Advertisement

Acta Diabetologica

, Volume 56, Issue 5, pp 515–523 | Cite as

Genetic characterization of suspected MODY patients in Tunisia by targeted next-generation sequencing

  • Hamza Dallali
  • Serena Pezzilli
  • Meriem Hechmi
  • Om Kalthoum Sallem
  • Sahar Elouej
  • Haifa Jmel
  • Yosra Ben Halima
  • Mariem Chargui
  • Mariem Gharbi
  • Luana Mercuri
  • Federica Alberico
  • Tommaso Mazza
  • Afaf Bahlous
  • Melika Ben Ahmed
  • Henda Jamoussi
  • Abdelmajid Abid
  • Vincenzo Trischitta
  • Sonia Abdelhak
  • Sabrina Prudente
  • Rym KefiEmail author
Original Article

Abstract

Aims

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes with autosomal dominant inheritance pattern. The diagnosis of MODY and its subtypes is based on genetic testing. Our aim was investigating MODY by means of next-generation sequencing in the Tunisian population.

Methods

We performed a targeted sequencing of 27 genes known to cause monogenic diabetes in 11 phenotypically suspected Tunisian patients. We retained genetic variants passing filters of frequency in public databases as well as their probable effects on protein structures and functions evaluated by bioinformatics prediction tools.

Results

Five heterozygous variants were found in four patients. They include two mutations in HNF1A and GCK that are the causative genes of the two most prevalent MODY subtypes described in the literature. Other possible mutations, including novel frameshift and splice-site variants were identified in ABCC8 gene.

Conclusions

Our study is the first to investigate the clinical application of targeted next-generation sequencing for the diagnosis of MODY in Africa. The combination of this approach with a filtering/prioritization strategy made a step towards the identification of MODY mutations in the Tunisian population.

Keywords

MODY Genetic testing Next-generation sequencing Targeted gene sequencing 

Notes

Acknowledgements

We thank the patients, their parents and healthcare professionals who participated in this study. We also thank the CSS-Mendel Institute (Rome, Italy) for the collaboration and the provision of infrastructure for this research. This work was supported by Institut Pasteur of Tunis (PCI-15) and the Tunisian Ministry of higher Education and Scientific Research (LR11 IPT05). This study was partly supported by the Italian Ministry of Health (“Ricerca Corrente 2015–2017” to S. Prudente).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were approved by Institut Pasteur of Tunis ethics committee (Reference: 2016/19/I/LR11IPT05) and were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

592_2018_1283_MOESM1_ESM.pdf (213 kb)
Supplementary material 1 (PDF 212 KB)

