Screening for monogenic diabetes in primary care

ARTICLE IN PRESS

PCD-805; No. of Pages 11

p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

Contents lists available at ScienceDirect

Primary Care Diabetes journal homepage: http://www.elsevier.com/locate/pcd

Review

Screening for monogenic diabetes in primary care Ian Baldacchino a,∗ , Nikolai Paul Pace b , Josanne Vassallo c a b c

Specialist Training Programme in Family Medicine, Birkirkara Health Centre, Birkirkara, Malta Faculty of Medicine & Surgery, Biomedical Sciences Building, University of Malta, Msida, Malta Division of Diabetes and Endocrinology, University of Malta Medical School, Mater Dei Hospital, Msida, Malta

a r t i c l e

i n f o

a b s t r a c t

Article history:

Aims: Updates on the latest diagnostic methods and features of MODY (Maturity Onset Dia-

Received 21 March 2019

betes of the Young) and promotion of education and awareness on the subject are discussed.

Received in revised form

Method: Previous recommendations were identified using PubMed and using combinations

24 May 2019

of terms including “MODY” “monogenic diabetes” “mature onset diabetes” “MODY case

Accepted 3 June 2019

review”. The diabetesgenes.org website and the US Monogenic Diabetes Registry (Univer-

Available online xxx

sity of Colorado) were directly referenced. The remaining referenced papers were taken from peer-reviewed journals. The initial literature search occurred in January 2017 and the

Keywords:

final search occurred in September 2018.

Genetics

Results: A diagnosis of MODY has implications for treatment, quality of life, management

Medical

in pregnancy and research. The threshold for referral and testing varies among different

Physicians

ethnic groups, and depends on body mass index, family history of diabetes and associated

Family

syndromes. Novel causative genetic variations are still being discovered however testing is

Referral and consultation

currently limited by low referral rates. Educational material is currently being promoted in

MODY

the UK in an effort to raise awareness. Conclusions: The benefits and implications of life altering treatment such as termination of insulin administration are significant but little can be done without appropriate identification and referral. © 2019 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00 Aims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. Description of methodology review process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. Clinical phenotype. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00 Algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗

Corresponding author. E-mail addresses: [email protected] (I. Baldacchino), [email protected] (N.P. Pace), [email protected] (J. Vassallo). https://doi.org/10.1016/j.pcd.2019.06.001 1751-9918/© 2019 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001

PCD-805; No. of Pages 11

ARTICLE IN PRESS

2

p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

4.

5.

6.

1.

3.1.1. HNF1A/4A versus type 1 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.2. HNF1A/4A versus type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.3. MODY subtypes (HNF1A, HNF4A and GCK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.4. Antibody testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.5. High-sensitivity CRP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.6. High density lipoprotein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.7. Other biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. Molecular diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3. Implications for quality of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.4. Monogenic diabetes and pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Case for screening and ethnic changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.3. Middle East . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.4. America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.5. North Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.1. What should primary care providers look for? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.2. Educational material for general practitioners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Introduction

In the 1960s Fajan came across a mild, asymptomatic variant of diabetes occurring in non-obese children, adolescents, and young adults as part of a study aimed at determining the normal range of the oral glucose tolerance test (OGTT1 ) [1]. Tattersall later reported three similar families showing characteristics of atypical non autoimmune diabetes with a dominant familial inheritance pattern. Tattersall went on to describe the difference between classical ‘juvenile-onset’ and ‘maturity-onset’ diabetes, the latter subtype being distinguished by successful management with sulphonylureas [2]. Subsequently, Fajan and Tattersall coined the term MODY to describe ‘fasting hyperglycemia diagnosed under age 25 which could be treated without insulin for more than two years’. MODY is currently defined as non-insulin dependent non-autoimmune diabetes diagnosed at a young age (less than 30 years old) with the presence of detectable C-peptide three years after diagnosis [3]. It is a rare disease caused by gene defects that impair beta cell function or development. The mutational spectrum of MODY has undergone significant expansion since the first description of the disease, and it is now characterized by extensive genetic and allelic heterogeneity. Clinical diagnosis is extremely challenging in view of the shared features with either type 1 or type 2 or gestational diabetes mellitus (GDM2 ) and genetic testing is not routinely available in many health care systems. The laboratory diagnosis is also very challenging, as the large number of genes limits the use of traditional Sanger sequencing in this context. The increasing availability and affordability of clinical exome sequencing has however revolutionized the

1 2

Oral glucose tolerance test. Gestational diabetes mellitus.

diagnosis of atypical forms of diabetes. Obtaining a genetic diagnosis is essential for predictive testing, proper prognostic information and personalized treatment. While technological advances have facilitated the molecular diagnosis of MODY, the importance of increasing awareness and fostering vigilance on MODY among clinicians needs to be reinforced. This is essential as obtaining a molecular diagnosis requires clinical suspicion of the disease, followed by careful phenotyping to ensure correct ascertainment of probands or families with an atypical diabetes phenotype.

2.

Aims

• To define monogenic diabetes. • To describe the common types of maturity onset diabetes of the young (MODY3 ). • To describe the clinical algorithms for diagnosis. • Laboratory testing for MODY. • To review treatments in MODY. • To address the quality of life of MODY patients. • To discuss identification of affected family members. • To discuss counseling regarding prognosis and treatment. • To highlight counseling and management of pregnancy in MODY.

2.1.

Description of methodology review process

The qualitative review was performed by a team consisting of an endocrinologist, a geneticist both clinically qualified and researchers in molecular and cellular endocrinology and one physician with training in general practice. Previous recommendations were identified using PubMed and using

3

Mature onset diabetes of the young.

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001

PCD-805; No. of Pages 11

ARTICLE IN PRESS p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

3

Table 1 – Classification of single gene mutations resulting in monogenic diabetes in the UK from Clinical features and treatment of maturity onset diabetes of the young (MODY) [9]. Gene

Prevalence amongst those with MODY (UK)

Mechanism

Distinguishing clinical features

HNF1A

30%–50%a

Highly penetrant. Large (>5 mmol/L) rise in 2-hour glucose levels on 75 g–OGTT. Progressive ␤-cell failure. Reduction in insulin sensitivity in third decade. Sensitivity to sulphonylureas.

GCK

30%–50%a

Mutation in hepatocyte nuclear factor 1 homeobox A (HNF1A17 ). HNF1A is a transcription factor that regulates beta cell expression of the insulin gene and of the glucose transporter 2 (GLUT218 ) transporter [10]. Mutations in glucokinase (GCK19 ) which converts glucose to glucose-6-phosphate stimulating the secretion of insulin from cells [11].

HNF4A

5%

HNF4A regulates glucose transport metabolism and mutations in HNF4A gene result in MODY 1 [12].

