH1 and avoids invasive diagnostic measures like renal biopsy.
  
  
  METHODS
  We examined 127 families (204 patients) with the presumed diagnosis of NPH using molecular genetic diagnostic techniques. In 68 families, renal biopsy was performed and was consistent with NPH, and in 61 families, there was more than one affected child ("multiplex families").
  
  
  RESULTS
  In 74 families (115 patients), there was proof of the diagnosis of NPH1 by detection of a homozygous deletion of the NPHP1 gene, and in 5 families a heterozygous deletion in combination with a point mutation in NPHP1 was demonstrated. Furthermore, for 16 families, NPH1 was excluded with high likelihood by linkage analysis, and for 20 families by detection of heterozygosity for two newly identified polymorphic markers within the deletion region. In 5 of the remaining 12 families, which were noninformative for these markers, fluorescence in situ hybridization did not detect any further heterozygous deletions.
  
  
  CONCLUSIONS
  The diagnosis of NPH1 was proven by molecular genetic techniques in 62% of families with one or more children with the presumed diagnosis of NPH. We present evidence that there is a fourth locus for NPH, since only 6 of the 26 multiplex families in whom the diagnosis of NPH1 was excluded were compatible with linkage to other loci for NPH. On the basis of the presented data, we propose an algorithm for molecular genetic diagnostics in NPH.
authors.affiliation: University Children's Hospital, Freiburg University, Freiburg, Germany. hildebra@kkl200.ukl.uni-freiburg.de
authors.forename: F
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: C
authors.initials: C
authors.lastname: Rensing
authors.forename: R
authors.initials: R
authors.lastname: Betz
authors.forename: U
authors.initials: U
authors.lastname: Sommer
authors.forename: S
authors.initials: S
authors.lastname: Birnbaum
authors.forename: A
authors.initials: A
authors.lastname: Imm
authors.forename: H
authors.initials: H
authors.lastname: Omran
authors.forename: M
authors.initials: M
authors.lastname: Leipoldt
authors.forename: E
authors.initials: E
authors.lastname: Otto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000465:Algorithms; D001483:Base Sequence / Q000235:genetics; D003598:Cytoskeletal Proteins; D017353:Gene Deletion; D005820:Genetic Testing; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000175:diagnosis* / Q000235:genetics*; D008565:Membrane Proteins; D008967:Molecular Biology / Q000379:methods*; D008969:Molecular Sequence Data; D017354:Point Mutation; D011506:Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human; D011506:Proteins