References

  1. 1.
    Hattersley A, Bruining J, Shield J et al (2009) The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 10:33–42.  https://doi.org/10.1111/j.1399-5448.2009.00571.x CrossRefGoogle Scholar
  2. 2.
    Kim SH (2015) Maturity-onset diabetes of the young: what do clinicians need to know? Diabetes Metab J 39:468–477.  https://doi.org/10.4093/dmj.2015.39.6.468 CrossRefGoogle Scholar
  3. 3.
    Prudente S, Jungtrakoon P, Marucci A et al (2015) Loss-of-function mutations in APPL1 in familial diabetes mellitus. Am J Hum Genet 97:177–185.  https://doi.org/10.1016/j.ajhg.2015.05.011 CrossRefGoogle Scholar
  4. 4.
    Anik A, Çatli G, Abaci A, Böber E (2015) Maturity-onset diabetes of the young (MODY): an update. J Pediatr Endocrinol Metab 28:251–263.  https://doi.org/10.1515/jpem-2014-0384 Google Scholar
  5. 5.
    Timsit J, Saint-Martin C, Dubois-Laforgue D, Bellanné-Chantelot C (2016) Searching for maturity-onset diabetes of the young (MODY): when and what for? Can J Diabetes 40:455–461.  https://doi.org/10.1016/j.jcjd.2015.12.005 CrossRefGoogle Scholar
  6. 6.
    Shields BM, Hicks S, Shepherd MH et al (2010) Maturity-onset diabetes of the young (MODY): How many cases are we missing? Diabetologia 53:2504–2508.  https://doi.org/10.1007/s00125-010-1799-4 CrossRefGoogle Scholar
  7. 7.
    Fendler W, Borowiec M, Baranowska-Jazwiecka A et al (2012) Prevalence of monogenic diabetes amongst Polish children after a nationwide genetic screening campaign. Diabetologia 55:2631–2635.  https://doi.org/10.1007/s00125-012-2621-2 CrossRefGoogle Scholar
  8. 8.
    Irgens HU, Molnes J, Johansson BB et al (2013) Prevalence of monogenic diabetes in the population-based Norwegian childhood diabetes registry. Diabetologia 56:1512–1519.  https://doi.org/10.1007/s00125-013-2916-y CrossRefGoogle Scholar
  9. 9.
    Pihoker C, Gilliam LK, Ellard S et al (2013) Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for diabetes in Youth. J Clin Endocrinol Metab 98:4055–4062.  https://doi.org/10.1210/jc.2013-1279 CrossRefGoogle Scholar
  10. 10.
    Thanabalasingham G, Pal A, Selwood MP et al (2012) Systematic assessment of etiology in adults with a clinical diagnosis of young-onset type 2 diabetes is a successful strategy for identifying maturity-onset diabetes of the young. Diabetes Care 35:1206–1212.  https://doi.org/10.2337/dc11-1243 CrossRefGoogle Scholar
  11. 11.
    Rubio-Cabezas O, Hattersley AT, Njølstad PR et al (2014) The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 15:47–64.  https://doi.org/10.1111/pedi.12192 CrossRefGoogle Scholar
  12. 12.
    Thanabalasingham G, Owen KR (2011) Diagnosis and management of maturity onset diabetes of the young (MODY). Bmj 343:d6044–d6044.  https://doi.org/10.1136/bmj.d6044 CrossRefGoogle Scholar
  13. 13.
    Pearson ER, Starkey BJ, Powell RJ et al (2003) Mechanisms of disease genetic cause of hyperglycaemia and response to treatment in diabetes GLOSSARY. Lancet 362:1275–1281.  https://doi.org/10.1016/S0140-6736(03)14571-0 CrossRefGoogle Scholar
  14. 14.
    Stride A, Shields B, Gill-carey O et al (2014) Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia 57:54–56.  https://doi.org/10.1007/s00125-013-3075-x CrossRefGoogle Scholar
  15. 15.
    Johansson S, Irgens H, Chudasama KK et al (2012) Exome sequencing and genetic testing for MODY. PLoS One 7:1–8.  https://doi.org/10.1371/journal.pone.0038050 Google Scholar
  16. 16.
    Ellard S, Lango Allen H, De Franco E et al (2013) Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia 56:1958–1963.  https://doi.org/10.1007/s00125-013-2962-5 CrossRefGoogle Scholar
  17. 17.
    Bonnefond A, Philippe J, Durand E et al (2014) Highly sensitive diagnosis of 43 monogenic forms of diabetes or obesity through one-step pcrbased enrichment in combination with next-generation sequencing. Diabetes Care 37:460–467.  https://doi.org/10.2337/dc13-0698 CrossRefGoogle Scholar
  18. 18.
    Gao R, Liu Y, Gjesing AP et al (2014) Evaluation of a target region capture sequencing platform using monogenic diabetes as a study-model. BMC Genet 15:6–8.  https://doi.org/10.1186/1471-2156-15-13 CrossRefGoogle Scholar
  19. 19.
    Alkorta-Aranburu G, Carmody D, Cheng YW et al (2014) Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. Mol Genet Metab 113:315–320.  https://doi.org/10.1016/j.ymgme.2014.09.007 CrossRefGoogle Scholar
  20. 20.
    Amara A, Chadli-Chaieb M, Ghezaiel H et al (2012) Familial early-onset diabetes is not a typical MODY in several Tunisian patients. Tunis Med 90:882–887Google Scholar
  21. 21.
    Amara A, Chadli-chaieb M, Chaieb L et al (2014) Challenges for molecular diagnosis of familial early-onset diabetes in unexplored populations. Iran J Public Health 43:1011–1013Google Scholar
  22. 22.
    Khelifa SB, Martinez R, Dandana A et al (2018) Maturity onset diabetes of the young (MODY) in Tunisia: low frequencies of GCK and HNF1A mutations. Gene 651:44–48.  https://doi.org/10.1016/j.gene.2018.01.081 CrossRefGoogle Scholar
  23. 23.
    Mcdonald TJ, Colclough K, Brown R et al (2011) Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type1 diabetes. Diabet Med 28:1028–1033.  https://doi.org/10.1111/j.1464-5491.2011.03287.x CrossRefGoogle Scholar
