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. 2023 Mar 24:14:1116880.
doi: 10.3389/fendo.2023.1116880. eCollection 2023.

Monogenic diabetes in New Zealand - An audit based revision of the monogenic diabetes genetic testing pathway in New Zealand

Francesca Harrington  1 , Mark Greenslade  1 , Kevin Colclough  2 , Ryan Paul  3 , Craig Jefferies  4   5 , Rinki Murphy  6
Affiliations

Monogenic diabetes in New Zealand - An audit based revision of the monogenic diabetes genetic testing pathway in New Zealand

Francesca Harrington et al. Front Endocrinol (Lausanne). .

Abstract

Aims: To evaluate (a) the diagnostic yield of genetic testing for monogenic diabetes when using single gene and gene panel-based testing approaches in the New Zealand (NZ) population, (b) whether the MODY (Maturity Onset Diabetes of the Young) pre-test probability calculator can be used to guide referrals for testing in NZ, (c) the number of referrals for testing for Māori/Pacific ethnicities compared to NZ European, and (d) the volume of proband vs cascade tests being requested.

Methods: A retrospective audit of 495 referrals, from NZ, for testing of monogenic diabetes genes was performed. Referrals sent to LabPlus (Auckland) laboratory for single gene testing or small multi-gene panel testing, or to the Exeter Genomics Laboratory, UK, for a large gene panel, received from January 2014 - December 2021 were included. Detection rates of single gene, small multi-gene and large gene panels (neonatal and non-neonatal), and cascade testing were analysed. Pre-test probability was calculated using the Exeter MODY probability calculator and ethnicity data was also collected.

Results: The diagnostic detection rate varied across genes, from 32% in GCK, to 2% in HNF4A, with single gene or small gene panel testing averaging a 12% detection rate. Detection rate by type of panel was 9% for small gene panel, 23% for non-neonatal monogenic diabetes large gene panel and 40% for neonatal monogenic diabetes large gene panel. 45% (67/147) of patients aged 1-35 years at diabetes diagnosis scored <20% on MODY pre-test probability, of whom 3 had class 4/5 variants in HNF1A, HNF4A or HNF1B. Ethnicity data of those selected for genetic testing correlated with population diabetes prevalence for Māori (15% vs 16%), but Pacific People appeared under-represented (8% vs 14%). Only 1 in 6 probands generated a cascade test.

Conclusions: A new monogenic diabetes testing algorithm for NZ is proposed, which directs clinicians to choose a large gene panel in patients without syndromic features who score a pre-test MODY probability of above 20%.

Keywords: Aotearoa (New Zealand); MODY; New Zealand; genetic testing; genomics; monogenic diabetes.

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Conflict of interest statement

FH and MG are affiliated with LabPlus, which provides publicly funded genetic testing for monogenic diabetes. KC is affiliated with the Exeter Genomics Laboratory. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overall test breakdown. Overview of the LabPlus testing for monogenic diabetes January 2014 – December 2020, using Sanger sequencing, and CGH array for dosage testing. 116 tests were also sent to Exeter for wider panel testing using NGS. C4/C5 = likely pathogenic/pathogenic variant, as defined by ACMG. C3 = Variant of uncertain significance, as defined by ACMG.
Figure 2
Figure 2
Volume and Detection Rate by test type. Other dosage: dosage analysis performed for genes other than HNF1B. MODY NGS panel: Exeter large NGS panel testing. Negative indicates no C3/C4/C5 variants found.
Figure 3
Figure 3
Range of MODY probability scores seen using the MODY pre-test probability calculator. MODY pre-test probability of patients referred to LabPlus, where sufficient clinical data was available (n=104); calculations as per Shields et al. (7).
Figure 4
Figure 4
The number of tests referred to LabPlus and Exeter, by ethnicity. % Indicates the proportion of testing each ethnicity represents of the total cohort.
Figure 5
Figure 5
New monogenic diabetes testing algorithm for NZ.
See this image and copyright information in PMC

References

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    1. Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): How many cases are we missing? Diabetologia (2010) 53(12):2504–8. doi: 10.1007/s00125-010-1799-4 - DOI - PubMed
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Supplementary concepts