King's College London

TY - JOUR

T1 - Comprehensive genetic screening

T2 - The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort

AU - Johnson, Stephanie R.

AU - Ellis, Jonathan J.

AU - Leo, Paul J.

AU - Anderson, Lisa K.

AU - Ganti, Uma

AU - Harris, Jessica E.

AU - Curran, Jacqueline A.

AU - McInerney-Leo, Aideen M.

AU - Paramalingam, Nirubasini

AU - Song, Xiaoxia

AU - Conwell, Louise S.

AU - Harris, Mark

AU - Jones, Timothy W.

AU - Brown, Matthew A.

AU - Davis, Elizabeth A.

AU - Duncan, Emma L.

PY - 2019/2

Y1 - 2019/2

N2 - Background: Maturity-onset diabetes of the young (MODY) is caused by autosomal dominant mutations in one of 13 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 2.6 million). 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 diagnosed with antibody-negative type 1 diabetes (T1DM), three diagnosed 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.

AB - Background: Maturity-onset diabetes of the young (MODY) is caused by autosomal dominant mutations in one of 13 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 2.6 million). 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 diagnosed with antibody-negative type 1 diabetes (T1DM), three diagnosed 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.

KW - childhood diabetes

KW - genetic testing

KW - massively parallel sequencing

KW - maturity-onset diabetes of the young

KW - prevalence

UR - http://www.scopus.com/inward/record.url?scp=85056477809&partnerID=8YFLogxK

U2 - 10.1111/pedi.12766

DO - 10.1111/pedi.12766

M3 - Article

C2 - 30191644

AN - SCOPUS:85056477809

VL - 20

SP - 57

EP - 64

JO - PEDIATRIC DIABETES

JF - PEDIATRIC DIABETES

SN - 1399-543X

IS - 1

ER -