CEN Case Reports

, Volume 8, Issue 1, pp 42–47 | Cite as

Exome sequencing identifies a novel frameshift variant causing hypomagnesemia with secondary hypocalcemia

  • M. Kamran AzimEmail author
  • Aisha Mehnaz
  • Javeria Z. Ahmed
  • Ghulam Mujtaba
Case Report


Hypomagnesemia with secondary hypocalcemia is a rare autosomal-recessive disorder characterized by intense hypomagnesemia associated with hypocalcemia (HSH). Mutations in the TRPM6 gene, encoding the epithelial Mg2+ channel TRPM6, have been proven to be the molecular cause of this disease. This study identified causal mutations in a 2-month-old male patient of hypomagnesemia from a consanguineous marriage. Biochemical analyses indicated the diagnosis of HSH due to primary gastrointestinal loss of magnesium. Whole exome sequencing of the trio (i.e. proband and both parents) was carried out with mean coverage of > 150×. ANNOVAR was used to annotate functional consequences of genetic variation from exome sequencing data. After variant filtering and annotation, a number of single nucleotide variants (SNVs) and 2 bp deletion at exon26:c.4402_4403delCT in TRPM6 gene were identified. This deletion which resulted in a novel frameshift mutation in exon 26 of this gene was confirmed by Sanger sequencing. With these investigations in hand, the patient was managed with magnesium sulphate. The patient remained asymptomatic and was developmentally and neurologically normal till his last follow up.


TRPM6 gene Hypomagnesimia TRPM7 gene Magnesium metabolism 


Compliance with ethical standards

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Independent Ethics Committee, ICCBS, University of Karachi, Karachi, Pakistan (IEC Approval Number ICCBS/IEC-010-SS-2016).

Conflict of interest

The authors have declared that no conflict of interest exists.

Supplementary material

13730_2018_362_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 14 KB)


