Mutations in 329 probands with suspected renal electrolyte disorders

The spectrum of coding and non-coding of mutations that contribute to Mendelian diseases is largely unknown. This question is broadly relevant to molecular diagnostic efforts in real-world settings, particularly when the scope of biochemical and other tests performed may be limited prior to genetic testing. We report the results of whole exome sequencing of DNA from 329 patients referred by physicians for suspicion of genetic causes of renal electrolyte disorders, predominantly featuring hypokalemia and/or hypomagnesemia with normal to low blood pressure. 295 probands were found to have known/likely disease-causing genotypes; these included 254 with biallelic mutations in one of 9 genes known to cause salt wasting, and 34 with monoallelic mutations in these same genes. Seven other probands had mutations in genes known to cause renal hypomagnesemia. Among these, 197 probands had biallelic or monoallelic (n = 7) damaging variants in the Gitelman syndrome (GS) gene SLC12A3, which encodes the Na-Cl cotransporter of the distal convoluted tubule. WGS sequencing in the 7 monoallelic probands, who all had pathognomonic electrolyte values for GS, identified two deep intronic variants that introduced splice sites producing frameshifting mutations, a small exonic deletion missed by WES, and a novel deep intronic variant of unknown function. Thus non-coding variation (outside exons and flanking splice sites) accounted for only two likely disease-related variants among 400 GS alleles, with 4 other alleles unexplained after WGS. Among patients with isolated hypomagnesemia, six had monoallelic deletions in HNF1B. Additionally, a novel homoplasmic mitochondrial isoleucine tRNA variant was associated with hypomagnesemia and depression/anxiety in seven relatives spanning three generations who shared a maternal lineage. The electrolyte profiles of probands with disease-associated genotypes were consistent with the paradigmatic features associated with mutation in each gene.