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

• 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
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.12988

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.