title: Clinical and genetic analysis of patients with cystinuria in the United Kingdom.
abstract: OBJECTIVE
  Cystinuria is a rare inherited renal stone disease. Mutations in the amino acid exchanger System b(0,+), the two subunits of which are encoded by SLC3A1 and SLC7A9, predominantly underlie this disease. The work analyzed the epidemiology of cystinuria and the influence of mutations in these two genes on disease severity in a United Kingdom cohort.
  
  
  METHODS
  Prevalent patients were studied from 2012 to 2014 in the northeast and southwest of the United Kingdom. Clinical phenotypes were defined, and genetic analysis of SLC3A1 and SLC7A9 combining Sanger sequencing and multiplex ligation probe-dependent amplification was performed.
  
  
  RESULTS
  In total, 76 patients (42 men and 34 women) were studied. All subjects had proven cystine stones. Median age of presentation (first stone episode) was 24 years old, but 21% of patients presented after 40 years old. Patients had varied clinical courses, with 37% of patients having ≥10 stone episodes; 70% had evidence of CKD, and 9% had reached ESRD as a result of cystinuria and its complications. Patients with cystinuria received a variety of different therapies, with no obvious treatment consensus. Notably, 20% of patients had staghorn calculi, with associated impaired renal function in 80% of these patients. Genetic analysis revealed that biallelic mutations were present in either SLC3A1 (n=27) or SLC7A9 (n=20); 22 patients had only one mutated allele detected (SLC3A1 in five patients and SLC7A9 in 17 patients). In total, 37 different mutant variant alleles were identified, including 12 novel mutations; 22% of mutations were caused by large gene rearrangements. No genotype-phenotype association was detected in this cohort.
  
  
  CONCLUSIONS
  Patients with cystinuria in the United Kingdom often present atypically with staghorn calculi at ≥40 years old and commonly develop significant renal impairment. There is no association of clinical course with genotype. Treatments directed toward reducing stone burden need to be rationalized and developed to optimize patient care.
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom;
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Rhodes
authors.affiliation: Bristol Genetics Laboratory-Pathology Sciences and.
authors.forename: Laura
authors.initials: L
authors.lastname: Yarram-Smith
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Rice
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Ayla
authors.initials: A
authors.lastname: Tabaksert
authors.affiliation: Institute of Genetic Medicine, International Centre for Life and.
authors.forename: Noel
authors.initials: N
authors.lastname: Edwards
authors.affiliation: Department of Urology, National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom;
authors.forename: Alice
authors.initials: A
authors.lastname: Hartley
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom;
authors.forename: Mark N
authors.initials: MN
authors.lastname: Woodward
authors.affiliation: Department of Clinical Genetics, University Hospitals, Bristol, United Kingdom; and.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Smithson
authors.affiliation: Richard Bright Renal Unit, Southmead Hospital, Bristol, United Kingdom; Department of Renal Medicine, Freeman Hospital, Newcastle upon Tyne, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Tomson
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom;
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Welsh
authors.affiliation: Bristol Genetics Laboratory-Pathology Sciences and.
authors.forename: Margaret
authors.initials: M
authors.lastname: Williams
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: David T
authors.initials: DT
authors.lastname: Thwaites
authors.affiliation: Institute of Genetic Medicine, International Centre for Life and Department of Renal Medicine, Freeman Hospital, Newcastle upon Tyne, United Kingdom John.Sayer@ncl.ac.uk Richard.Coward@bristol.ac.uk.
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
authors.affiliation: Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom;
authors.forename: Richard J M
authors.initials: RJ
authors.lastname: Coward
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics*; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003555:Cystinuria / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D004252:DNA Mutational Analysis / Q000379:methods; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007669:Kidney Calculi / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D010641:Phenotype; D015995:Prevalence; D012042:Registries; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D012189:Retrospective Studies; D012720:Severity of Illness Index; D006113:United Kingdom / Q000453:epidemiology; D055815:Young Adult
chemical_list: D026923:Amino Acid Transport Systems, Basic; D026921:Amino Acid Transport Systems, Neutral; C489857:SLC3A1 protein, human; C499489:SLC7A9 protein, human
keywords: CKD; kidney stones; kidney tubule