HNF1B

5%

MODY 5 results in developmental structural anomalies of the pancreas and other organs.

INS

<1%

Mutations in the insulin gene.

IPF1

<1%

NDF1

<1%

CEL

<1%

PAX4

<1%

MODY ‘X’

10%

Partial pancreatic agenesis is seen with neonatal diabetes in homozygotes and the MODY 4 phenotype in heterozygotes [15]. Reduced insulin production (developmental ␤-cell dysfunction). Exocrine pancreatic insufficiency (dysfunction of the mature acinar cell). Involved in islet cell development and repression of promoter activity of insulin and glucagon. Undiagnosed MODY. This suggests that there are other genes involved apart from those dedicated to beta cell development and maintenance [17,18].

Raised fasting glucose levels, with small (<3 mmol/L) rise in 2 hour glucose following 75 g–OGTT. Mild hyperglycemia; generally does not require treatment. Presents in similar manner to HNF1A mutations. Associated with higher birth weight and transient neonatal hypoglycemia. Progressive ␤-cell failure. Sensitivity to sulphonylureas. Characterized by renal cysts and diabetes syndrome (RCAD20 ) also relates to renal tract anomalies, renal cyst formation and non-diabetic kidney disease. Patients with structural renal disease can have HNF1B mutations or deletions without diabetes [13,14]. Wide clinical spectrum. Most present with neonatal diabetes, but may also present in early childhood and adulthood. Average age of onset is 35 years.

Very rare, adult onset (mid-20 s). Individuals may be overweight or obese, similar to type 2 diabetes. Very rare, adult onset (mean age 36 years). Pathophysiology of endocrine dysfunction not clear. Severe form of diabetes with early onset renal complications [16]. The prevalence of patients presenting with features of MODY but who do not yet have a genetic diagnosis is still unknown. Limits placed on referral criteria, candidate gene testing, and the possibility of encountering a new unrecognized MODY type can leave subjects without a diagnosis.

Abbreviations: HNF1A, hepatocyte nuclear factor 1 – homeobox A; GCK, glucokinase; HNF4A21 , hepatocyte nuclear factor 4 – homeobox A; HNF1B, hepatocyte nuclear factor 1 homeobox B; INS22 , insulin; IPF123 , insulin promoter factor 1; NDF124 , neurogenic differentiation 1; CEL25 , carboxyl ester lipase; PAX426 , paired box 4. a Dependent on the populations studied.

combinations of terms including “MODY” “monogenic diabetes” “mature onset diabetes” “MODY case review”. The diabetesgenes.org website was directly referenced in view of its significant contribution to identifying cases of MODY [4]. The US Monogenic Diabetes Registry was also directly referenced containing data gathered by the University of Colorado [5]. The remaining referenced papers were taken from peerreviewed journals. The initial literature search occurred in January 2017 and the final search occurred in September 2018.

(OMIM4 ) reports 14 different subtypes of MODY, each characterized by unique genetic, clinical and metabolic features [8]. Table 1 provides a summary of the salient features of the different MODY subtypes.

4 17 18 19

2.2.

Clinical phenotype

20 21 22

Maturity onset diabetes of the young (MODY) and neonatal diabetes are both monogenic defects of beta cell development or function. They account for approximately 2% of diabetes cases in the UK [6,7]. Online Mendelian Inheritance in Man

23 24 25 26

Online Mendelian Inheritance in Man. HNF1A – Hepatocyte nuclear factor 1 - homeobox A. GLUT2 – Glucose transporter 2. GCK – Glucokinase. RCAD – Renal cysts and diabetes syndrome. HNF4A – Hepatocyte nuclear factor 4 - homeobox A. INS – Insulin. IPF1 – Insulin promoter factor 1. NDF1 – Neurogenic differentiation 1. CEL – Carboxyl ester lipase. PAX4 – Paired box 4.

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001

PCD-805; No. of Pages 11

ARTICLE IN PRESS

4

p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

Fig. 1 – Online MODY Calculator [4].

Table 2 – European Studies of HNF4A, GCK and HNF1A MODY by nation [53]. Nation

Latitude

Norway 57◦ 57 –80◦ 49 Denmark 54◦ 34 –57◦ 45 Netherlands 50◦ 45 –53◦ 32 UK 49◦ 51 –60◦ 51 Poland 49◦ 00 –54◦ 50 Germany/Austria47◦ 17 –55◦ 03 , 46◦ 23 –49◦ 01 Czech Rep. 48◦ 33 –51◦ 02 Italy 35◦ 30 –47◦ 05 Greece Spain a b

3.

Study Undiagnosed. Genetic participants MODY MODY

HNF4A MODY

GCK MODY HNF-1A MODY

Ratio of GCK/HNF-1A MODY

Source

>1500a 78 1,319 2,072 1351 272

>69% (>1042) 51% (40) 65% (817) 73% (1508) 93% (1251) 3% (9)

<31% (458) 49% (38) 39% (502) 27% (564) 7% (100) 97% (263)

<3% (40) 3% (2) 6% (76) 3% (56) <0.3% (4b ) 4% (10)

<9% (139) 10% (8) 15% (204) 9% (180) 6.2% (84) 62% (169)

<14% (208) 36% (28) 17% (222) 14% (293) <0.3% (4b ) 31% (84)

0.67 0.29 0.92 0.61 21b 2

[57] [58] [59] [56] [52] [60]

61 172, 58

52% (32) 30% (51), 22% (13) 34% (46) 11% (10)

48% (29) 70% (121), 78% (45) 66% (88) 89% (85)

5% (3) N/A, 5% (3)

31% (19) 63% (109), 53% (31) 54% (72) 80% (76)

11.5% (7) 7% (12), 16% (9) 12% (16) 8% (8)

2.7 9.1, 3.4

[61] [54,55]

4.5 9.5

[63] [64]

34◦ 49 –41◦ 43 134 28◦ 38 –43◦ 47 95

N/A 0% (0)

Study did not provide precise number of registry participants. Study did not differentiate between HNF1A and HNF4A mutations.