  24. 24.
    Pezzilli S, Ludovico O, Biagini T et al (2018) Insights from molecular characterization of adult patients of families with multigenerational diabetes. Diabetes 67:137–145.  https://doi.org/10.2337/db17-0867 CrossRefGoogle Scholar
  25. 25.
    Desvignes J-P, Bartoli M, Delague V et al (2018) VarAFT: a variant annotation and filtration system for human next generation sequencing data. Nucleic Acids Res 46:W545–W553.  https://doi.org/10.1093/nar/gky471 CrossRefGoogle Scholar
  26. 26.
    Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164–e164.  https://doi.org/10.1093/nar/gkq603 CrossRefGoogle Scholar
  27. 27.
    Desmet FO, Hamroun D, Lalande M et al (2009) Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37:1–14.  https://doi.org/10.1093/nar/gkp215 CrossRefGoogle Scholar
  28. 28.
    Leman R, Gaildrat P, Gac GL et al (2018) Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort. Nucleic Acids Res 46:7913–7923.  https://doi.org/10.1093/nar/gky372 CrossRefGoogle Scholar
  29. 29.
    Fokkema IFAC, Taschner PEM, Schaafsma GCP et al (2011) LOVD v.2.0: the next generation in gene variant databases. Hum Mutat 32:557–563.  https://doi.org/10.1002/humu.21438 CrossRefGoogle Scholar
  30. 30.
    Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PEM (2008) Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Hum Mutat 29:6–13.  https://doi.org/10.1002/humu.20654 CrossRefGoogle Scholar
  31. 31.
    Hall TA (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 41:95–98Google Scholar
  32. 32.
    Ellard S, De Franco E (2014) Next-generation sequencing for the diagnosis of monogenic diabetes and discovery of novel aetiologies. Front Diabetes 23:71–86.  https://doi.org/10.1159/000362468 CrossRefGoogle Scholar
  33. 33.
    Castellana S, Fusilli C, Mazza T (2016) Chap. 22 A broad overview of computational methods for predicting the pathophysiological effects of non-synonymous variants. Methods Mol Biol 1415:423–440.  https://doi.org/10.1007/978-1-4939-3572-7 CrossRefGoogle Scholar
  34. 34.
    Ellard S, Bellanné-Chantelot C, Hattersley AT (2008) Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia 51:546–553.  https://doi.org/10.1007/s00125-008-0942-y CrossRefGoogle Scholar
  35. 35.
    Murphy R, Ellard S, Hattersley AT (2008) Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 4:200–213.  https://doi.org/10.1038/ncpendmet0778 CrossRefGoogle Scholar
  36. 36.
    George DCP, Chakraborty C, Haneef SAS et al (2014) Evolution- and structure-based computational strategy reveals the impact of deleterious missense mutations on MODY 2 (maturity-onset diabetes of the young, type 2). Theranostics 4:366–385.  https://doi.org/10.7150/thno.7473 CrossRefGoogle Scholar
  37. 37.
    Bowman P, Flanagan SE, Edghill EL et al (2012) Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia 1:123–127.  https://doi.org/10.1007/s00125-011-2319-x CrossRefGoogle Scholar
  38. 38.
    Ovsyannikova AK, Rymar OD, Shakhtshneider EV (2016) ABCC8-related maturity-onset diabetes of the young (MODY12): clinical features and treatment perspective. Diabetes Ther 7:591–600.  https://doi.org/10.1007/s13300-016-0192-9 CrossRefGoogle Scholar
  39. 39.
    Riveline J-P, Rousseau E, Reznik Y et al (2012) Clinical and metabolic features of adult-onset diabetes caused by ABCC8 mutations. Diabetes Care 35:248–251.  https://doi.org/10.2337/dc11-1469 CrossRefGoogle Scholar
  40. 40.
    Klee P, Bellanné-chantelot C, Depret G et al (2012) A novel ABCC8 mutation illustrates the variability of the diabetes phenotypes associated with a single mutation. Diabetes Metab 38:179–182.  https://doi.org/10.1016/j.diabet.2011.12.001 CrossRefGoogle Scholar
  41. 41.
    Singh A, Satchell SC (2011) Microalbuminuria: causes and implications. Pediatr Nephrol 26:1957–1965.  https://doi.org/10.1007/s00467-011-1777-1 CrossRefGoogle Scholar
  42. 42.
    Pruhova S, Dusatkova P, Neumann D et al (2013) Two cases of diabetic ketoacidosis in HNF1A-MODY linked to severe dehydration: is it time to change the diagnostic criteria for MODY? Diabetes Care 36:2573–2574.  https://doi.org/10.2337/dc13-0058 CrossRefGoogle Scholar
  43. 43.
    Egan AM, Cunningham A, Jafar-Mohammadi B, Dunne FP (2015) Diabetic ketoacidosis in the setting of HNF1A-maturity onset diabetes of the young. BMJ Case Rep 2015:bcr2014209163.  https://doi.org/10.1136/bcr-2014-209163 CrossRefGoogle Scholar
  44. 44.
    Fen S, Chi S, Sh C et al (2016) A preliminary study to evaluate the strategy of combining clinical criteria and next generation sequencing (NGS) for the identification of monogenic diabetes among multi-ethnic Asians. Diabetes Res Clin Pract 119:13–22.  https://doi.org/10.1016/j.diabres.2016.06.008 CrossRefGoogle Scholar
  45. 45.
    Szopa M, Ludwig-Gałęzowska A, Radkowski P et al (2015) Genetic testing for monogenic diabetes using targeted next-generation sequencing in patients with maturity-onset diabetes of the young. Polish Arch Intern Med 125:845–851.  https://doi.org/10.20452/pamw.3164 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2019

