Genetic variant profiling of neonatal diabetes mellitus in Iranian patients: Unveiling 58 distinct variants in 14 genes.
molecular diagnosis
neonatal diabetes
novel variants
Journal
Journal of diabetes investigation
ISSN: 2040-1124
Titre abrégé: J Diabetes Investig
Pays: Japan
ID NLM: 101520702
Informations de publication
Date de publication:
06 Jul 2024
06 Jul 2024
Historique:
revised:
11
05
2024
received:
12
10
2023
accepted:
04
06
2024
medline:
6
7
2024
pubmed:
6
7
2024
entrez:
6
7
2024
Statut:
aheadofprint
Résumé
Neonatal diabetes mellitus (NDM) is a rare non-immunological monogenic disorder characterized by hyperglycemic conditions primarily occurring within the first 6 months of life. The majority of cases are attributed to pathogenic variants in genes affecting beta-cell survival, insulin regulation, and secretion. This study aims to investigate the genetic landscape of NDM in Iran. We recruited a total of 135 patients who were initially diagnosed with diabetes at <12 months of age in Iran and referred to pediatric endocrinology clinics across the country. These patients underwent genetic diagnostic tests conducted by the Exeter Molecular Genetics Laboratory in the UK. The pathogenic variants identified were sorted and described based on type, pathogenicity (according to ACMG/AMP criteria), novelty, and the affected protein domain. Genetic defects were identified in 93 probands, presenting various pathogenic abnormalities associated with NDM and its associated syndromes. 76% of the patients were born as a result of consanguineous marriage, and a familial history of diabetes was found in 43% of the cases. A total of 58 distinct variants in 14 different genes were discovered, including 20 variants reported for the first time. Causative variants were most frequently identified in EIF2AK3, KCNJ11, and ABCC8, respectively. Notably, EIF2AK3 and ABCC8 exhibited the highest number of novel variants. These findings provide valuable insights into the genetic landscape of NDM in the Iranian population and contribute to the knowledge of novel pathogenic variants within known causative genes.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Dr Yaghootkar's Wellcome Trust
ID : 108101/Z/15/Z
Organisme : National Institute for Medical Research Development (NIMAD), Tehran, Iran
Informations de copyright
© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.
Références
Glovaci D, Fan W, Wong ND. Epidemiology of diabetes mellitus and cardiovascular disease. Curr Cardiol Rep 2019; 21: 21.
GDaH C. Global Burden of Disease Study 2015 (GBD 2015) Results. Seattle, WA: Institute for Health Metrics and Evaluation (IHME), 2016.
Ali Khan I. Do second generation sequencing techniques identify documented genetic markers for neonatal diabetes mellitus? Heliyon 2021; 7: e07903.
Beltrand J, Busiah K, Vaivre‐Douret L, et al. Neonatal diabetes mellitus. Front Pediatr 2020; 8: 540718.
Hattersley AT, Greeley SAW, Polak M, et al. ISPAD clinical practice consensus guidelines 2018: the diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2018; 19(Suppl 27): 47–63.
Demirbilek H, Arya VB, Ozbek MN, et al. Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the south‐eastern region of Turkey: predominance of non‐KATP channel mutations. Eur J Endocrinol 2015; 172: 697–705.
Edghill EL, Flanagan SE, Patch A‐M, et al. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes 2008; 57: 1034–1042.
Cao B, Gong C, Wu D, et al. Genetic analysis and follow‐up of 25 neonatal diabetes mellitus patients in China. J Diabetes Res 2016; 2016: 6314368.
Schwarz JM, Cooper DN, Schuelke M, et al. MutationTaster2: mutation prediction for the deep‐sequencing age. Nat Methods 2014; 11: 361–362.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405–424.
Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG‐AMP guidelines. Am J Hum Genet 2017; 100: 267–280.
Pérez‐Palma E, May P, Iqbal S, et al. Identification of pathogenic variant enriched regions across genes and gene families. Genome Res 2020; 30: 62–71.