Algorithms

The diagnosis of MODY is easily missed. This impacts negatively on the quality of clinical care, with patients likely to receive suboptimal or inappropriate treatment, including insulin with no resulting improvement in outcomes. Bosma et al. noted that MODY patients and their families were disappointed by the lack of knowledge, guidance and advice about MODY from health professionals [19]. The patients themselves also were often not surprised with being diagnosed with an atypical form of diabetes ie non-type 1 and non-type 2 as they discerned differences as compared with those affected by Type 1 and Type 2 diabetes. When should one suspect MODY? Features include a strong family history of diabetes, lack of autoantibodies (although some cases of MODY are IA2 antibody positive), evidence of

endogenous insulin production (detectable C-peptide), low insulin requirements or insulin independence, lack of stigmata of insulin resistance, absence of obesity and lack of ketosis. In a subpopulation classified as Type 2 who do require insulin, atypical characteristics (lack of obesity and acanthosis nigricans) and a relatively normal lipid profile may also point towards MODY [9]. There is also evidence to suggest that a significant percentage of older adults with multigenerational type 2 diabetes may have mutations in monogenic diabetes genes [20]. Shields et al. aimed at producing a clinical prediction model for patients with young onset diabetes (diagnosed before 35 years of age) and produced an online web-based algorithm that calculates the positive predictive value of having MODY as opposed to type 1 and type 2 diabetes (Fig. 1) [21]. The algorithm was found to be more sensitive when compared to previous clinical criteria for testing (91%

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001

PCD-805; No. of Pages 11

ARTICLE IN PRESS p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

versus 72%) and similarly more specific (94% versus 91%) enabling correct classification of more affected individuals overall (92% vs 81%, p < 0.0001%). An online tool is available at www.diabetesgenes.org [4]. However, the performance of this prediction model needs to be evaluated in different populations as ethnic-specific differences in its performance may be present. Candidates with a positive-predictive value of ≥25% on the MODY calculator may be referred to the next phase of testing according to the algorithms where a UCPCR test is recommended [22,23].

3.1.5.

Biomarkers

3.1.1.

HNF1A/4A versus type 1 diabetes

A significant challenge in the diagnosis of monogenic diabetes lies in its overlap with type 1 and type 2 diabetes. Notably, HNF1A or HNF4A MODY are frequently misdiagnosed as type 1 diabetes, resulting in inappropriate treatment with insulin. C-peptide is co-secreted in equimolar amounts to insulin and is excreted in urine. Practical limitations, such as its rapid degradation, the need for stimulation and the need to discontinue short-acting insulin restrict the measurement of C-peptide in the clinical setting. A urine C-peptide creatinine ratio (UCPCR5 ) of 0.2 nmol/mmol confirms ongoing insulin secretion and excludes type 1 diabetes with 97% sensitivity and 96% specificity (ROC curve discrimination showing an area under curve 0.98), easily differentiating type I DM from HNF1A/4A MODY [23]. Additionally, Besser et al describe a subset (4%) of UCPCR positive type I DM patients with a diabetes duration of over 25 years and no HNF1A or HNF4A mutations.

High-sensitivity CRP

Highly sensitivity CRP (hsCRP10 ) has shown promise as a biomarker of HNF-1A MODY. The CRP promoter contains binding sites for HNF1A. In HNF1A knockout mice downregulation of CRP expression has been demonstrated [25–28]. hsCRP levels were reproducibly lower in HNF1A MODY when compared to other subtypes of diabetes, including T1DM, young onset type 2 diabetes, GCK MODY, HNF4A MODY and HNF1B MODY [29].

3.1.6. 3.1.

5

High density lipoprotein

Lower levels of high-density lipoprotein cholesterol (HDL-C11 ) were identified in GCK and HNF1A subjects compared to type 1 diabetics (AUC 0.81 and 0.79). HNF1A MODY subjects studied also demonstrated high levels of HDL-C compared to type 2 diabetics with moderate discriminatory capacity (AUC 0.76) [30].

3.1.7.

Other biomarkers

Mughal, Thanabalsingham and Owen (2013) assessed the suitability of the following non-genetic biomarkers:

Despite postprandial UCPCR being lower in HNF1A/4A subjects compared to type 2 diabetics there was weak discrimination between the two (area under ROC curve; AUC6 0.64). Similarly, insulin requiring type 2 diabetes subjects also did not show appropriate discrimination cut offs (AUC 0.69) [23].

- Urinary amino acids — the difference in urinary amino acid profiles between diabetes subtypes was driven by glycosuria and not by the type of diabetes. - Serum amino acids — specific changes in serum amino acids of mouse models were not observed in subjects with HNF1A MODY. - Complement 5 and 8, and transthyretin. Although sensitive (60–90%) they lacked specificity (2–10%). - Urine glucose — large variations in urine glucose levels showed poor discrimination between different diabetes types with a C-statistic less than 0.60. - Apolipoprotein M (ApoM12 ) — further studies are needed to ascertain the importance of apoM in MODY. - Cystatin C — it is unlikely to be of use due to lack of reproducibility between studies [30].

3.1.3.

3.2.

3.1.2.

HNF1A/4A versus type 2 diabetes

MODY subtypes (HNF1A, HNF4A and GCK)

There was no difference in UCPCR between HNF1A and HNF4A MODY but combined values were significantly lower than GCK MODY [23].

3.1.4.

Antibody testing

For patients referred during the first five years of diagnosis or who have a UCPCR ratio of less than 0.2 nmol/mmol, testing for GAD65, IA-2, Insulin antibodies (IA7 ), Islet Cell antibodies (ICA8 ), & Zinc Transporter 8 (ZnT89 ) autoantibodies close to time of diagnosis will help confirm/rule out type 1 diabetes [24]. The prevalence of these antibodies co-existing in MODY patients is less than 1%, thus discriminating between autoimmune and monogenic diabetes. Subjects confirmed as antibody negative should be referred for genetic testing [22].

5 6 7 8 9

UCPCR – Urine c-peptide creatinine ratio. AUC – Area under ROC curve. IA – Insulin antibodies. ICA – Islet cell antibodies. ZNT8 – Zinc transporter 8.

Molecular diagnosis

The molecular diagnosis of monogenic diabetes presents several challenges. The use of Sanger sequencing in this context is extremely limited, given the extent of locus heterogeneity and allelic heterogeneity associated with monogenic diabetes. Increasingly, laboratories are making use of whole or targeted -exome capture and high-throughput sequencing to facilitate the detection of both known mutations in a defined gene panel and novel unreported rare variants as possible diabetescausing mutations. The interpretation of exome-sequencing datasets involves frequency-based filtering and prioritization of variants to identify potentially deleterious mutations, which are ranked for pathogenicity according to the American College of Medical Genetics guidelines [31]. Aggregate genomic datasets such as GnomAD and ExAC available in the public domain are invaluable and powerful resources for genetic

10 11 12

hsCRP – Highly sensitive CRP. HDL – High density lipoprotein. ApoM – Apolipoprotein M.

