CoChat
Sign Up
Cited by 349Pancreatic function and diabetesDiabetes and associated disordersGenomics and Rare Diseases

The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study

Open access
De Franco, Elisa, Flanagan, Sarah E, Houghton, Jayne AL, Allen, Hana Lango, Mackay, Deborah JG, Temple, I Karen, Ellard, Sian, Hattersley, Andrew T·2015·The Lancet
DOI 10.1016/s0140-6736(15)60098-8PMC PMC4772451
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: Traditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes. METHODS: In this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes. FINDINGS: Between January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p<0·0001). Median duration of diabetes at the time of genetic testing decreased from more than 4 years before 2005 to less than 3 months after 2012. Earlier referral for genetic testing affected the clinical phenotype. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from diagnosis had isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0·0001), in whom skeletal and liver involvement was common. Similarly, for patients with genetically diagnosed transient neonatal diabetes, the diabetes had remitted in only ten (10%) of 101 patients tested early (<3 months) compared with 60 (100%) of the 60 later referrals (p<0·0001). INTERPRETATION: Patients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management. FUNDING: Wellcome Trust and Diabetes UK.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/s0140-6736(15)60098-8

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 30-50% of people with ATP-sensitive potassium channel mutations can replace insulin with sulfonylureas.

    “As monogenic diabetes was less likely to have been considered in the past, molecular genetic testing for neonatal diabetes should be considered for all people with type 1 diabetes, regardless of current age, who were diagnosed under 6 months of age as more than 80% have monogenic neonatal diabetes, and the 30-50% with ATP-sensitive potassium (K ATP ) channel mutations can replace insulin with sulf”

    From The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2021) · cites this paper as [32]

    The Discussion reports that about 40% of the neonatal-diabetes cohort had potassium-channel mutations and that most of those patients achieved improved glycaemic control after switching from insulin to sulfonylureas. The cited 30–50% range therefore describes the proportion with mutations, not the proportion of mutation carriers who can replace insulin, as the quoted claim states. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Diabetes occurring under 6 months of age is termed neonatal or congenital diabetes, and about 80-85% of cases can be found to have an underlying monogenic cause.

    “Diabetes occurring under 6 months of age is termed neonatal or congenital diabetes, and about 80 -85% of cases can be found to have an underlying monogenic cause (36,157 -160).”

    From 2. Diagnosis and Classification of Diabetes: <i>Standards of Care in Diabetes—2024</i> (2024) · cites this paper as [157]

  • About 80-85% of neonatal diabetes cases can be found to have an underlying monogenic cause.

    “about 80-85% of cases can be found to have an underlying monogenic cause (36,(154)(155)(156)(157).”

    From 2. Diagnosis and classification of diabetes: standards of care in diabetes-2025 (2025) · cites this paper as [154]

  • More than 80% of people with diabetes diagnosed under 6 months of age have monogenic neonatal diabetes.

    “As monogenic diabetes was less likely to have been considered in the past, molecular genetic testing for neonatal diabetes should be considered for all people with type 1 diabetes, regardless of current age, who were diagnosed under 6 months of age as more than 80% have monogenic neonatal diabetes, and the 30-50% with ATP-sensitive potassium (K ATP ) channel mutations can replace insulin with sulf”

    From The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2021) · cites this paper as [32]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 37

