Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

Maturity‐onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK ‐MODY and HNF1A ‐MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medic...

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Bibliographic Details
Published in:Clinical genetics Vol. 92; no. 4; pp. 388 - 396
Main Authors: Santana, L.S., Caetano, L.A., Costa‐Riquetto, A.D., Quedas, E.P.S., Nery, M., Collett‐Solberg, P., Boguszewski, M.C.S., Vendramini, M.F., Crisostomo, L.G., Floh, F.O., Zarabia, Z.I., Kohara, S.K., Guastapaglia, L., Passone, C.G.B., Sewaybricker, L.E., Jorge, A.A.L., Teles, M.G.
Format: Journal Article
Language:English
Published: Oxford, UK Blackwell Publishing Ltd 01-10-2017
Subjects:
ACMG
Adolescent
Adult
Autosomal dominant inheritance
Brazil - epidemiology
Child
Child, Preschool
Cohort Studies
Diabetes
Diabetes mellitus
Diabetes Mellitus, Type 2 - epidemiology
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - pathology
Female
GCK
Genotype & phenotype
Hepatocyte Nuclear Factor 1-alpha - genetics
Heredity
HNF1A
Humans
Male
MODY
Mutation
Pathogenicity
Phenotype
Protein-Serine-Threonine Kinases - genetics
Young Adult
ACMG
MODY
HNF1A
GCK
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Summary:Maturity‐onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK ‐MODY and HNF1A ‐MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK ‐MODY and 55% with suspicion of HNF1A ‐MODY. Twenty‐five different variants were identified in GCK gene (30 probands—61% of positivity), and 7 variants in HNF1A (10 probands—17% of positivity). Fourteen of them were novel (12— GCK /2— HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%— GCK /86%— HNF1A ) and likely pathogenic (44%— GCK /14%— HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.
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ISSN:0009-9163
1399-0004
DOI:10.1111/cge.12988