  1. 1.
    Konrad M, Weber S. Recent advances in molecular genetics of hereditary magnesium-losing disorders. J Am Soc Nephrol. 2003;14:249–60.CrossRefGoogle Scholar
  2. 2.
    Sanders GT, Hujjgen HJ, Sanders R. Magnesium in disease: a review with special emphasis on the serum ionized magnesium. Clin Chem Lab Med. 1999;37:1011–33.Google Scholar
  3. 3.
    Cole DEC, Quamme GA. Inherited disorders of renal magnesium handling. J Am Soc Nephrol. 2000;11:1937–47.Google Scholar
  4. 4.
    Lainez S, Schlingmann KP, van der Wijst J, Dworniczak B, van Zeeland F, Konrad v M, Bindels RJ, Hoenderop JG. New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia. Eur J Hum Genet. 2014;22(4):497–504.CrossRefGoogle Scholar
  5. 5.
    Chubanov V, Schlingmann KP, Waring J, Heinzinger J, Kaske S, Waldegger S, Schnitzler MM, Gudermann T. Hypomagnesemia with secondary hypocalcemia due to a missense mutation in the putative pore-forming region of TRPM6. Proc Natl Acad Sci USA. 2007;101(9):2894–99.CrossRefGoogle Scholar
  6. 6.
    De Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and disease. Physiol Rev. 2015;95:1–46.CrossRefGoogle Scholar
  7. 7.
    Chubanov V, Waldegger S, Schnitzler MM, Vitzthum H, Sassen MC, Seyberth HW, Konrad M, Gudermann T. Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. 2004; 101:2894–99.Google Scholar
  8. 8.
    Schmitz C, Dorovkov MV, Zhao X, Bennett JD, Ryazanov AG, Perraud A-L. The channel kinases TRPM6 and TRPM7 are functionally nonredundant. J Biol Chem. 2005;280:37763–71.CrossRefGoogle Scholar
  9. 9.
    Schlingmann KP, Gudermann T. A critical role of TRPM channel-kinase for human magnesium transport. J Physiol. 2005;566:301–8.CrossRefGoogle Scholar
  10. 10.
    Schuchardt JP, Hahn A. Intestinal absorption and factors influencing bioavailability of magnesium-an update. Curr Nutr Food Sci. 2017;13(4):260–78.CrossRefGoogle Scholar
  11. 11.
    Zhang YJ, Zhang S, Liu XZ, Wen HA, Wang M. A simple method of genomic DNA extraction suitable for analysis of bulk fungal strains. Lett Appl Microbiol. 2010; Scholar
  12. 12.
    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R. 1000 Genome Project Data Processing Subgroup. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25(16):2078–79.CrossRefGoogle Scholar
  13. 13.
    Yang H, Wang K. Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat Protoc. 2015;10:1556–66.CrossRefGoogle Scholar
  14. 14.
    Yang H, Robinson PN, Wang K. Phenolyzer: phenotype-based prioritization of candidate genes for human diseases. Nat Methods. 2015;12:841–3.CrossRefGoogle Scholar
  15. 15.
    Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, Vertino-Bell A, Smaoui N, Neidich J, Monaghan KG, McKnight D, Bai R, Suchy S, Friedman B, Tahiliani J, Pineda-Alvarez D, Richard G, Tracy Brandt T, Haverfield E, Chung WK, Bale S. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016; 18:696–704.CrossRefGoogle Scholar
  16. 16.
    Schlingmann KP, Sassen MC, Weber S, Pechmann U, Kusch K, Pelken L, Lotan D, Syrrou M, Prebble JJ, Cole DE, Metzger DL, Rahman S, Tajima T, Shu SG, Waldegger S, Seyberth HW, Konrad M. Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia. J Am Soc Nephrol. 2005;16:3061–69.CrossRefGoogle Scholar
  17. 17.
    Zhao Z, Pei Y, Huang X, Liu Y, Yang W, Sun J, Si N, Xing X, Li M, Wang O, Jiang Y, Zhang X, Xia W. Novel TRPM6 mutations in familial hypomagnesemia with secondary hypocalcemia. Am J Nephrol. 2013;37:541–48.CrossRefGoogle Scholar
  18. 18.
    Thebault S, Alexander RT, Groenestege WMT, Hoenderop JG, Bindels RJ. EGF increases TRPM6 activity and surface expression. J Am Soc Nephrol. 2009;20:78–85.CrossRefGoogle Scholar
  19. 19.
    Li H, Sun S, Chen J, Xu G, Wang H, Qian Q. Genetics of magnesium disorders. Kidney Dis (Basel). 2017;3(3):85–97.CrossRefGoogle Scholar
  20. 20.
    van der Made CI, Hoorn EJ, de la Faille R, Karaaslan H, Knoers NV, Hoenderop JG, Vargas Poussou R, de Baaij JH. Hypomagnesemia as first clinical manifestation of ADTKD-HNF1B: a case series and literature review. Am J Nephrol. 2015;42(1):85–90.CrossRefGoogle Scholar
  21. 21.
    Hou J. Claudins and mineral metabolism. Curr Opin Nephrol Hypertens. 2016;25(4):308–13.CrossRefGoogle Scholar
  22. 22.
    Viering DHHM, de Baaij JHF, Walsh SB, Kleta R, Bockenhauer D. Genetic causes of hypomagnesemia, a clinical overview. Pediatr Nephrol. 2017;32(7):1123–35.CrossRefGoogle Scholar
  23. 23.
    de Baaij JH. The art of magnesium transport. Magnes Res. 2015;28(3):85–91.Google Scholar
  24. 24.
    Lü Q, Zhang Y, Song C, An Z, Wei S, Huang J, Huang L, Tang L, Tong N. A novel SLC12A3 gene homozygous mutation of Gitelman syndrome in an Asian pedigree and literature review. J Endocrinol Invest. 2016;39(3):333–340CrossRefGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2018

Authors and Affiliations

  1. 1.International Center for Chemical and Biological SciencesUniversity of KarachiKarachiPakistan
  2. 2.Department of Paediatrics, Dow Medical CollegeDow University of Health SciencesKarachiPakistan
  3. 3.Department of BiosciencesMohammad Ali Jinnah UniversityKarachiPakistan

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