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

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 investi gated, 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 patho genic (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.