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001

PCD-805; No. of Pages 11

ARTICLE IN PRESS

6

p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

Table 3 – Type 1 and type 2 diabetes characteristics vs MODY [19]. Feature

Type 1 diabetes

Young Type 2 diabetes

GCK MODY

HNF1A MODY

HNF4A MODY

HNF1B MODY

Insulin dependent Parent affected Age of onset

Yes 2–4% six months – young adult

No Usually Adolescent and young adult

No Yes Teens – young adult

No Yes Teens – young adult

No Yes Teens – young adult

Obesity

Population frequency No High FPG often

Yes Yes Variable FPG often

No Yes Birth (may be diagnosed at any age) Population frequency No Mild FPG >5.5 mmol/L

>7.1 mmol/L

>7.1 mmol/L

(120 min–0 min)

(120 min–0 min)

(120 min–0 min)

usually <3.0 mmol/L

Population frequency No High FPG often <5.5 mmol/L (120 min–0 min) usually >3.5 mmol/L

Population frequency No High FPG often <5.5 mmol/L (120 min–0 min) usually >3.5 mmol/L

Population frequency No High FPG often <5.5 mmol/L (120 min–0 min) usually >3.5 mmol/L

usually >3.5 mmol/L <200 (>5 years)

usually >3.5 mmol/L 500–>1000

100–700

100–700

100–700

Acanthosis nigricans Glycaemia Oral glucose tolerance test characteristics

Typical stimulated serum C-peptide (pmol/L)

100–900

Population frequency: the frequency of obesity seen in the general population; OHA27 : oral hypoglycaemic agents; SU28 : sulphonylurea; FPG29 : fasting plasma glucose; GCK: glucokinase; HNF1A/ HNF4A: hepatocyte nuclear factor 1A/4A; HDL: high density lipoprotein; LDL30 : low density lipoprotein.

Table 4 – Features suspicious of MODY. - Mildly elevated fasting glucose levels or OGTT but appear otherwise relatively well and do not have the typical risk factors for type 2 diabetes. - Glycosuria or dysglycemia in childhood that is antibody independent and typically ketone exclusive. - Brittle diabetes later in life that does not respond well to changes in insulin. - Have associated syndromes — renal cysts, deafness, pancreatic agenesis. - As part of screening in pregnancy: antenatal checks with impaired glucose tolerance testing. - By implementing a validated MODY calculator. - In neonatal life with evidence of hyperglycemia and/or hypoglycemia.

studies and variant annotation [32,33]. However, the absence of phenotype data sharing from these knowledge bases limits direct clinical translation. As the exploration and analysis of the vast amount of genomic data becomes increasingly relevant in the clinic, there is a need to establish ethnic-specific mutation databases to aid in the interpretation of sequencing data. The subtle overlap between monogenic diabetes and type 2 diabetes also requires careful consideration. A number of rare mutations in late-onset MODY genes also drive disease risk in common type 2 diabetes. Similarly, common variants in most of the monogenic diabetes genes have been identified in genome-wide association studies as risk variants for type 2 diabetes mellitus. Hence, special caution to avoid ascertainment bias, overinterpretation and misidentification of risk variants is warranted.

3.3.

Implications for quality of life

Treatment tailored to a genetic diagnosis leads to considerable cost benefit both financially and in the achievement of better glycaemic control, earlier detection in relatives, and a lower incidence of diabetes-related complications. Additionally, genetic diagnosis can lessen the demand on healthcare services as there may be no need for intense clinical follow up, especially in HNF1A and HNF4A MODY [34,35]. Carriers of mutations in these genes are more sensitive to the effect of sulphonylureas and insulin compared to type 2 diabetics and respond better to sulphonylureas when compared to metformin therapy. In one observational study, 79% of subjects with HNF1A MODY were successfully switched from insulin to sulphonylurea therapy without compromising glycaemic control. [36]

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001

PCD-805; No. of Pages 11

ARTICLE IN PRESS p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

General practitioners play a special role in supporting affected subjects and their families until a diagnosis is established. Their knowledge regarding the social and family history of the patient can facilitate transferring from insulin to sulphonylureas, thus promoting better quality of life in different ways. [37,38]

• Patients taking insulin for years may experience uncertainty, fear, anxiety and excitement on changing to tablets. • Changing from a routine of 2–4 insulin injections a day to tablet therapy improves lifestyle and self-image. • Patients appreciate that non targeted treatment could have been the cause of difficult glycemic control when reflecting on their past experiences. • Some may be unable to accept the fact they did not need insulin therapy, despite evidence that adequate control can be achieved on sulphonylureas.

Fajans & Brown demonstrated that in patients with a genetic diagnosis of HNF1A or HNF4A MODY sulphonylureas led to maintenance of glycaemic control after discontinuing insulin, even in patients on insulin for more than 30 years [39]. A molecular diagnosis in this context reinforces the clinical utility of precision medicine and pharmacogenetics in targeting therapy. Patients considered for sulphonylurea therapy should be counseled about the following before starting treatment:

• Sulphonylureas dramatically improve glycaemic control. • Hypoglycaemia may occur on initiating treatment therefore low doses should be used primarily. • Stopping sulfphonylureas should be done cautiously as this could result in significant decline in glucose control [40,41].

Patients with GCK MODY have a very mild form of disease and usually do not require medication for glycaemic control except in pregnancy with HbA1c levels rarely going higher than 7.5%. Parents may be normal or have mild type 2 disease with a very benign course [42]. Oral and insulin treatment are seldom effective and result in a decrease in endogenous insulin production [34,43,44]. Significantly, in cases where therapy with oral hypoglycemic agents or insulin would have been initiated, a molecular diagnosis of GCK MODY leads to cessation of therapy and improvement in quality of life [37]. Counseling in pregnancy should be directed towards:

- Activating mutations in the heterozygous state that can cause persistent hyperinsulinaemic hypoglycaemia in infants (PHIH13 ). - Homozygous mutations in GCK that can cause permanent neonatal diabetes mellitus (PNDM14 ) in infants [45–47].

13 14

PHIH – Persistent hyperinsulinaemic hypoglycaemia. PNDM – Permanent neonatal diabetes mellitus.

3.4.

