Hypomagnesemia Panel

Hereditary hypomagnesemia comprises a group of disorders with either primary or secondary renal magnesium ion wasting (Viering et al. 2016; Konrad et al. 2014). Symptoms as consequences of hypomagnesemia vary in severity ranging from leg cramps and tiredness, hypoparathyroidism, to seizures, cardiac arrhythmias, coma and even death. In terms of clinical manifestations, electrolyte abnormalities, localization and pathophysiological mechanism, genetic causes of hypomagnesemia are classified into four categories: hypercalciuric hypomagnesemias, Gitelman-like hypomagnesemias, mitochondrial hypomagnesemias and other hypomagnesemias.

Hereditary hypomagnesemia is a group of highly genetically heterogeneous diseases. To date, at least 16 genes have been linked to a monogenic form of hypomagnesemia in autosomal dominant or recessive inheritance as listed below (Viering et al. 2016; Konrad et al. 2014). The spectrum of pathogenic variant throughout these genes includes all types of changes.

Autosomal dominant: CASR, CNNM2, FAM111A, FXYD2, HNF1B, and KCNA1

Autosomal recessive: BSND, CLDN16, CLDN19, EGF, EGFR, KCNJ10, PCBD1, SARS2, SLC12A3, and TRPM6

As mentioned above, in terms of clinical manifestations, electrolyte abnormalities, localization and pathophysiological mechanism, genetic causes of hypomagnesemia are classified into four categories (Viering et al. 2016). All known genes encode proteins expressed in the thick ascending limb of Henle’s loop (TAL) and/or distal convoluted tubule (DCT).

Hypercalciuric hypomagnesemias: CLDN16, CLDN19, CASR

Gitelman-like hypomagnesemias: BSND, FXYD2, HNF1B, KCNJ10, PCBD1, SLC12A3

Mitochondrial hypomagnesemias: SARS2

Other hypomagnesemias: CNNM2, EGF, EGFR, FAM111A, KCNA1, TRPM6

Our current panel does not include the CLCNKB gene (Bartter syndrome, type 3) due to next generation sequencing technology’s limitations at dealing with pseudogenes.

See individual gene test descriptions for more information on molecular biology of gene products.

Screenings for pathogenic variants in the associated genes in a large cohort of patients with hypomagnesemia have not been reported. To date, studies have focused on individual genes in a limited number of families per study. Therefore, the mutation detection rate of this panel is difficult to predict.

Large deletions and/or duplications appear to be relatively common in Human Gene Mutation Database (HGMD) in these genes: HNF1B, SLC12A3 and TRPM6.

Large deletions and/or duplications have been documented in HGMD in these genes but are relatively uncommon: BSND, CASR, CLDN16, CLDN19, and KCNA1.

No large deletions or duplications have been reported in the other 8 genes of the current panel.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).