title: A family with the Arg103Pro mutation in the NEUROD1 gene detected by next-generation sequencing - Clinical characteristics of mutation carriers.
abstract: Until now only a few families with early onset autosomal diabetes due to the NEUROD1 gene mutations have been identified. Moreover, only some of them meet strict MODY (maturity-onset diabetes of the young) criteria. Next-generation sequencing (NGS) provides an opportunity to detect more pathogenic mutations in this gene. Here, we evaluated the segregation of the Arg103Pro mutation in the NEUROD1 gene in a pedigree in which it was detected, and described the clinical characteristics of the mutation carriers.
  
  
  METHODS
  We included 156 diabetic probands of MODY families, among them 52 patients earlier tested for GCK-MODY and/or HNF1A-MODY by Sanger sequencing with negative results. Genetic testing was performed by targeted NGS sequencing using a panel of 28 monogenic diabetes genes.
  
  
  RESULTS
  As detected by NGS, one patient had the missense Arg103Pro (CGC/CCC) mutation in the gene NEUROD1 changing the amino-acid structure of the DNA binding domain of this transcription factor. We confirmed this sequence difference by Sanger sequencing. This family had previously been tested with negative results for HNF1A gene mutations. 17 additional members of this family were invited for further testing. We confirmed the presence of the mutation in 11 subjects. Seven adult mutation carriers (all but one) from three generations had been already diagnosed with diabetes. There were 3 individuals with the Arg103Pro mutation diagnosed before the age of 30 years in the family. The range of age of the four unaffected mutation carriers (3 minors and 1 adult) was 3-48 years. Interestingly, one mutation carrier had a history of transient neonatal hypoglycemia, of which the clinical course resembled episodes typical for HNF4A-MODY.
  
  
  CONCLUSIONS
  We report a family with autosomal dominant diabetes related to a new NEUROD1 mutation, one of very few meeting MODY criteria. The use of the NGS method will facilitate identification of more families with rare forms of MODY.
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University, Medical College, Krakow, Poland; University Hospital, Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Szopa
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University, Medical College, Krakow, Poland; Center for Medical Genomics OMICRON, Poland.
authors.forename: Agnieszka H
authors.initials: AH
authors.lastname: Ludwig-Galezowska
authors.affiliation: Center for Medical Genomics OMICRON, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Radkowski
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University, Medical College, Krakow, Poland; Center for Medical Genomics OMICRON, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Skupien
authors.affiliation: Center for Medical Genomics OMICRON, Poland.
authors.forename: Julita
authors.initials: J
authors.lastname: Machlowska
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University, Medical College, Krakow, Poland; University Hospital, Krakow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Klupa
authors.affiliation: Center for Medical Genomics OMICRON, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Wolkow
authors.affiliation: Department of Clinical Genetics and Laboratory Medical University, Lodz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Borowiec
authors.affiliation: Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Mlynarski
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University, Medical College, Krakow, Poland; University Hospital, Krakow, Poland. Electronic address: maciej.malecki@uj.edu.pl.
authors.forename: Maciej T
authors.initials: MT
authors.lastname: Malecki
mesh_terms: D019943:Amino Acid Substitution; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011044:Poland
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C093970:NEUROD1 protein, human
keywords: Diabetes; MODY; NEUROD1