Deep resequencing of in 762 F508del homozygotes reveals clusters of non-coding variants associated with cystic fibrosis disease traits.

Extensive phenotypic variability is commonly observed in individuals with Mendelian disorders, even among those with identical genotypes in the disease-causing gene. To determine whether variants within and surrounding contribute to phenotypic variability in cystic fibrosis (CF), we performed deep sequencing of in 762 patients homozygous for the common CF-causing variant, F508del. In phase 1, ~200 kb encompassing and extending 10 kb 5' and 5 kb 3' of the gene was sequenced in 486 F508del homozygotes selected from the extremes of sweat chloride concentration.

Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease.

Elevated sweat chloride levels, failure to thrive (FTT), and lung disease are characteristic features of cystic fibrosis (CF, OMIM #219700). Here we describe variants in CA12 encoding carbonic anhydrase XII in two pedigrees exhibiting CF-like phenotypes. Exome sequencing of a white American adult diagnosed with CF due to elevated sweat chloride, recurrent hyponatremia, infantile FTT and lung disease identified deleterious variants in each CA12 gene: c.