The use of targeted gene panels now allows the analysis of all the genes known to cause a disease in a single test. For neonatal diabetes, this has resulted in a paradigm shift with patients receiving a genetic diagnosis early and the genetic results guiding their clinical management. Exome and genome sequencing are powerful tools to identify novel genetic causes of known diseases. For neonatal diabetes, the use of these technologies has resulted in the identification of 2 novel disease genes ( GATA6 and STAT3 ) and a novel regulatory element of PTF1A , in which mutations cause pancreatic agenesis.
Key points
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Next-generation sequencing has revolutionized the approach to genetic testing and research.
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The 3 main applications of next-generation sequencing technology are targeted gene panels and exome and genome sequencing.
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Neonatal diabetes is a genetically and clinically heterogeneous disease, which means that genetic testing and research of new causes of the disease are challenging.
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A targeted gene panel has been developed to test all the known causes of neonatal diabetes in a single test. Early comprehensive testing has changed the way patients with neonatal diabetes are managed.
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Exome sequencing is a powerful tool to identify novel disease genes. In neonatal diabetes, it has led to the identification of 2 novel causes: mutations in GATA6 and STAT3.
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Genome sequencing is the most comprehensive test available, and it was used to identify mutations in a novel enhancer that cause pancreatic agenesis.
Introduction to neonatal diabetes
Neonatal diabetes diagnosed before 6 months is a rare disease (approximate incidence of 1:100,000 live births ) that reflects severe β-cell dysfunction ( Fig. 1 ). Two separate studies have shown that diabetes diagnosed before 6 months of age is most likely to have a monogenic cause rather than being caused by autoimmunity.
Neonatal diabetes is a clinically and genetically heterogeneous disease. To date there are 23 different genetic causes of neonatal diabetes that identify different clinical subtypes of the disease (De Franco and colleagues, submitted for publication and ) (see Fig. 1 , Table 1 ).
| Gene | Mode of Inheritance | Neonatal Diabetes Phenotype | Additional Features | Frequency in NDM Patients (De Franco et al, Submitted ) (%) | References |
|---|---|---|---|---|---|
| 6q24 | — | Transient | Intrauterine growth retardation, macroglossia, umbilical hernia, neurologic features (rare) | 11.1 | Gardner et al, Temple et al, Temple & Shield |
| ABCC8 | Dominant/recessive | Transient, permanent | Developmental delay with/without epilepsy | 14.7 | Babenko et al, Proks et al |
| EIF2AK3 | Recessive | Permanent | Skeletal dysplasia, liver dysfunction | 7.5 | Delepine et al, Rubio-Cabezas et al |
| FOXP3 | X-linked | Permanent | Eczema, enteropathy, other autoimmune features | 1.4 | Chatila et al |
| GATA4 | Dominant | Transient, permanent | Exocrine insufficiency, congenital heart malformations | 0.4 | D’Amato et al, Shaw-Smith et al |
| GATA6 | Dominant | Transient, permanent | Exocrine insufficiency, congenital heart malformation, neurologic defects, hypothyroidism, gut and hepatobiliary malformations | 2.8 | Lango Allen et al, De Franco et al |
| GCK | Recessive | Permanent | — | 2.9 | Njolstad et al, Barbetti et al |
| GLIS3 | Recessive | Permanent | Hypothyroidism | 0.9 | Dimitri et al, Senee et al |
| HNF1B | Dominant | Transient | Exocrine insufficiency, renal cysts | 0.2 | Edghill et al, Yorifuji et al |
| IER3IP1 | Recessive | Permanent | Microcephaly, epilepsy | 0.1 | Abdel-Salam et al, Poulton et al |
| INS | Dominant/recessive | Transient, permanent | — | 10.8 | Garin et al, Stoy et al |
| KCNJ11 | Dominant | Transient, permanent | Developmental delay with/without epilepsy | 23.5 | Gloyn et al, Gloyn et al |
| MNX1 | Recessive | Permanent | Sacral agenesis, neurologic defects | 0.1 | Flanagan et al |
