title: A novel PKD1 variant demonstrates a disease-modifying role in trans with a truncating PKD1 mutation in patients with autosomal dominant polycystic kidney disease.
abstract: BACKGROUND
  Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of Polycystic Kidney Disease (PKD) and occurs at a frequency of 1/800 to 1/1000 affecting all ethnic groups worldwide. ADPKD shows significant intrafamilial phenotypic variability in the rate of disease progression and extra-renal manifestations, which suggests the involvement of heritable modifier genes. Here we show that the PKD1 gene can act as a disease causing and a disease modifier gene in ADPKD patients.
  
  
  METHODS
  Clinical evaluation of a family with ADPKD was performed to diagnose and assess disease progression in each individual. PKD1 was genotyped in each individual by targeted sequencing.
  
  
  RESULTS
  Targeted screening analysis showed that the patients with ADPKD in the family had the PKD1: p.Q2243X nonsense mutation. A more severe disease phenotype, in terms of estimated Glomerular Filtration Rate (eGFR) and total kidney volume, was observed in two patients where in addition to the mutation, they carried a novel PKD1 variant (p.H1769Y). Other patients from the same family carrying only the (p.Q2243X) mutation showed milder disease manifestations.
  
  
  CONCLUSIONS
  ADPKD shows significant intrafamilial phenotypic variability that is generally attributed to other modifier genes. In this rare case, we have shown that a variant at PKD1, in trans with the PKD1 mutation, can also act as a modifier gene in ADPKD patients. Understanding the molecular mechanism through which the gene exerts its disease modifying role may aid our understanding of the pathogenesis of ADPKD.
authors.affiliation: Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Health Sciences Center, Kuwait University, Jabriya, Kuwait. hamad.ali@hsc.edu.kw.
authors.forename: Hamad
authors.initials: H
authors.lastname: Ali
authors.affiliation: Division of Nephrology, Mubarak Al-Kabeer Hospital, Ministry of Health, Jabriya, Kuwait. nhussainku@yahoo.com.
authors.forename: Naser
authors.initials: N
authors.lastname: Hussain
authors.affiliation: Division of Nephrology, Mubarak Al-Kabeer Hospital, Ministry of Health, Jabriya, Kuwait. medhat_naim@hotmail.com.
authors.forename: Medhat
authors.initials: M
authors.lastname: Naim
authors.affiliation: Department of Radio diagnosis, Mubarak Al-Kabeer Hospital, Ministry of Health, Jabriya, Kuwait. moh.zayed81@gmail.com.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Zayed
authors.affiliation: Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University, Jabriya, Kuwait. Fahd@al-mulla.org.
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.affiliation: Department of Surgery, Division of Urology, Faculty of Medicine, Health Sciences Center, Kuwait University, Jabriya, Kuwait. ekehinde@hotmail.com.
authors.forename: Elijah O
authors.initials: EO
authors.lastname: Kehinde
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, USA. Seaburg.Lauren@mayo.edu.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Seaburg
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, USA. Sundsbak.Jamie@mayo.edu.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Sundsbak
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, USA. Harris.Peter@mayo.edu.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016891:Polycystic Kidney, Autosomal Dominant / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D011237:Predictive Value of Tests; D050396:TRPP Cation Channels / Q000235:genetics*
chemical_list: D050396:TRPP Cation Channels