Turner T. Plot protein: visualization of mutations. J Clin Bioinforma 2013; 3: 14.
Madeira F, Pearce M, Tivey ARN, et al. Search and sequence analysis tools services from EMBL‐EBI in 2022. Nucleic Acids Res 2022; 50(W1): W276–W279.54
Kelly MA, Caleshu C, Morales A, et al. Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel. Genetics in Medicine 2018; 20(3): 351–359.
Zhao N, Yang Y, Li P, et al. Identification of two novel compound heterozygous EIF2AK3 mutations underlying Wolcott‐Rallison syndrome in a Chinese family. Front Pediatr 2021; 9: 679646.
Zhang HJ, Wang SB, Guo XF, et al. A case report of EIF2AK3‐related Wolcott‐Rallison syndrome and literature review. Zhongguo Dang Dai Er Ke Za Zhi 2019; 21: 176–179.
Lin YW, Akrouh A, Hsu Y, et al. Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic K(ATP) channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits. Channels (Austin) 2012; 6: 133–138.
Vasanwala RF, Lim SH, Ellard S, et al. Neonatal diabetes in a Singapore children's hospital: molecular diagnoses of four cases. Ann Acad Med Singap 2014; 43: 314–319.
De Franco E, Saint‐Martin C, Brusgaard K, et al. Update of variants identified in the pancreatic β‐cell K(ATP) channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes. Hum Mutat 2020; 41: 884–905.
Gopi S, Kavitha B, Kanthimathi S, et al. Genotype‐phenotype correlation of K(ATP) channel gene defects causing permanent neonatal diabetes in Indian patients. Pediatr Diabetes 2021; 22: 82–92.
Zhang M, Chen X, Shen S, et al. Sulfonylurea in the treatment of neonatal diabetes mellitus children with heterogeneous genetic backgrounds. J Pediatr Endocrinol Metab 2015; 28: 877–884.
Borowiec M, Fendler W, Antosik K, et al. Doubling the referral rate of monogenic diabetes through a nationwide information campaign – update on glucokinase gene mutations in a Polish cohort. Clin Genet 2012; 82: 587–590.
De Franco E, Shaw‐Smith C, Flanagan SE, et al. GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult‐onset diabetes without exocrine insufficiency. Diabetes 2013; 62: 993–997.
Sellick GS, Garrett C, Houlston RS. A novel gene for neonatal diabetes maps to chromosome 10p12.1‐p13. Diabetes 2003; 52: 2636–2638.
Weedon MN, Cebola I, Patch AM, et al. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat Genet 2014; 46: 61–64.
Fendler W, Pietrzak I, Brereton MF, et al. Switching to sulphonylureas in children with iDEND syndrome caused by KCNJ11 mutations results in improved cerebellar perfusion. Diabetes Care 2013; 36: 2311–2316.
Asl SN, Vakili R, Vakili S, et al. Wolcott‐Rallison syndrome in Iran: a common cause of neonatal diabetes. J Pediatr Endocrinol Metab 2019; 32: 607–613.
Rubio‐Cabezas O, Patch AM, Minton JA, et al. Wolcott‐Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab 2009; 94: 4162–4170.
Laimon W, El‐Ziny M, El‐Hawary A, et al. Genetic and clinical heterogeneity of permanent neonatal diabetes mellitus: a single tertiary centre experience. Acta Diabetol 2021; 58: 1689–1700.
Abbasi F, Habibi M, Enayati S, et al. A genotype‐first approach for clinical and genetic evaluation of Wolcott‐Rallison syndrome in a large cohort of Iranian children with neonatal diabetes. Can J Diabetes 2018; 42: 272–275.
Habeb AM, Flanagan SE, Deeb A, et al. Permanent neonatal diabetes: different aetiology in Arabs compared to Europeans. Arch Dis Child 2012; 97: 721–723.
