Presence of De Novo Mutations in Autosomal Dominant Polycystic Kidney Disease Patients Without Family History
Received 21 December 2007; accepted 22 May 2008. published online 21 July 2008.
Background
At the University of Colorado Health Sciences Center, on detailed questioning, approximately 10% of patients with autosomal dominant polycystic kidney disease (ADPKD) gave no family history of ADPKD. There are several explanations for this observation, including occurrence of a de novo pathogenic sequence variant or extreme phenotypic variability. To confirm de novo sequence variants, we have undertaken clinical and genetic screening of affected offspring and their parents.
Study Design
Case series.
Setting & Participants
24 patients with a well-documented ADPKD phenotype and no family history of polycystic kidney disease (PKD) and both parents of each patient.
Outcome
Presence or absence of PKD1 or PKD2 pathogenic sequence variants in parents of affected offspring.
Measurements
Abdominal ultrasound of affected offspring and their parents for ADPKD diagnosis. Parentage testing by genotyping. Complete screening of PKD1 and PKD2 genes by using genomic DNA from affected offspring; analysis of genomic DNA from both parents to confirm the absence or presence of all DNA variants found.
Results
A positive diagnosis of ADPKD by means of ultrasound or genetic screening was made in 1 parent of 4 patients (17%). No PKD1 or PKD2 pathogenic sequence variants were identified in 10 patients (42%), whereas possible pathological DNA variants were identified in 4 patients (17%) and 1 of their respective parents. Parentage was confirmed in the remaining 6 patients (25%), and de novo sequence variants were documented.
Limitations
Size of patient group. No direct examination of RNA.
Conclusion
Causes other than de novo pathogenic sequence variants may explain the negative family history of ADPKD in certain families.
6Barbara Davis Center for Juvenile Diabetes, American Indian and Alaska Native Program at the University of Colorado at Denver and Health Science Center, Aurora, CO
7Department of Psychiatry, American Indian and Alaska Native Program at the University of Colorado at Denver and Health Science Center, Aurora, CO
Address correspondence to Berenice Reed, PhD, Polycystic Kidney Disease Research Group, University of Colorado Denver, MS C283, Bldg 500, Rm C5000, 13001 E 17th Pl, PO Box 6508, Aurora, CO 8004
ABSTRACT