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

The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study
The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study
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
0140-6736
957-963
De Franco, Elisa
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Flanagan, Sarah E.
ad5fb709-7f4b-4063-9b9f-bdf9c1cf1d2b
Houghton, Jayne A.L.
f3b605d5-5caf-48f6-a378-417582c0ccd7
Allen, Hana Lango
f8e411b9-3c54-42e5-92d6-eadfb95963b7
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Ellard, Sian
6c9b0ede-8980-4602-b063-444b165baa09
Hattersley, Andrew T.
429254b8-e75b-46bd-a6f6-274130336b0d
De Franco, Elisa
8095fa27-0cd3-47c9-add4-037182ed1af2
Flanagan, Sarah E.
ad5fb709-7f4b-4063-9b9f-bdf9c1cf1d2b
Houghton, Jayne A.L.
f3b605d5-5caf-48f6-a378-417582c0ccd7
Allen, Hana Lango
f8e411b9-3c54-42e5-92d6-eadfb95963b7
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Ellard, Sian
6c9b0ede-8980-4602-b063-444b165baa09
Hattersley, Andrew T.
429254b8-e75b-46bd-a6f6-274130336b0d

De Franco, Elisa, Flanagan, Sarah E., Houghton, Jayne A.L., Allen, Hana Lango, Mackay, Deborah J.G., Temple, I. Karen, Ellard, Sian and Hattersley, Andrew T. (2015) The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. The Lancet, 386 (9997), 957-963. (doi:10.1016/S0140-6736(15)60098-8). (PMID:26231457)

Record type: Article

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

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e-pub ahead of print date: 29 July 2015
Published date: 5 September 2015
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 380029
URI: http://eprints.soton.ac.uk/id/eprint/380029
ISSN: 0140-6736
PURE UUID: 97b42d55-83df-457d-a3e8-9854554d3409
ORCID for Deborah J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

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Date deposited: 01 Sep 2015 13:26
Last modified: 16 Aug 2024 01:36

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Contributors

Author: Elisa De Franco
Author: Sarah E. Flanagan
Author: Jayne A.L. Houghton
Author: Hana Lango Allen
Author: I. Karen Temple ORCID iD
Author: Sian Ellard
Author: Andrew T. Hattersley

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