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

摘要

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.