7

Monogenic diabetes and pregnancy

Gestational diabetes mellitus (GDM15 ) is defined as “any degree of glucose intolerance with onset or first recognition during pregnancy” [48]. Experience regarding pregnancy in the commonest forms of MODY in pregnancy is limited. The link between MODY and GDM is not clear in many populations, a problem compounded by the varying diagnostic criteria used in GDM. Despite this a number of case reports on monogenic diabetes diagnosed in pregnancy can be found in the literature. Gjesing et al. diagnosed 5–6% of women with GDM with GCK MODY. Furthermore, 6% of diet treated GDM Danish women were identified as having possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B or INS [38]. These women are at high risk of developing diabetes after pregnancy, and the authors recommended that screening for mutations in these genes should be offered to women with GDM. In pregnant mothers with HNF1A or HNF4A MODY, sulphonylurea therapy was continued in the past but recognition that sulphonylureas cross the placenta and predispose the fetus to hyperinsulinaemia resulting in macrosomia as well as hypoglycaemia has led to an expert recommendation to switch to insulin pre-pregnancy or in the first trimester during pregnancy [37]. Pearson et al. noted that neonates with HNF4A mutations are prone to neonatal hypoglycaemia and macrosomia. Neonates also weighed an average of 790 g more than unaffected sibs [44]. Neonates of parents known to carry the HNF4A mutations should be monitored for hypoglycaemia in the postnatal period. Neonates with transient or persistent neonatal hypoglycaemia and/or macrosomia and a family history of diabetes at a young age could be considered as candidates for HNF4A mutation testing [44]. In GCK MODY, fetuses who inherit the GCK mutation from their affected mother are not born with a higher than average birth weight as the mutation protects them from sensing higher glucose levels and therefore their baseline insulin secretion remains at a normal level. Treating hyperglycaemia in the mother may have adverse effects on fetal growth with intrauterine growth retardation occurring. Those fetuses who do not have the mutation respond to maternal hyperglycaemia with hyperinsulinaemia and consequently macrosomia [49–51]. In the absence of readily available prenatal genetic testing, affected mothers with unaffected fetuses should therefore be monitored every 2 weeks after week 26 of pregnancy and treated with glucose lowering agents if fetal abdominal circumference rises above the 75th centile to avoid fetal macrosomia [52].

4.

Case for screening and ethnic changes

The prevalence of MODY, as well as the spectrum of pathogenic mutations identified varies in different populations (Table 2). There is an increasing body of data on MODY from European countries but data on prevalence and characteristics of monogenic diabetes in persons of African, Latin American, Middle Eastern and Asian descent is still lacking [53]. This lack

15

GDM – Gestational diabetes mellitus.

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001

PCD-805; No. of Pages 11

ARTICLE IN PRESS

8

p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

of epidemiological data, together with the need to validate the MODY calculator in different populations as well as the regional differences in access to health care and specialized testing makes heightened clinical awareness essential and should provide an impetus for further research and validation.

types are present as well [73–75]. The prevalence of MODY in the Indian population is unknown in but mutations involving HNF4A, GCK, HNF1A, PDX1, HNF1B, NDF1, and PAX4 have been described in this population [76].

4.3. 4.1.

Within European populations, regional differences in MODY have been reported. Some Italian studies have reported a high prevalence of GCK MODY in Southern European paediatric populations, while HNF1A MODY is the commonest MODY subtype in Northern Europe [54,55]. In the UK the confirmed genetic variants include HNF4A, GCK, HNF1A, PDX1, HNF1B, NDF1 and INS. HNF1A mutations made up the majority (52%) followed up GCK (32%) and HNF4A (10%). Significant variation occurred between testing sites despite a central referral centre indicating that cases were underreported. A minimum prevalence of 68–108 cases per million persons in UK is estimated [56]. Several other studies conducted in European countries show similar frequencies of MODY with GCK MODY being the most prevalent followed by HNF4A and HNF1A MODY [53–64].

4.2.

Asia

The South Asian population referred for MODY testing in the UK comprised 7.3% of proband referrals [65]. The pickup rate in referred adults differed significantly (29% in the Caucasian European group vs 12.6% in the South Asian group) but not in children less than 12 years of age. Detection rates in MODY referrals were lesser in the South Asian group even though cases were more likely to meet the clinical criteria for MODY testing indicating a lack of sensitivity in distinguishing between MODY carriers and type 2 diabetics. The best predictors differentiating mutation carriers and non-carriers were a lower body mass index (BMI16 ) and lower age at onset. Type 2 diabetes is 6 times more common in people of South Asian descent and up to three times more common in those of African and African-Caribbean descent, compared with the white population in the UK. It is also more common in individuals of Chinese descent and other non-white groups [66] Department of Health 2001. Part of the reason for this higher prevalence is that South Asian people living in the UK may accumulate significantly more ’metabolically active’ fat in the abdomen and around the waist than white European populations. ’Metabolically active’ fat is closely associated with insulin resistance, pre-diabetes and type 2 diabetes even if in the range of a normal BMI [67–70]. In such cases the MODY probability calculator was recommended to be revalidated with a lower cut off for BMI and age at diagnosis. Kleinberger and Pollin reported that studies carried out in Japan identified GCK mutations as the most common subtype, followed by HNF1A, HNF1B and HNF4A. IPF1, HNF1B or NDF1 mutation subtypes were rarely picked up in Japanese families [53,71,72]. In China HNF1A, GCK and HNF4A MODY appear much less common but variants of GCK and HNF1A

16

Middle East

Europe

BMI – Body mass index.

Family specific mutations in GCK, HNF4A and HNF1A have been described in Israeli probands, including the GCK p.T206P variant which was detected in six unrelated individuals of Ashkenazi-Jewish descent, suggestive of an ethnic-specific founder effect [77,78].

4.4.

America

The University of Colorado houses the US Monogenic Diabetes Registry and detected GCK mutations in 54.7% of probands selected for GCK mutation testing [5]. Half of these cases were treated unnecessarily. Minorities including African–American, Latino and Asian subjects represented only 20% of screened probands with 17.2% having GCK MODY [5]. As many as 95% of MODY cases are misdiagnosed as type 1 or type 2 diabetes [53].

4.5.

North Africa

A study performed on 23 unrelated Tunisian probands fulfilling strict clinical criteria for monogenic diabetes identified no mutations in HNF1A and INS genes. Three index cases were shown to carry mutations in the promoters of GCK and HNF4A genes [79]. Another study performed in Tunisia had identified one HNF4A missense mutation from 12 patients selected for testing [80]. The findings from these two studies are significant, as they highlight the fact that the most common MODY genes in northern Europeans do not explain the etiology of MODY in Tunisians.

5.

Recommendations

The diagnosis of diabetes is usually carried out in primary care with subsequent referral to specialist clinics. Family doctors also have a secondary role in providing counseling about MODY and supporting families until a diagnosis is reached. Poor referral rates negatively impact the possibility of: - Improving quality of life in patients started on insulin inappropriately. - Screening family members and prevention of complications in potentially damaging variants. - Giving advice and tailored management of specific MODY subtypes. - Discovering new MODY types in different populations. - Addressing the different phenotypes geographically. - Proper antenatal care.

5.1.

What should primary care providers look for?

One should be aware of the salient clinical and biochemical features that distinguish MODY from the commoner subtypes

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001

PCD-805; No. of Pages 11

ARTICLE IN PRESS p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

of diabetes. These features are summarized in Table 3. Additionally, primary care physicians should vigilant for atypical diabetes phenotypes as summarized in Table 4 that provide strong cues for the possibility of MODY to ensure appropriate and timely referral for genetic testing.

5.2.

