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A genetic diagnosis of HNF1A MODY

Dan’s family wanted to clarify the cause of his diabetes, so they contacted us via our Diabetes Genes website and we organised genetic testing for him.

As mentioned in Week 2, the test confirmed HNF1A MODY. The specific genetic change identified results in the substitution of a T base for C base which changes the amino acid at position 447 from proline to leucine. In the figure below, the base substitution is shown by the arrow and is described as P447L (or NM_000545.6 c.1340C>T; p.Pro447Leu according to the HGVS recommended mutation nomenclature system).

A DNA sequencer produces data in the form of an electropherogram which is made up of a series of individual coloured peaks that represent the order of nucleotides in the DNA sequence.  Each colour represents one of the four different nucleotides. Red is thymine, blue is cytosine, green is adenine and black is guanine, and the DNA sequence is read from left to right. Analysis of DNA sequences for mutations is performed on a comparative basis; a ‘normal’ or reference DNA electropherogram is used to compare against the patient’s DNA electropherogram, and any differences are investigated as potential mutations. The mutation in Dan’s HNF1A gene is highlighted by the presence of a red and blue peak at nucleotide position c.1340, compared to the single blue peak in the reference sequence at this position.  This means that Dan is heterozygous for a C>T nucleotide change at this position (c.1340C>T) which results in a different amino acid being encoded (leucine instead of proline). Created by Mutation Surveyor v 4.0.6 SoftGenetics, State College PA USA 16803

Our research previously showed that patients with HNF1A MODY are extremely sensitive to low doses of sulphonylureas and this is the optimal treatment in these cases. Consequently Dan was able to stop his insulin injections and transfer to a low dose of Gliclazide. On just 20mg Gliclazide daily Dan’s HbA1c improved to 6.2% or 44mmol/mol and the problematic hypoglycaemic episodes he’d been having on insulin stopped.

He was initially concerned whether the tablets would work and recalls testing his blood glucose frequently but was delighted with the difference changing treatment made.

It was May 2005, the ‘big day’ where I just didn’t take any insulin at all. I tested my blood count about 48 times over 24 hours. I can’t emphasise enough how different it’s been. I was looking to fail college, and then to get out with ‘A’s at A level, get into vet school and spend the year doing physical work with animals, it’s fantastic. Dan

Dan’s mother also described the benefit of the genetic diagnosis and treatment change.

I cannot tell you what a huge relief it has been to get an exact diagnosis and the appropriate treatment. The change for Dan is immense. Being diagnosed with diabetes was bad enough, but watching him inject himself 4 times a day, having hypos to the point we couldn’t leave him alone was a nightmare. Dan’s Mum

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Genomic Medicine: Transforming Patient Care in Diabetes

University of Exeter

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