Startseite Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry
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Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

  • Emily Breidbart EMAIL logo , Liyong Deng , Patricia Lanzano , Xiao Fan , Jiancheng Guo , Rudolph L. Leibel , Charles A. LeDuc und Wendy K. Chung
Veröffentlicht/Copyright: 13. April 2021
Journal of Pediatric Endocrinology and Metabolism
Aus der Zeitschrift Journal of Pediatric Endocrinology and Metabolism Band 34 Heft 5

Abstract

Objectives

There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY.

Methods

We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%.

Results

Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation.

Conclusions

Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

Keywords: diabetes; genetics in diabetes and obesity; MODY; molecular genetics
Corresponding author: Emily Breidbart, Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, NYU School of Medicine, 150 East 32nd Street, 2nd Floor, New York, NY 10016, USA, Phone: +1 212 263 5940, Fax: +1 929 455 9225, E-mail:

Funding source: National Institutes of Health

Award Identifier / Grant number: P30DK26687

Funding source: National Institute of Diabetes and Digestive and Kidney Diseases

Award Identifier / Grant number: R01-DK52431T32 training grant 2T32DK065522

Funding source: Endocrine Fellows Foundation

Award Identifier / Grant number: Marilyn Fishman Grant for Diabetes Research

Acknowledgments

The authors gratefully thank the doctors at the Naomi Berrie Diabetes Center for referring eligible patients to their study, as well as referring providers across the country and globe who submitted patients. The authors thank the patients and their families for their contribution to research.

  1. Research funding: Research reported in this publication was supported by the NIDDK NRSA Institutional Research Training Grant (T32) 2T32DK065522 (PI Oberfield), Endocrine Fellows Foundation Grant, DK52431 (RLL), and P30DK26687 (WKC).

  2. Author contributions: Emily Breidbart and Wendy K. Chung designed the study. Emily Breidbart carried out the data collection, WES analysis, and wrote the initial draft of this paper. Liyong Deng, Charles LeDuc, and Jiancheng Guo performed and analyzed the Sanger sequencing. Patricia Lanzano coordinated data collection and kept the database. Xiao Fan helped with the WES analysis. Rudy L. Leibel gave input throughout the study and critically reviewed the data. Wendy K. Chung supervised each stage of the research and was the second reviewer of this manuscript. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  3. Competing interests: The funding organization played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

  4. Ethical approval: The study was reviewed and approved by the Institutional Review Board at Columbia University (IRB-AAAA4485). All participants provided written informed consent.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2020-0501).

Received: 2020-08-25
Accepted: 2021-02-12
Published Online: 2021-04-13
Published in Print: 2021-05-26

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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  4. Original Articles
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  17. Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry
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  19. Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China
  20. Case Reports
  21. Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family
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https://doi.org/10.1515/jpem-2020-0501
Schlagwörter für diesen Artikel
diabetes; genetics in diabetes and obesity; MODY; molecular genetics

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. Covid19 pandemic and pediatric endocrinology and metabolism—Are we through with it?
  4. Original Articles
  5. Invisible burden of COVID-19: enzyme replacement therapy disruptions
  6. Anthropometric, biochemical and hormonal profiles of the partially admixed pygmoid group in Rampasasa (Flores, Indonesia)
  7. Etiologies, profile patterns and characteristics of children with short stature in Jordan
  8. Sexual maturity assessment in Indian children—a study from western India
  9. Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study
  10. Sensory, voluntary, and motor postural control in children and adolescents with mucopolysaccharidosis
  11. Prevalence and MRI findings of incidentally detected pituitary non-enhancing lesion on brain MRI in children
  12. Oral glucose tolerance response curve predicts disposition index but not other cardiometabolic risk factors in healthy adolescents
  13. Early menarche is associated with insulin-resistance and non-alcoholic fatty liver disease in adolescents with obesity
  14. Liraglutide combined with intense lifestyle modification in the management of obesity in adolescents
  15. Exploring the inter-subject variability in the relationship between glucose monitoring metrics and glycated hemoglobin for pediatric patients with type 1 diabetes
  16. Screening for asymptomatic diabetes and metabolic comorbidities in pediatric patients during therapy for acute lymphoblastic leukemia
  17. Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry
  18. Experience with the targeted next-generation sequencing in the diagnosis of hereditary hypophosphatemic rickets
  19. Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China
  20. Case Reports
  21. Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family
  22. Severe hypercalcemia in an infant with unbalanced translocation of chromosomes 2 and 8: a possible contribution of 2p duplication
  23. Epileptic phenotype in late-onset hyperinsulinemic hypoglycemia successfully treated by diazoxide
  24. Precocious sexual development in a male toddler caused by unrecognized transdermal exposure to testosterone: case report and review of the literature
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