Comprehensive genetic screening: the prevalence of MODY gene variants in a population-based childhood diabetes cohort.

Johnson SR1,2,3, Ellis JJ2, Leo P2, Anderson LK2, Ganti U4,5, Harris JE2, Curran JA4,5, McInerney-Leo A2, Paramalingam N4,5, Song X2, Conwell LS1,3, Harris M1,3,6, Jones TW4,5,7, Brown MA2, Davis EA4,5,7, Duncan EL2,3,8.

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Abstract

BACKGROUND:

Maturity-onset diabetes of the young (MODY) is caused by autosomal dominant mutations in one of thirteen confirmed genes. Estimates of MODY prevalence vary widely, as genetic screening is usually restricted based on clinical features, even in population studies. We aimed to determine prevalence of MODY variants in a large and unselected pediatric diabetes cohort.

METHODS:

MODY variants were assessed using massively parallel sequencing in the population-based diabetes cohort (n=1363) of the sole tertiary pediatric diabetes service for Western Australia (population 2.6million). All individuals were screened, irrespective of clinical features. MODY variants were also assessed in a control cohort (n=993).

RESULTS:

DNA and signed consent were available for 821 children. Seventeen children had pathogenic/likely pathogenic variants in MODY genes - two diagnosed with type 2 diabetes, four with antibody-negative type 1 diabetes (T1DM), three with antibody-positive T1DM, and eight previously diagnosed with MODY. Prevalence of MODY variants in the sequenced cohort was 2.1%, compared to 0.3% of controls.

CONCLUSIONS:

This is the first comprehensive study of MODY variants in an unselected population-based pediatric diabetes cohort. The observed prevalence, increasing access to rapid and affordable genetic screening, and significant clinical implications suggest that genetic screening for MODY could be considered for all children with diabetes, irrespective of other clinical features. This article is protected by copyright. All rights reserved.