| NEUROD1 | Recessive | Permanent | Cerebellar hypoplasia, sensorineural deafness, visual impairment | 0.3 | Rubio-Cabezas et al |
| NEUROG3 | Recessive | Permanent | Congenital malabsorptive diarrhea | 0.2 | Rubio-Cabezas et al |
| NKX2-2 | Recessive | Permanent | Corpus callosum agenesis | 0.2 | Flanagan et al |
| PDX1 | Recessive | Permanent | Exocrine insufficiency | 0.6 | Schwitzgebel et al, Stoffers et al, Thomas et al, De Franco et al, Nicolino et al |
| PTF1A | Recessive | Permanent | Exocrine insufficiency, cerebellar agenesis (only for coding mutations) | 2.2 | Al-Shammari et al, Sellick et al, Tutak et al, Weeden et al |
| RFX6 | Recessive | Permanent | Intestinal atresia and/or malrotation, gall bladder agenesis | 0.1 | Smith et al, Spiegel et al |
| SLC19A2 | Recessive | Permanent | Thiamine-responsive megaloblastic anemia, sensorineural deafness | 0.7 | Bay et al, Bergmann et al, Mandel et al, Shaw-Smith et al |
| SLC2A2 | Recessive | Transient | Hepatorenal glycogen accumulation, renal dysfunction, impaired utilization of glucose and galactose | 0.6 | Sansbury et al |
| STAT3 | Dominant | Permanent | Autoimmune enteropathy, thyroid dysfunction, pulmonary disease, juvenile-onset arthritis | 0.4 | Flanagan et al |
| ZFP57 | Recessive | Transient | Intrauterine growth retardation | 1.2 | Mackay et al, Mackay & Temple |
The most common causes of neonatal diabetes are mutations in the genes encoding the subunits of the voltage-dependent potassium channel ABCC8 and KCNJ11 . Correct function of the potassium channel is necessary for secretion of insulin in response to glucose levels. Approximately 40% of patients with neonatal diabetes have a potassium channel gene mutation. Patients with mutations in these two genes are sensitive to sulfonylurea treatment, and their glycemic control can be greatly improved switching from insulin to sulfonylurea therapy. This finding has led to international guidelines suggesting immediate referral for genetic testing after a clinical diagnosis of neonatal diabetes. Mutations in KCNJ11 and ABCC8 can cause transient neonatal diabetes, permanent neonatal diabetes, or DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome.
Clinically neonatal diabetes can be divided into 3 broad categories:
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Transient neonatal diabetes (The diabetes remits and eventually relapses later in life.)
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Permanent neonatal diabetes (The diabetes does not remit.)
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Syndromic neonatal diabetes (Neonatal diabetes is one of the clinical features characterizing a syndrome.)
The most common causes of transient neonatal diabetes are methylation abnormalities resulting in overexpression of paternally expressed genes at the 6q24 locus and mutations in ABCC8 or KCNJ11 (see Table 1 ). Patients with a transient form of neonatal diabetes are diagnosed with hyperglycemia in the first 6 months of life; the diabetes then remits, and in most cases it relapses later in life.
Isolated insulin-requiring permanent neonatal diabetes is caused by mutations in the INS and GCK genes. Mutations in 18 genes are known to cause syndromic neonatal diabetes (see Table 1 ), in which neonatal diabetes is just one of the features of the clinical spectrum that defines a particular condition. Because neonatal diabetes is diagnosed in the first 6 months of life, in most cases it is the presenting feature of the syndrome; additional clinical features will sequentially appear later in life. For this reason, a differential clinical diagnosis in the first 6 months of life is often difficult and can only be achieved months or even years after the first presentation with neonatal diabetes.
Introduction to neonatal diabetes
Neonatal diabetes diagnosed before 6 months is a rare disease (approximate incidence of 1:100,000 live births ) that reflects severe β-cell dysfunction ( Fig. 1 ). Two separate studies have shown that diabetes diagnosed before 6 months of age is most likely to have a monogenic cause rather than being caused by autoimmunity.