[9]

Educational material for general practitioners

The intention here is to raise awareness and educate family doctors on genomic medicine involving diabetes. Certified online courses such as that provided by the University of Exeter explaining the clinical application of genomics medicine can play a significant part in raising knowledge and awareness about diagnostic and management issues [4,81].

6.

[8]

Conclusion

Although the diagnosis may have been significantly delayed, patients are generally willing to participate in testing particularly if current management is associated with poor control or unexplained glycaemic excursions. The benefits and implications of targeted treatment possibly resulting in termination of insulin administration are clear making appropriate identification and referral crucial.

Conflict of interest

[10]

[11]

[12]

[13]

[14]

[15]

The authors state that they have no conflict of interest.

references

[1] S.S. Fajans, J.W. Conn, An approach to the prediction of diabetes mellitus by modification of the glucose tolerance test with cortisone, Diabetes 3 (1954) 296–302, discussion, 302–4. [2] R.B. Tattersall, Mild familial diabetes with dominant inheritance, Q. J. Med. 43 (1974) 339–357. [3] G. Thanabalasingham, A. Pal, M.P. Selwood, et al., Systematic assessment of etiology in adults with a clinical diagnosis of young-onset type 2 diabetes is a successful strategy for identifying maturity-onset diabetes of the young, Diabetes Care 35 (2012) 1206–1212, http://dx.doi.org/10.2337/dc11-1243. [4] University of Exeter, DiabetesGenes, Available at: diabetesgenes.org. (Accessed 1 March 2019), 2019. [5] D. Carmody, R.N. Naylor, C.D. Bell, et al., GCK MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated, Acta Diabetol. 53 (2016) 703–708, http://dx.doi.org/10.1007/s00592-016-0859-8. [6] H.M. Ledermann, Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed? Diabetologia 38 (1995) 1482. [7] A. Galler, T. Stange, G. Müller, et al., Incidence of childhood diabetes in children aged less than 15 years and its clinical and metabolic characteristics at the time of diagnosis: data from the Childhood Diabetes Registry of Saxony, Germany,

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23] 27 28 29 30

OHA – Oral hypoglycaemic agents. SU – Sulphonylurea. FPG – Fasting plasma glucose. LDL – Low density lipoprotein.

9

Horm. Res. Paediatr. 74 (2010) 285–291, http://dx.doi.org/10.1159/000303141. H. Ada, Online Mendelian Inheritance of Man Entry – 606391, Available at: https://www.omim.org/entry/606391. (Accessed 27 November 2016), 2016. D.S. Gardner, E.S. Tai, Clinical features and treatment of maturity onset diabetes of the young (MODY), Diabetes Metab. Syndr. Obes. 5 (2012) 101–108, http://dx.doi.org/10.2147/DMSO.S23353. K. Yamagata, N. Oda, P.J. Kaisaki, et al., Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3), Nature 384 (1996) 455–458, http://dx.doi.org/10.1038/384455a0. P. Froguel, M. Vaxillaire, F. Sun, et al., Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus, Nature 356 (1992) 162–164, http://dx.doi.org/10.1038/356162a0. H. Wang, P. Maechler, P.A. Antinozzi, et al., Hepatocyte nuclear factor 4␣ regulates the expression of pancreatic ␤-Cell genes implicated in glucose metabolism and nutrient-induced insulin secretion, J. Biol. Chem. 275 (2000) 35953–35959. Y. Horikawa, N. Iwasaki, M. Hara, et al., Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY, Nat. Genet. 17 (1997) 384–385, http://dx.doi.org/10.1038/ng1297-384. C. Bellanné-Chantelot, D. Chauveau, J.-F. Gautier, et al., Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations, Ann. Intern. Med. 140 (2004) 510–517. I.H. Thomas, N.K. Saini, A. Adhikari, et al., Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 Pro63fsX60 mutation, Pediatr. Diabetes 10 (2009) 492–496, http://dx.doi.org/10.1111/j.1399-5448.2009.00526.x. N. Plengvidhya, S. Kooptiwut, N. Songtawee, et al., PAX4 mutations in Thais with maturity onset diabetes of the young, J. Clin. Endocrinol. Metab. 92 (2007) 2821–2826, http://dx.doi.org/10.1210/jc.2006-1927. M. McCarthy, A. Hattersley, Learning from molecular genetics: novel insights arising from the definition of genes for monogenic and type 2 diabetes, Diabetes 57 (2008) 2889–2898. E. Edghill, J. Minton, C. Groves, et al., Sequencing of candidate genes selected by beta cell experts in monogenic diabetes of unknown aetiology, J. Pancreas 11 (2009) 14–17. A.R. Bosma, T. Rigter, S.S. Weinreich, M.C. Cornel, L. Henneman, A genetic diagnosis of maturity-onset diabetes of the young (MODY): experiences of patients and family members, Diabet. Med. 32 (2015) 1385–1392, http://dx.doi.org/10.1111/dme.12742. S. Pezzilli, O. Ludovico, T. Biagini, et al., Insights from molecular characterization of adult patients of families with multigenerational diabetes, Diabetes 67 (2018) 137–145, http://dx.doi.org/10.2337/db17-0867. B.M. Shields, T.J. McDonald, S. Ellard, et al., The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes, Diabetologia 55 (2012) 1265–1272, http://dx.doi.org/10.1007/s00125-011-2418-8. T.J. McDonald, K. Colclough, R. Brown, et al., Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from type 1 diabetes, Diabet. Med. 28 (2011) 1028–1033, http://dx.doi.org/10.1111/j.1464-5491.2011.03287.x. R.E.J. Besser, M.H. Shepherd, T.J. McDonald, et al., Urinary C-peptide creatinine ratio is a practical outpatient tool for identifying hepatocyte nuclear factor 1-{alpha}/hepatocyte nuclear factor 4-{alpha} maturity-onset diabetes of the

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001

PCD-805; No. of Pages 11

ARTICLE IN PRESS

10

p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32] [33] [34]

[35]

[36]

[37]

[38]

