Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Novel ALPK3 mutation in a Tunisian patient with pediatric cardiomyopathy and facio-thoraco-skeletal features

Abstract

Pediatric cardiomyopathy is a complex disease with clinical and genetic heterogeneity. Recently, the ALPK3 gene was described as a new hereditary cardiomyopathy gene underlying pediatric cardiomyopathies. Only eight patients carrying mutations in ALPK3 have been reported to date. Here, we report a 3-year-old male patient with both hypertrophic and dilated cardiomyopathy. The patient presented dysmorphic features and skeletal deformities of hands and feet, pectus excavatum, and cleft palate. The genetic investigation was performed by whole-exome sequencing in the patient and his parents. We identified a novel homozygous mutation in ALPK3 (c.1531_1532delAA; p.Lys511Argfs*12). Our work extends the phenotypic spectrum of the ALPK3-associated cardiomyopathy by reporting additional clinical features. This is the first study of a Tunisian patient with mutation in the ALPK3 gene. In conclusion, ALPK3 should be included in the list of genes to be considered in genetic studies for patients affected with pediatric syndromic cardiomyopathy.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Kimura A. Molecular genetics and pathogenesis of cardiomyopathy. J Hum Genet. 2016;61:41.

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Mestroni L, Rocco C, Gregori D, Sinagra G, Di Lenarda A, Miocic S, et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol. 1999;34:181–90.

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Wilkinson JD, Sleeper LA, Alvarez JA, Bublik N, Lipshultz SE. The Pediatric Cardiomyopathy Registry: 1995–2007. Prog Pediatr Cardiol. 2008;25:31–6.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Kindel SJ, Miller EM, Gupta R, Cripe LH, Hinton RB, Spicer RL, et al. Pediatric cardiomyopathy: importance of genetic and metabolic evaluation. J Card Fail. 2012;18:396–403.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. 5.

    Wilkinson JD, Westphal JA, Bansal N, Czachor JD, Razoky H, Lipshultz SE. Lessons learned from the Pediatric Cardiomyopathy Registry (PCMR) Study Group. Cardiol Young. 2015;25(Suppl 2):140–53.

    Article  PubMed  Google Scholar 

  6. 6.

    Lee TM, Hsu DT, Kantor P, Towbin JA, Ware SM, Colan SD, et al. Pediatric cardiomyopathies. Circ Res. 2017;121:855–73.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. 7.

    Mestroni L, Sweet ME, Taylor MRG. Pediatric cardiomyopathy. J Am Coll Cardiol. 2016;67:526–8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Almomani R, Verhagen JMA, Herkert JC, Brosens E, van Spaendonck-Zwarts KY, Asimaki A, et al. Biallelic truncating mutations in ALPK3 cause severe pediatric cardiomyopathy. J Am Coll Cardiol. 2016;67:515–25.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Hosoda T, Monzen K, Hiroi Y, Oka T, Takimoto E, Yazaki Y, et al. A novel myocyte-specific gene Midori promotes the differentiation of P19CL6 cells into cardiomyocytes. J Biol Chem. 2001;276:35978–89.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Phelan DG, Anderson DJ, Howden SE, Wong RCB, Hickey PF, Pope K, et al. ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy. Eur Heart J. 2016;37:2586–90.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Çağlayan AO, Sezer RG, Kaymakçalan H, Ulgen E, Yavuz T, Baranoski JF, et al. ALPK3 gene mutation in a patient with congenital cardiomyopathy and dysmorphic features. Mol Case Stud. 2017;3:a001859.

    Article  Google Scholar 

  12. 12.

    Van Sligtenhorst I, Ding Z-M, Shi Z-Z, Read RW, Hansen G, Vogel P. Cardiomyopathy in α-kinase 3 (ALPK3)–deficient mice. Vet Pathol. 2012;49:131–41.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Spirito P, Maron BJ. Absence of progression of left ventricular hypertrophy in adult patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1987;9:1013–7.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Hecht GM, Klues HG, Roberts WC, Maron BJ. Coexistence of sudden cardiac death and end-stage heart failure in familial hypertrophic cardiomyopathy. J Am Coll Cardiol. 1993;22:489–97.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Freeman K, Colon-Rivera C, Olsson MC, Moore RL, Weinberger HD, Grupp IL, et al. Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene. Am J Physiol Heart Circ Physiol. 2001;280:H151–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patient's family for their collaboration. This work was supported by the Tunisian Ministry of Public Health, the Ministry of Higher Education and Scientific Research (LR16IPT05). The project leading to this publication has received funding from Excellence Initiative of Aix-Marseille University - A*MIDEX, a French “Investissements d’Avenir” programme (RARE-MED project).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Rym Benkhalifa or Stéphane Zaffran.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jaouadi, H., Kraoua, L., Chaker, L. et al. Novel ALPK3 mutation in a Tunisian patient with pediatric cardiomyopathy and facio-thoraco-skeletal features. J Hum Genet 63, 1077–1082 (2018). https://doi.org/10.1038/s10038-018-0492-1

Download citation

Further reading

Search

Quick links