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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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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Abstract	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.
AbstractList	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. 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. 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.
Author	Caetano, L.A. Nery, M. Kohara, S.K. Zarabia, Z.I. Teles, M.G. Costa‐Riquetto, A.D. Collett‐Solberg, P. Crisostomo, L.G. Floh, F.O. Jorge, A.A.L. Santana, L.S. Sewaybricker, L.E. Passone, C.G.B. Quedas, E.P.S. Guastapaglia, L. Boguszewski, M.C.S. Vendramini, M.F.
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Snippet	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... 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... Maturity‐onset diabetes of the young ( MODY ) is a form of monogenic diabetes with autosomal dominant inheritance. GCK ‐ MODY and HNF1A ‐ MODY are the... 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...
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SubjectTerms	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
Title	Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families
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