[39]

young from long-duration type 1 diabetes, Diabetes Care 34 (2011) 286–291, http://dx.doi.org/10.2337/dc10-1293. J.M. Wenzlau, K. Juhl, L. Yu, et al., The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes, Proc. Natl. Acad. Sci. U.S.A. 104 (2007) 17040–17045, http://dx.doi.org/10.1073/pnas.0705894104. D.Q. Shih, M. Bussen, E. Sehayek, et al., Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism, Nat. Genet. 27 (2001) 375–382, http://dx.doi.org/10.1038/86871. A.P. Reiner, M.J. Barber, Y. Guan, et al., Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein, Am. J. Hum. Genet. 82 (2008) 1193–1201, http://dx.doi.org/10.1016/j.ajhg.2008.03.017. P.M. Ridker, G. Pare, A. Parker, et al., Loci related to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women’s Genome Health Study, Am. J. Hum. Genet. 82 (2008) 1185–1192, http://dx.doi.org/10.1016/j.ajhg.2008.03.015. P. Elliott, J.C. Chambers, W. Zhang, et al., Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease, JAMA 302 (2009) 37–48, http://dx.doi.org/10.1001/jama.2009.954. G. Thanabalasingham, N. Shah, M. Vaxillaire, et al., A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes, Diabetologia 54 (2011) 2801–2810, http://dx.doi.org/10.1007/s00125-011-2261-y. S.A. Mughal, G. Thanabalasingham, K.R. Owen, Biomarkers currently used for the diagnosis of maturity-onset diabetes of the young, Diabetes Manag. 3 (2013) 71–80, http://dx.doi.org/10.2217/DMT.12.82. S. Richards, N. Aziz, S. Bale, et al., Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, Genet. Med. 17 (2015) 405–424, http://dx.doi.org/10.1038/gim.2015.30. GnomAD. Available at: https://gnomad.broadinstitute.org/. (Accessed 1 March 2019). ExAC. Available at: http://exac.broadinstitute.org/. (Accessed 1 March 2019). T.J. McDonald, S. Ellard, Maturity onset diabetes of the young: identification and diagnosis, Ann. Clin. Biochem. 50 (2013) 403–415, http://dx.doi.org/10.1177/0004563213483458. R.N. Naylor, P.M. John, A.N. Winn, et al., Cost-effectiveness of MODY genetic testing: translating genomic advances into practical health applications, Diabetes Care 37 (2014) 202–209, http://dx.doi.org/10.2337/dc13-0410. M. Shepherd, B. Shields, S. Ellard, et al., A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients, Diabet. Med. 26 (2009) 437–441, http://dx.doi.org/10.1111/j.1464-5491.2009.02690.x. ˛ A. Wedrychowicz, E. Tobór, M. Wilk, E. Ziółkowska-Ledwith, et al., Phenotype heterogeneity in glucokinase-maturity-onset diabetes of the young (GCK MODY) patients, J. Clin. Res. Pediatr. Endocrinol. 9 (2017) 246–252, http://dx.doi.org/10.4274/jcrpe.4461. A.P. Gjesing, G. Rui, J. Lauenborg, C.T. Have, M. Hollensted, E. Andersson, et al., High prevalence of diabetes-predisposing variants in MODY genes among Danish women with gestational diabetes mellitus, J Endocr. Soc. 1 (2017) 681–690. S. Fajans, M. Brown, Administration of sulfonylureas can increase glucose-induced insulin secretion for decades in patients with maturity-onset diabetes of the young, Diabetes Care 16 (1993) 1254–1261.

[40] E.R. Pearson, W.G. Liddell, M. Shepherd, et al., Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes, Diabet. Med. 17 (2000) 543–545. [41] E.R. Pearson, B.J. Starkey, R.J. Powell, et al., Genetic cause of hyperglycaemia and response to treatment in diabetes, Lancet 362 (2003) 1275–1281, http://dx.doi.org/10.1016/S0140-6736. [42] A. Chakera, A. Steele, A. Gloyn, M. Shepherd, B. Shields, S. Ellard, A. Hattersley, Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation, Diabetes Care 38 (7) (2015) 1383–1392. [43] M. Shepherd, A.J. Brook, A.J. Chakera, A.T. Hattersley, Management of sulfonylurea-treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer, Diabet. Med. 34 (2017) 1332–1339, http://dx.doi.org/10.1111/dme.13388. [44] E.R. Pearson, S.F. Boj, A.M. Steele, et al., Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene, PLoS Med. 4 (2007) e118, http://dx.doi.org/10.1371/journal.pmed.0040118. [45] N. Vionnet, M. Stoffel, J. Takeda, et al., Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus, Nature 356 (1992) 721–722, http://dx.doi.org/10.1038/356721a0. ˜ [46] P.R. Njølstad, O. Søvik, A. Cuesta-Munoz, et al., Neonatal diabetes mellitus due to complete glucokinase deficiency, N. Engl. J. Med. 344 (2001) 1588–1592, http://dx.doi.org/10.1056/NEJM200105243442104. [47] A.L. Gloyn, Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy, Hum. Mutat. 22 (2003) 353–362, http://dx.doi.org/10.1002/humu.10277. [48] Gestational diabetes mellitus, Diabetes Care 26 (2003) S103–S105, http://dx.doi.org/10.2337/diacare.26.2007.S103. [49] A.T. Hattersley, F. Beards, E. Ballantyne, et al., Mutations in the glucokinase gene of the fetus result in reduced birth weight, Nat. Genet. 19 (1998) 268–270, http://dx.doi.org/10.1038/953. [50] G. Spyer, A.T. Hattersley, J.E. Sykes, et al., Influence of maternal and fetal glucokinase mutations in gestational diabetes, Am. J. Obstet. Gynecol. 185 (2001) 240–241, http://dx.doi.org/10.1067/mob.2001.113127. [51] G. Spyer, K.M. MacLeod, M. Shepherd, et al., Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation, Diabet. Med. 26 (2009) 14–18, http://dx.doi.org/10.1111/j.1464-5491.2008.02622.x. [52] T.A. Buchanan, A.H. Xiang, K.A. Page, Gestational diabetes mellitus: risks and management during and after pregnancy, Nat. Rev. Endocrinol. 8 (2012) 639–649. [53] J.W. Kleinberger, T.I. Pollin, Undiagnosed MODY: time for action, Curr. Diab. Rep. 15 (2015) 110, http://dx.doi.org/10.1007/s11892-015-0681-7. [54] R. Lorini, C. Klersy, G. d’Annunzio, et al., Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families, Diabetes Care 32 (2009) 1864–1866, http://dx.doi.org/10.2337/dc08-2018. [55] M. Delvecchio, O. Ludovico, C. Menzaghi, et al., Low prevalence of HNF1A mutations after molecular screening of multiple MODY genes in 58 Italian families recruited in the pediatric or adult diabetes clinic from a single Italian hospital, Diabetes Care 37 (2014) e258–e260, http://dx.doi.org/10.2337/dc14-1788.