Ibrahim MN, Laghari TM, Riaz M, et al. Monogenic diabetes in Pakistani infants and children: challenges in a resource poor country. J Pediatr Endocrinol Metab 2021; 34: 1095–1103.
Lemelman MB, Letourneau L, Greeley SAW. Neonatal diabetes mellitus: an update on diagnosis and management. Clin Perinatol 2018; 45: 41–59.
Brickwood S, Bonthron DT, Al‐Gazali LI, et al. Wolcott‐Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet 2003; 40: 685–689.
Busiah K, Drunat S, Vaivre‐Douret L, et al. Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study [corrected]. Lancet Diabetes Endocrinol 2013; 1: 199–207.
Vaxillaire M, Dechaume A, Busiah K, et al. New ABCC8 mutations in relapsing neonatal diabetes and clinical features. Diabetes 2007; 56: 1737–1741.
Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the gene encoding the ATP‐sensitive potassium‐channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004; 350: 1838–1849.
Edghill EL, Gloyn AL, Goriely A, et al. Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. J Clin Endocrinol Metab 2007; 92: 1773–1777.
Flanagan SE, Edghill EL, Gloyn AL, et al. Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia 2006; 49: 1190–1197.
Ješić MM, Ješić MD, Maglajlić S, et al. Successful sulfonylurea treatment of a neonate with neonatal diabetes mellitus due to a new KCNJ11 mutation. Diabetes Res Clin Pract 2011; 91: e1–e3.
Suzuki S, Makita Y, Mukai T, et al. Molecular basis of neonatal diabetes in Japanese patients. J Clin Endocrinol Metab 2007; 92: 3979–3985.
Garin I, Perez de Nanclares G, Gastaldo E, et al. Permanent neonatal diabetes caused by creation of an ectopic splice site within the INS gene. PLoS One 2012; 7: e29205.
Courtney R, Gamble C, Arango ML, et al. Novel homozygous likely‐pathogenic intronic variant in INS causing permanent neonatal diabetes in siblings. J Pediatr Endocrinol Metab 2016; 29: 1089–1093.
Støy J, Edghill EL, Flanagan SE, et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA 2007; 104: 15040–15044.
Garin I, Edghill EL, Akerman I, et al. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proc Natl Acad Sci USA 2010; 107: 3105–3110.
Aykut A, Karaca E, Onay H, et al. Analysis of the GCK gene in 79 MODY type 2 patients: a multicenter Turkish study, mutation profile and description of twenty novel mutations. Gene 2018; 641: 186–189.
Thomson KL, Gloyn AL, Colclough K, et al. Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity‐onset diabetes of the young (MODY). Hum Mutat 2003; 22: 417.
Zubkova N, Burumkulova F, Plechanova M, et al. High frequency of pathogenic and rare sequence variants in diabetes‐related genes among Russian patients with diabetes in pregnancy. Acta Diabetol 2019; 56: 413–420.
Ozdemir MA, Akcakus M, Kurtoglu S, et al. TRMA syndrome (thiamine‐responsive megaloblastic anemia): a case report and review of the literature. Pediatr Diabetes 2002; 3: 205–209.
Sahebi L, Niknafs N, Dalili H, et al. Iranian neonatal diabetes mellitus due to mutation in PDX1 gene: a case report. J Med Case Rep 2019; 13: 258.
Johnson MB, De Franco E, Lango Allen H, et al. Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. Diabetes 2017; 66: 2316–2322.
Bonnefond A, Vaillant E, Philippe J, et al. Transcription factor gene MNX1 is a novel cause of permanent neonatal diabetes in a consanguineous family. Diabetes Metab 2013; 39: 276–280.
Sansbury FH, Flanagan SE, Houghton JA, et al. SLC2A2 mutations can cause neonatal diabetes, suggesting GLUT2 may have a role in human insulin secretion. Diabetologia 2012; 55: 2381–2385.