  1. [1]Iafusco D Massa O Pasquino B the Early Diabetes Study Group of ISPED Minimal incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births Acta Diabetol 49 2012 405 408 21953423 PMC3464369
  2. [2]Slingerland AS Shields BM Flanagan SE Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260?000 live births Diabetologia 52 2009 1683 1685 19499210 PMC2709852
  3. [3]Edghill EL Dix RJ Flanagan SE HLA genotyping supports a nonautoimmune etiology in patients diagnosed with diabetes under the age of 6 months Diabetes 55 2006 1895 1898 16731860
  4. [4]Iafusco D Stazi MA Cotichini R the Early Onset Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetology Permanent diabetes mellitus in the first year of life Diabetologia 45 2002 798 804 12107723
  5. [6]Proks P Arnold AL Bruining J A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes Hum Mol Genet 15 2006 1793 1800 16613899
  6. [7]Babenko AP Polak M Cavé H Activating mutations in the ABCC8 gene in neonatal diabetes mellitus N Engl J Med 355 2006 456 466 16885549
  7. [8]Sagen JV Raeder H Hathout E Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy Diabetes 53 2004 2713 2718 15448106
  8. [9]Pearson ER Flechtner I Njølstad PR the Neonatal Diabetes International Collaborative Group Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations N Engl J Med 355 2006 467 477 16885550
  9. [10]Codner E Flanagan S Ellard S García H Hattersley AT High-dose glibenclamide can replace insulin therapy despite transitory diarrhea in early-onset diabetes caused by a novel R201L Kir6.2 mutation Diabetes Care 28 2005 758 759 15735229
  10. [11]Rafiq M Flanagan SE Patch AM Shields BM Ellard S Hattersley AT the Neonatal Diabetes International Collaborative Group Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations Diabetes Care 31 2008 204 209 18025408 PMC7611807
  11. [12]Hattersley A Bruining J Shield J Njolstad P Donaghue K the International Society for Pediatric and Adolescent Diabetes ISPAD Clinical Practice Consensus Guidelines 2006–2007. The diagnosis and management of monogenic diabetes in children Pediatr Diabetes 7 2006 352 360 17212604
  12. [13]Bonnefond A Philippe J Durand E Highly sensitive diagnosis of 43 monogenic forms of diabetes or obesity through one-step PCR-based enrichment in combination with next-generation sequencing Diabetes Care 37 2014 460 467 24041679
  13. [14]Ellard S Lango Allen H De Franco E Improved genetic testing for monogenic diabetes using targeted next-generation sequencing Diabetologia 56 2013 1958 1963 23771172 PMC3737433
  14. [15]Gao R Liu Y Gjesing AP Evaluation of a target region capture sequencing platform using monogenic diabetes as a study-model BMC Genet 15 2014 13 24476040 PMC3943834
  15. [16]Bittles AH A community genetics perspective on consanguineous marriage Community Genet 11 2008 324 330 18690000
  16. [17]Lander ES Botstein D Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children Science 236 1987 1567 1570 2884728
  17. [18]Flanagan SE Patch AM Locke JM Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees J Clin Endocrinol Metab 96 2011 E498 E502 21252247 PMC3100671
  18. [19]Rubio-Cabezas O Flanagan SE Damhuis A Hattersley AT Ellard S KATP channel mutations in infants with permanent diabetes diagnosed after 6 months of life Pediatr Diabetes 13 2012 322 325 21981029
  19. [20]Mackay DJ Temple IK Shield JP Robinson DO Bisulphite sequencing of the transient neonatal diabetes mellitus DMR facilitates a novel diagnostic test but reveals no methylation anomalies in patients of unknown aetiology Hum Genet 116 2005 255 261 15635480
  20. [21]Delépine M Nicolino M Barrett T Golamaully M Lathrop GM Julier C EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome Nat Genet 25 2000 406 409 10932183
  21. [22]Støy J Edghill EL Flanagan SE the Neonatal Diabetes International Collaborative Group Insulin gene mutations as a cause of permanent neonatal diabetes Proc Natl Acad Sci USA 104 2007 15040 15044 17855560 PMC1986609
  22. [23]Garin I Edghill EL Akerman I the Neonatal Diabetes International Group Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis Proc Natl Acad Sci USA 107 2010 3105 3110 20133622 PMC2840338
  23. [24]Shearer AE DeLuca AP Hildebrand MS Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing Proc Natl Acad Sci USA 107 2010 21104 21109 21078986 PMC3000272
  24. [25]Valencia CA Ankala A Rhodenizer D Comprehensive mutation analysis for congenital muscular dystrophy: a clinical PCR-based enrichment and next-generation sequencing panel PLoS One 8 2013 e53083 23326386 PMC3543442
  25. [26]O'Sullivan J Mullaney BG Bhaskar SS A paradigm shift in the delivery of services for diagnosis of inherited retinal disease J Med Genet 49 2012 322 326 22581970
  26. [27]Gardner RJ Mackay DJ Mungall AJ An imprinted locus associated with transient neonatal diabetes mellitus Hum Mol Genet 9 2000 589 596 10699182
  27. [28]Temple IK Gardner RJ Robinson DO Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22-q23 Hum Mol Genet 5 1996 1117 1121 8842729
  28. [29]Temple IK Shield JP Transient neonatal diabetes, a disorder of imprinting J Med Genet 39 2002 872 875 12471198 PMC1757233
  29. [30]Flanagan SE Patch AM Mackay DJ Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood Diabetes 56 2007 1930 1937 17446535 PMC7611811
  30. [31]Gloyn AL Reimann F Girard C Relapsing diabetes can result from moderately activating mutations in KCNJ11 Hum Mol Genet 14 2005 925 934 15718250
  31. [32]Busiah K Drunat S Vaivre-Douret L Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study Lancet Diabetes Endocrinol 1 2013 199 207 24622368
  32. [33]Julier C Nicolino M Wolcott-Rallison syndrome Orphanet J Rare Dis 5 2010 29 21050479 PMC2991281
  33. [34]Proks P Antcliff JF Lippiat J Gloyn AL Hattersley AT Ashcroft FM Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features Proc Natl Acad Sci USA 101 2004 17539 17544 15583126 PMC536014
  34. [35]Slingerland AS Nuboer R Hadders-Algra M Hattersley AT Bruining GJ Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene Diabetologia 49 2006 2559 2563 17047922
  35. [36]Shimomura K Hörster F de Wet H A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain Neurology 69 2007 1342 1349 17652641
  36. [37]Chatila TA Blaeser F Ho N JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome J Clin Invest 106 2000 R75 R81 11120765 PMC387260
  37. [38]Barzaghi F Passerini L Bacchetta R Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity Front Immunol 3 2012 211 23060872 PMC3459184