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001

PCD-805; No. of Pages 11

ARTICLE IN PRESS p r i m a r y c a r e d i a b e t e s x x x ( 2 0 1 9 ) xxx–xxx

[56] B.M. Shields, S. Hicks, M.H. Shepherd, et al., Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 53 (2010) 2504–2508, http://dx.doi.org/10.1007/s00125-010-1799-4. [57] O. Søvika, H.U. Irgens, J. Molnes, et al., Monogenic diabetes mellitus in Norway, Nor. J. Epidemiol. 23 (2013), http://dx.doi.org/10.5324/nje.v23i1.1603. [58] A. Johansen, J. Ek, H.B. Mortensen, et al., Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1, J. Clin. Endocrinol. Metab. 90 (2005) 4607–4614, http://dx.doi.org/10.1210/jc.2005-0196. [59] S.S. Weinreich, A. Bosma, L. Henneman, et al., A decade of molecular genetic testing for MODY: a retrospective study of utilization in the Netherlands, Eur. J. Hum. Genet. 23 (2015) 29–33, http://dx.doi.org/10.1038/ejhg.2014.59. [60] W. Fendler, M. Borowiec, A. Baranowska-Jazwiecka, et al., Prevalence of monogenic diabetes amongst Polish children after a nationwide genetic screening campaign, Diabetologia 55 (2012) 2631–2635, http://dx.doi.org/10.1007/s00125-012-2621-2. [61] E. Schober, B. Rami, M. Grabert, et al., Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with Type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database, Diabet. Med. 26 (2009) 466–473, http://dx.doi.org/10.1111/j.1464-5491.2009.02720.x. [62] S. Pruhova, J. Ek, J. Lebl, et al., Genetic epidemiology of MODY in the Czech Republic: new mutations in the MODY genes HNF4Alpha, GCK and HNF1Alpha, Diabetologia 46 (2003) 291–295, http://dx.doi.org/10.1007/s00125-002-1010-7. [63] C. Tatsi, C. Kanaka-Gantenbein, A. Vazeou-Gerassimidi, et al., The spectrum of HNF1A gene mutations in Greek patients with MODY3: relative frequency and identification of seven novel germline mutations, Pediatr. Diabetes 14 (2013) 526–534, http://dx.doi.org/10.1111/pedi.12032. [64] I. Estalella, I. Rica, G. Perez de Nanclares, et al., Mutations in GCK and HNF1Alpha explain the majority of cases with clinical diagnosis of MODY in Spain, Clin. Endocrinol. (Oxf) 67 (2007) 538–546, http://dx.doi.org/10.1111/j.1365-2265.2007.02921.x. [65] S. Misra, B. Shields, K. Colclough, et al., South Asian individuals with diabetes who are referred for MODY testing in the UK have a lower mutation pick-up rate than white European people, Diabetologia 59 (2016) 2262–2265, http://dx.doi.org/10.1007/s00125-016-4056-7. [66] Department of Health, U.K, National Service Framework for Diabetes: Foreword, Department of Health, U. K., London, 2001. [67] M.A. Banerji, N. Faridi, R. Atluri, et al., Body composition, visceral fat, leptin, and insulin resistance in Asian Indian men, J. Clin. Endocrinol. Metab. 84 (1999) 137–144, http://dx.doi.org/10.1210/jcem.84.1.5371. [68] P.M. McKeigue, B. Shah, M.G. Marmot, Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians, Lancet 337 (1991) 382–386.

11

[69] P.M. McKeigue, T. Pierpoint, J.E. Ferrie, M.G. Marmot, Relationship of glucose intolerance and hyperinsulinaemia to body fat pattern in south Asians and Europeans, Diabetologia 35 (1992) 785–791. [70] P.M. McKeigue, J.E. Ferrie, T. Pierpoint, M.G. Marmot, Association of early-onset coronary heart disease in South Asian men with glucose intolerance and hyperinsulinemia, Circulation 87 (1993) 152–161. [71] H. Furuta, Y. Horikawa, N. Iwasaki, et al., Beta-cell transcription factors and diabetes: mutations in the coding region of the BETA2/NeuroD1 (NEUROD1) and Nkx2.2 (NKX2B) genes are not associated with maturity-onset diabetes of the young in Japanese, Diabetes 47 (1998) 1356–1358. [72] M. Hara, T.H. Lindner, V.P. Paz, et al., Mutations in the coding region of the insulin promoter factor 1 gene are not a common cause of maturity-onset diabetes of the young in Japanese subjects, Diabetes 47 (1998) 845–846. [73] M.C. Ng, B.N. Cockburn, T.H. Lindner, et al., Molecular genetics of diabetes mellitus in Chinese subjects: identification of mutations in glucokinase and hepatocyte nuclear factor-1alpha genes in patients with early-onset type 2 diabetes mellitus/MODY, Diabet. Med. 16 (1999) 956–963. [74] J.Y. Xu, V. Chan, W.Y. Zhang, et al., Mutations in the hepatocyte nuclear factor-1alpha gene in Chinese MODY families: prevalence and functional analysis, Diabetologia 45 (2002) 744–746, http://dx.doi.org/10.1007/s00125-002-0814-9. [75] J.Y. Xu, Q.H. Dan, V. Chan, et al., Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients, Eur. J. Hum. Genet. 13 (2005) 422–427, http://dx.doi.org/10.1038/sj.ejhg.5201347. [76] A. Chapla, M.D. Mruthyunjaya, H.S. Asha, et al., Maturity onset diabetes of the young in India - a distinctive mutation pattern identified through targeted next-generation sequencing, Clin. Endocrinol. (Oxf) 82 (2015) 533–542, http://dx.doi.org/10.1111/cen.12541. [77] Y. Gozlan, A. Tenenbaum, S. Shalitin, et al., The glucokinase mutation p.T206P is common among MODY patients of Jewish Ashkenazi descent, Pediatr. Diabetes 13 (2012) e14–e21, http://dx.doi.org/10.1111/j.1399-5448.2011.00822.x. [78] E. Stern, C. Strihan, O. Potievsky, et al., Four novel mutations. Including the first gross deletion in TCF1 identified in HNF-4 alpha, GCK and TCF1 in patients with MODY in Israel, J. Pediatr. Endocrinol. Metab. 20 (2007) 909–921. [79] S. Ben Khelifa, R. Martinez, A. Dandana, et al., Maturity onset diabetes of the young (MODY) in Tunisia: low frequencies of GCK and HNF1A mutations, Gene 651 (2018) 44–48, http://dx.doi.org/10.1016/j.gene.2018.01.081. [80] A. Amara, M. Chadli-Chaieb, H. Ghezaiel, et al., Familial early-onset diabetes is not a typical MODY in several Tunisian patients, Tunis. Med. 90 (2012) 882–887. [81] FutureLearn, Genomic Medicine — Online Course, Available at: https://www.futurelearn.com/courses/diabetes-genomicmedicine. (Accessed 26 February 2019), 2019.

Please cite this article in press as: I. Baldacchino, et al., Screening for monogenic diabetes in primary care, Prim. Care Diab. (2019), https://doi.org/10.1016/j.pcd.2019.06.001