Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness

J Med Genet. 2008 Mar;45(3):182-6. doi: 10.1136/jmg.2007.052944.


Background: Bartter syndrome (BS) is a genetic disorder accompanied by hypokalaemic metabolic alkalosis. BS with sensorineural deafness (SND, OMIM602522) is a newly identified phenotype caused by mutations in the BSND gene that encodes barttin, a beta-subunit for chloride channel ClC-Ka and ClC-Kb and classified as type IV BS. Type IV BS features the most severe phenotype entailing life-threatening neonatal volume depletion and chronic renal failure developing during infancy. A recent report described a case of BS with SND from a consanguineous family who showed homozygous mutations in the CLCNKA and CLCNKB genes. This case indicated the possibility of the occurrence of digenic inheritance in BS with SND resulting from double mutations in the CLCNKA and CLCNKB genes.

Subject and results: The current report concerns a 2-year-old girl from a non-consanguineous family with BS accompanied by SND. In our case, four loss-of-function mutations, consisting of mutations in both parental alleles in both CLCNKA and CLCNKB, were identified. The paternal allele had a nonsense mutation (Q260X) in CLCNKA and a splicing site mutation (IVS17+1 g>a) in CLCNKB. The maternal allele had a large deletion mutation (about 12 kbp) extending from CLCNKA to CLCNKB. Our case provides clear evidence that loss-of-function alleles in both alleles of both CLCNKA and CLCNKB results in a phenotype indistinguishable from that of mutations in BSND (type IV BS).

Conclusions: Recent advances in genetics have resulted in a better understanding of many human inherited diseases, but most of them are monogenic disorders and more complex inheritance patterns remain unresolved. Our case provides clear evidence of digenic inheritance outside the scope of Mendelian inheritance disorders.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Bartter Syndrome / complications*
  • Bartter Syndrome / genetics*
  • Base Sequence
  • Child, Preschool
  • Chloride Channels / genetics*
  • Codon, Nonsense
  • DNA / genetics
  • DNA Mutational Analysis
  • DNA Primers / genetics
  • Female
  • Hearing Loss, Sensorineural / complications*
  • Hearing Loss, Sensorineural / genetics*
  • Heterozygote
  • Humans
  • Male
  • Mutation*
  • Phenotype
  • RNA Splice Sites
  • Sequence Deletion


  • CLCNKA protein, human
  • CLCNKB protein, human
  • Chloride Channels
  • Codon, Nonsense
  • DNA Primers
  • RNA Splice Sites
  • DNA