Cited by

Sorted by citations

Authors
De Franco, E., Flanagan, S. E., Houghton, J. A., Allen, H. L., Mackay, D. J., Temple, I. K., Ellard, S., & Hattersley, A. T.
Affiliations
  • University of Exeter (GB)
  • University Hospital Southampton NHS Foundation Trust (GB)
Corresponding author
Hattersley, Andrew T
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2015-09
Volume
386
Issue
9997
Pages
957-963
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(15)60098-8
PMC
PMC4772451
OpenAlex
W1757525562
Cited by
349
References
1
Citations by year
2026: 18 · 2025: 28 · 2024: 30 · 2023: 35 · 2022: 34 · 2021: 49 · 2020: 34 · 2019: 31 · 2018: 35 · 2017: 28 · 2016: 22 · 2015: 5
FWCI
30.24
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • Figshare (submittedVersion)
  • Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
Funders
  • Wellcome Trust (098395, WT101650MA, 098395/Z/12/Z, WT097835MF, WT098395/Z/12/Z)
  • National Institute for Health and Care Research (NF-SI-0611-10219)
  • Diabetes UK (WT097835MF, 12/0004501)
  • University of Exeter
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
neonatal diabetes, potassium channel mutations, Wolcott-Rallison syndrome, transient neonatal diabetes, consanguinity, diabetes remission, clinical phenotype prediction, targeted next-generation sequencing, Sanger sequencing, genotype-phenotype correlation
MeSH terms
Diabetes Mellitus, Female, Genetic Testing, Humans, Infant, Infant, Newborn, Infant, Newborn, Diseases, Male, Mutation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review