Neonatal diabetes is a clinically and genetically heterogeneous disease. To date there are 23 different genetic causes of neonatal diabetes that identify different clinical subtypes of the disease (De Franco and colleagues, submitted for publication and ) (see Fig. 1 , Table 1 ).
| Gene | Mode of Inheritance | Neonatal Diabetes Phenotype | Additional Features | Frequency in NDM Patients (De Franco et al, Submitted ) (%) | References |
|---|---|---|---|---|---|
| 6q24 | — | Transient | Intrauterine growth retardation, macroglossia, umbilical hernia, neurologic features (rare) | 11.1 | Gardner et al, Temple et al, Temple & Shield |
| ABCC8 | Dominant/recessive | Transient, permanent | Developmental delay with/without epilepsy | 14.7 | Babenko et al, Proks et al |
| EIF2AK3 | Recessive | Permanent | Skeletal dysplasia, liver dysfunction | 7.5 | Delepine et al, Rubio-Cabezas et al |
| FOXP3 | X-linked | Permanent | Eczema, enteropathy, other autoimmune features | 1.4 | Chatila et al |
| GATA4 | Dominant | Transient, permanent | Exocrine insufficiency, congenital heart malformations | 0.4 | D’Amato et al, Shaw-Smith et al |
| GATA6 | Dominant | Transient, permanent | Exocrine insufficiency, congenital heart malformation, neurologic defects, hypothyroidism, gut and hepatobiliary malformations | 2.8 | Lango Allen et al, De Franco et al |
| GCK | Recessive | Permanent | — | 2.9 | Njolstad et al, Barbetti et al |
| GLIS3 | Recessive | Permanent | Hypothyroidism | 0.9 | Dimitri et al, Senee et al |
| HNF1B | Dominant | Transient | Exocrine insufficiency, renal cysts | 0.2 | Edghill et al, Yorifuji et al |
| IER3IP1 | Recessive | Permanent | Microcephaly, epilepsy | 0.1 | Abdel-Salam et al, Poulton et al |
| INS | Dominant/recessive | Transient, permanent | — | 10.8 | Garin et al, Stoy et al |
| KCNJ11 | Dominant | Transient, permanent | Developmental delay with/without epilepsy | 23.5 | Gloyn et al, Gloyn et al |
| MNX1 | Recessive | Permanent | Sacral agenesis, neurologic defects | 0.1 | Flanagan et al |
| NEUROD1 | Recessive | Permanent | Cerebellar hypoplasia, sensorineural deafness, visual impairment | 0.3 | Rubio-Cabezas et al |
| NEUROG3 | Recessive | Permanent | Congenital malabsorptive diarrhea | 0.2 | Rubio-Cabezas et al |
| NKX2-2 | Recessive | Permanent | Corpus callosum agenesis | 0.2 | Flanagan et al |
| PDX1 | Recessive | Permanent | Exocrine insufficiency | 0.6 | Schwitzgebel et al, Stoffers et al, Thomas et al, De Franco et al, Nicolino et al |
| PTF1A | Recessive | Permanent | Exocrine insufficiency, cerebellar agenesis (only for coding mutations) | 2.2 | Al-Shammari et al, Sellick et al, Tutak et al, Weeden et al |
| RFX6 | Recessive | Permanent | Intestinal atresia and/or malrotation, gall bladder agenesis | 0.1 | Smith et al, Spiegel et al |
| SLC19A2 | Recessive | Permanent | Thiamine-responsive megaloblastic anemia, sensorineural deafness | 0.7 | Bay et al, Bergmann et al, Mandel et al, Shaw-Smith et al |
| SLC2A2 | Recessive | Transient | Hepatorenal glycogen accumulation, renal dysfunction, impaired utilization of glucose and galactose | 0.6 | Sansbury et al |
| STAT3 | Dominant | Permanent | Autoimmune enteropathy, thyroid dysfunction, pulmonary disease, juvenile-onset arthritis | 0.4 | Flanagan et al |
| ZFP57 | Recessive | Transient | Intrauterine growth retardation | 1.2 | Mackay et al, Mackay & Temple |
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