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Maturity-onset diabetes of the young type 5 in a family with
diabetes and mild kidney disease diagnosed by whole
exome sequencing
J. M. Wentworth,
1,2,4
V. Lukic,
1
M. Bahlo,
1,4,5
M. Finlay,
3
C. Nguyen,
6,7
G. Morahan
6,7
and L. C. Harrison
1,4
1
Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Departments of
2
Diabetes and Endocrinology and
3
Anatomical
Pathology, Royal Melbourne Hospital, Departments of
4
Medical Biology and
5
Mathematics and Statistics, The University of Melbourne, Melbourne,
Victoria,
6
Centre for Diabetes Research, The Western Australian Institute for Medical Research, and
7
Centre for Medical Research, University of
Western Australia, Perth, Western Australia, Australia
Key words
MODY5, HNF1B, glomerulocystic kidney
disease, maturity-onset diabetes of the young,
whole exome sequencing.
Correspondence
John M. Wentworth, Walter and Eliza Hall
Institute of Medical Research, 1G Royal Parade,
Parkville, Vic. 3052, Australia.
Email: wentworth@wehi.edu.au
Received 7 April 2014; accepted 10 June 2014.
doi:10.1111/imj.12584
Abstract
Exome sequencing is being increasingly used to identify disease-associated gene muta-
tions. We used whole exome sequencing to determine the genetic basis of a syndrome
of diabetes and renal disease affecting a mother and her son. We identified a mutation
in the hepatocyte nuclear factor 1-b (HNF1B) gene that encoded a methionine to valine
amino acid change (M160V) in the HNF1B protein. This leads us to the previously
unappreciated diagnosis of maturity-onset diabetes of the young type 5 and provided a
basis for genetic counselling of other family members.
In 1967, the mother, aged 16 years and not overweight,
presented with thirst and polyuria following a bout of
tonsillitis. Hyperglycaemia was confirmed and she com-
menced insulin therapy for presumed type 1 diabetes. At
the same time, she was noted to have moderate renal
impairment (creatinine 0.17 μM), normal urine micros-
copy and <1 g/24 h proteinuria. Her pregnancy at age 22
years was complicated by hypertension and further
deterioration of renal function. Her male child was deliv-
ered at 33 weeks gestation weighing 1260 g, 40 g below
the third centile for age. In 1975, she had a renal biopsy
that was reported to show minor, non-specific features
that included focal tubular atrophy, interstitial fibrosis
and mesangial proliferation. A second pregnancy to the
same father delivered another son, of normal birth
weight (2130 g), at 33 weeks gestation. Her renal func-
tion then progressively deteriorated, and she required
dialysis at age 50 years followed by combined kidney/
pancreas transplantation at age 53 years. At the time of
her transplant, her fasting C-peptide level was below the
Funding: This work was funded by programme (1037321) and
infrastructure grants from the National Health and Medical
Research Council of Australia (NHMRC), a Victorian State Gov-
ernment Operational Infrastructure Support Grant, the Diabetes
Australia Research Trust, and the Royal Australian College of
Physicians Research Foundation.
Conflict of interest: None.
Brief Communications
© 2014 The Authors
Internal Medicine Journal © 2014 Royal Australasian College of Physicians 1137