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 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.
Monogenic Diabetes Group, Genetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
L S
http://orcid.org/0000-0003-0428-2386
LS
Santana
Monogenic Diabetes Group, Genetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.|Diabetes Unit, Clinics Hospital, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
L A
http://orcid.org/0000-0002-4645-5858
LA
Caetano
Monogenic Diabetes Group, Genetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.|Diabetes Unit, Clinics Hospital, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
A D
AD
Costa-Riquetto
Monogenic Diabetes Group, Genetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
E P S
EPS
Quedas
Diabetes Unit, Clinics Hospital, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
M
M
Nery
Department of Endocrinology, University of Rio de Janeiro State (UERJ), Rio de Janeiro, RJ, Brazil.
P
P
Collett-Solberg
Departamento de Pediatria, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.
M C S
MCS
Boguszewski
Serviço de Endocrinologia, Hospital do Servidor Público Estadual de São Paulo (HSPE-SP), Sao Paulo, SP, Brazil.
M F
MF
Vendramini
Serviço de Endocrinologia, Hospital Israelita Albert Eisntein, Sao Paulo, SP, Brazil.|Faculdade de Medicina, Centro Universitário São Camilo, Sao Paulo, SP, Brazil.
L G
LG
Crisostomo
Serviço de Endocrinologia, Hospital Israelita Albert Eisntein, Sao Paulo, SP, Brazil.
F O
FO
Floh
Serviço de Endocrinologia, Hospital Infantil Dr. Jeser Amarante Faria, Joinville, SC, Brazil.
Z I
ZI
Zarabia
Serviço de Endocrinologia, Universidade da Região de Joinville (UNIVILLE), Joinville, SC, Brazil.
S K
SK
Kohara
Serviço de Endocrinologia, Hospital do Servidor Público Municipal de São Paulo (HSPM-SP), Sao Paulo, SP, Brazil.
L
L
Guastapaglia
Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (USP), Sao Paulo, SP, Brazil.
C G B
CGB
Passone
Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
L E
LE
Sewaybricker
Monogenic Diabetes Group, Genetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
A A L
AAL
Jorge
Monogenic Diabetes Group, Genetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.|Diabetes Unit, Clinics Hospital, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
M G
MG
Teles
D000293:Adolescent; D000328:Adult; D001938:Brazil / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D000081410:Germinal Center Kinases; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D055815:Young Adult
D000081410:Germinal Center Kinases; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D017346:Protein Serine-Threonine Kinases
ACMG; GCK; HNF1A; MODY