Authors and Affiliations

  • Hamza Dallali
    • 1
    • 2
  • Serena Pezzilli
    • 3
    • 4
  • Meriem Hechmi
    • 1
    • 2
  • Om Kalthoum Sallem
    • 5
  • Sahar Elouej
    • 1
    • 6
  • Haifa Jmel
    • 1
    • 7
  • Yosra Ben Halima
    • 1
    • 8
  • Mariem Chargui
    • 1
  • Mariem Gharbi
    • 1
  • Luana Mercuri
    • 3
  • Federica Alberico
    • 3
  • Tommaso Mazza
    • 9
  • Afaf Bahlous
    • 10
  • Melika Ben Ahmed
    • 11
  • Henda Jamoussi
    • 1
    • 12
  • Abdelmajid Abid
    • 1
    • 12
  • Vincenzo Trischitta
    • 3
    • 4
  • Sonia Abdelhak
    • 1
    • 8
  • Sabrina Prudente
    • 3
  • Rym Kefi
    • 1
    • 8
    Email author
  1. 1.Laboratory of Biomedical Genomics and OncogeneticsInstitut Pasteur de TunisTunisTunisia
  2. 2.National Institute of Applied Sciences and TechnologyUniversity of CarthageTunisTunisia
  3. 3.Research Unit of Metabolic and Cardiovascular DiseasesFondazione IRCCS Casa Sollievo della SofferenzaSan Giovanni RotondoItaly
  4. 4.Department of Experimental MedicineSapienza UniversityRomeItaly
  5. 5.Fattouma Bourguiba University HospitalMonastirTunisia
  6. 6.Faculty of Medicine La Timone, INSERM, GMGFAix Marseille UniversityMarseilleFrance
  7. 7.Faculty of Sciences of BizerteUniversity of CarthageTunisTunisia
  8. 8.University of Tunis El ManarTunisTunisia
  9. 9.Unit of BioinformaticsIRCCS Casa Sollievo della SofferenzaSan Giovanni RotondoItaly
  10. 10.Central Laboratory of Medical BiologyInstitut Pasteur de TunisTunisTunisia
  11. 11.Laboratory of Transmission, Control and Immunobiology of InfectionsInstitut Pasteur de TunisTunisTunisia
  12. 12.Research Unit on ObesityNational Institute of Nutrition and Food TechnologyTunisTunisia

Personalised recommendations