A cross-sectional study of patients referred for HNF1B-MODY genetic testing due to cystic kidneys and diabetes.
Adolescent
Adult
Central Nervous System Diseases
/ diagnosis
Child
Child, Preschool
Cross-Sectional Studies
Dental Enamel
/ abnormalities
Diabetes Mellitus, Type 2
/ diagnosis
Diagnosis, Differential
Female
Follow-Up Studies
Genetic Predisposition to Disease
Genetic Testing
Hepatocyte Nuclear Factor 1-beta
/ genetics
Humans
Infant
Kidney Diseases, Cystic
/ diagnosis
Male
Middle Aged
Mutation
Patient Selection
Poland
/ epidemiology
Referral and Consultation
/ statistics & numerical data
Young Adult
MODY
cystic kidneys
diabetes mellitus
genetic testing
phenotype
Journal
Pediatric diabetes
ISSN: 1399-5448
Titre abrégé: Pediatr Diabetes
Pays: Denmark
ID NLM: 100939345
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
22
08
2019
revised:
22
10
2019
accepted:
04
12
2019
pubmed:
12
12
2019
medline:
16
6
2021
entrez:
12
12
2019
Statut:
ppublish
Résumé
Patients referred for HNF1B testing present very heterogeneous phenotypes. Despite suggestive characteristics, many do not harbor mutations in HNF1B. Our objective was to evaluate the clinical characteristics of probands referred for HNF1B genetic testing through a nationwide monogenic diabetes screening program. Probands tested for HNF1B mutations in the 2005-2018 period (N = 50) were identified in the Polish Monogenic Diabetes Registry, which prospectively recruits primarily pediatric patients and their families on a nationwide scale. Variants that had been reported pathogenic were reassessed using criteria of the American College of Medical Genetics and Genomics (ACMG). A structured medical interview was performed with all available individuals, their parents, and/or their physicians. For each patient, HNF1B score was calculated based on available clinical information. The study group numbered 36 unrelated probands (28% lost to follow-up): 14 with pathogenic or likely-pathogenic variants in HNF1B, one with a variant of uncertain significance, and 21 negative for HNF1B mutations. Presence of cystic kidneys (OR = 9.17, 95% CI:1.87-44.92), pancreatic abnormalities (OR = 15, 95% CI:1.55-145.23), elevated liver enzymes (OR = 15, 95% CI:1.55-145.23) best discriminated HNF1B-positive cases from the negative ones. Presence of impaired glucose tolerance coupled with kidney disease in the proband and one parent was also highly predictive for HNF1B mutations (OR = 11.11, 95% CI:1.13-109.36). HNF1B-score with recommended cutoff distinguished patients with and without HNF1B findings with 100% sensitivity and 47.6% specificity. Addition of four clinical variables to select patients based on HNF1B score improved specificity to 71.4% (95% CI:47.8%-88.7%) while retaining 100% sensitivity. Detailed medical interview may enable more accurate patient selection for targeted genetic testing.
Sections du résumé
BACKGROUND/OBJECTIVES
Patients referred for HNF1B testing present very heterogeneous phenotypes. Despite suggestive characteristics, many do not harbor mutations in HNF1B. Our objective was to evaluate the clinical characteristics of probands referred for HNF1B genetic testing through a nationwide monogenic diabetes screening program.
METHODS
Probands tested for HNF1B mutations in the 2005-2018 period (N = 50) were identified in the Polish Monogenic Diabetes Registry, which prospectively recruits primarily pediatric patients and their families on a nationwide scale. Variants that had been reported pathogenic were reassessed using criteria of the American College of Medical Genetics and Genomics (ACMG). A structured medical interview was performed with all available individuals, their parents, and/or their physicians. For each patient, HNF1B score was calculated based on available clinical information.
RESULTS
The study group numbered 36 unrelated probands (28% lost to follow-up): 14 with pathogenic or likely-pathogenic variants in HNF1B, one with a variant of uncertain significance, and 21 negative for HNF1B mutations. Presence of cystic kidneys (OR = 9.17, 95% CI:1.87-44.92), pancreatic abnormalities (OR = 15, 95% CI:1.55-145.23), elevated liver enzymes (OR = 15, 95% CI:1.55-145.23) best discriminated HNF1B-positive cases from the negative ones. Presence of impaired glucose tolerance coupled with kidney disease in the proband and one parent was also highly predictive for HNF1B mutations (OR = 11.11, 95% CI:1.13-109.36). HNF1B-score with recommended cutoff distinguished patients with and without HNF1B findings with 100% sensitivity and 47.6% specificity. Addition of four clinical variables to select patients based on HNF1B score improved specificity to 71.4% (95% CI:47.8%-88.7%) while retaining 100% sensitivity.
CONCLUSIONS
Detailed medical interview may enable more accurate patient selection for targeted genetic testing.
Identifiants
pubmed: 31825128
doi: 10.1111/pedi.12959
pmc: PMC7217165
doi:
Substances chimiques
HNF1B protein, human
0
Hepatocyte Nuclear Factor 1-beta
138674-15-4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
422-430Informations de copyright
© 2019 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.
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