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ObjectivesIntroduction: Neonatal Diabetes Mellitus (NDM) is a rare genetic condition (~ 1 in 90,000 live births) with over 30 known genetic causes occurring mainly before 6 months of age. It is defined by the presence of severe hyperglycaemia associated with insufficient or no circulating insulin. Variable phenotypic spectrum has been observed in NDM patients with different genetic subtypes, including those with mutations in either GATA6 or PDX1 genes, exhibiting complex cardiac defects, pancreatic, and gall bladder malformations and other abnormalities. Aim: To underscore the phenotypic variability of individuals with mutations in GATA6 or PDX1 in order to determine whether there is a phenotype-genotype correlation.MethodsWe classified 95 variants in the GATA6 gene from 148 patients and 22 variants in PDX1 from 37 patients. Variants were classified according to the ACGS Best Practice Guidelines, and clinical data was obtained from published literature and referral notes for individuals referred to the Exeter Genomics Laboratory. The Chi-square test was used to investigate phenotype-genotype relationships.Results66 GATA6 variants were identified as likely pathogenic/pathogenic in 107 individuals and are categorised into 22 missense variants, 9 splicings, 23 insertions/deletions (frameshifts) and 12 non-sense changes. These patients either had diabetes with an extra-pancreatic phenotype (n=66) or extra-pancreatic characteristics without diabetes (n=41). We found that de novo mutations (p-value <0.0001), missense changes in the second GATA6 Zinc Finger (ZF) binding domain (p=0.014), and loss- off-function GATA6 variations (p=0.003) were more likely to result in patients having diabetes. Among 26 individuals with recessive PDX1 variants, 19 disease-causing variants were identified which include 15 missense variants, 3 frameshifts, and 1 non-sense. These individuals either had a pancreatic phenotype only (NDM with or without exocrine pancreatic insufficiency) or a pancreatic phenotype with extra-pancreatic features. The genotype-phenotype correlation within this cohort was not significant. However, our findings showed that 1 in 3 patients with PDX1 mutation present additional features, affecting the gut or liver along with NDM.ConclusionOur study confirmed a statistically significant phenotype-genotype relationship in individuals with pathogenic GATA6 mutations. These findings might increase clinicians’ awareness of the possibilities and implications of GATA6 and/or PDX1 mutations in individuals with diabetes and heterogeneous clinical features.

Traditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes. In this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes. Between January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p<0·0001). Median duration of diabetes at the time of genetic testing decreased from more than 4 years before 2005 to less than 3 months after 2012. Earlier referral for genetic testing affected the clinical phenotype. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from diagnosis had isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0·0001), in whom skeletal and liver involvement was common. Similarly, for patients with genetically diagnosed transient neonatal diabetes, the diabetes had remitted in only ten (10%) of 101 patients tested early (<3 months) compared with 60 (100%) of the 60 later referrals (p<0·0001). Patients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management. Wellcome Trust and Diabetes UK.

Identifying copy number variants (CNVs) can provide diagnoses to patients and provide important biological insights into human health and disease. Current exome and targeted sequencing approaches cannot detect clinically and biologically-relevant CNVs outside their target area. We present SavvyCNV, a tool which uses off-target read data from exome and targeted sequencing data to call germline CNVs genome-wide. Up to 70% of sequencing reads from exome and targeted sequencing fall outside the targeted regions. We have developed a new tool, SavvyCNV, to exploit this ‘free data’ to call CNVs across the genome. We benchmarked SavvyCNV against five state-of-the-art CNV callers using truth sets generated from genome sequencing data and Multiplex Ligation-dependent Probe Amplification assays. SavvyCNV called CNVs with high precision and recall, outperforming the five other tools at calling CNVs genome-wide, using off-target or on-target reads from targeted panel and exome sequencing. We then applied SavvyCNV to clinical samples sequenced using a targeted panel and were able to call previously undetected clinically-relevant CNVs, highlighting the utility of this tool within the diagnostic setting. SavvyCNV outperforms existing tools for calling CNVs from off-target reads. It can call CNVs genome-wide from targeted panel and exome data, increasing the utility and diagnostic yield of these tests. SavvyCNV is freely available at https://github.com/rdemolgen/SavvySuite .

Neonatal diabetes mellitus (NDM) is a monogenic condition diagnosed <6 months of age with >40 genetic causes. International guidelines recommend referral for genetic testing immediately after diagnosis since the genetic result guides clinical management. We used next‐generation sequencing to identify a homozygous pathogenic variant, p.(Arg244*), in COQ9 in 2 individuals referred for NDM testing. Both had insulin‐treated hyperglycemia, severe structural brain defects, dysmorphic features, and lactic acidosis. Recessive loss‐of‐function variants in COQ9 cause Coenzyme Q10 deficiency‐5, a multi‐system mitochondrial disease, with 7 cases reported. Neonatal hyperglycemia has not been reported in any of these cases but has been described for two other Coenzyme Q10 disorders caused by variants in COQ2 and COQ4. Our report shows that individuals with COQ9‐related disease can present with neonatal hyperglycemia, expanding the clinical spectrum of this disorder. We recommend the inclusion of COQ9, as well as COQ2 and COQ4, to gene panels used for NDM testing. NDM is a monogenic condition diagnosed <6 months. We present the first two cases of individuals with pathogenic variants in COQ9 who presented with neonatal hyperglycemia. COQ9 should be included on NDM genetic testing panels.

Neonatal diabetes mellitus (NDM) may be transient or permanent, and the majority is caused by genetic mutations. Early diagnosis is essential to select the patients who will respond to oral treatment. In this investigation, we aimed to present the phenotype and genotype of our patients with NDM and share our experience in a single tertiary center A total of 16 NDM patients from 12 unrelated families are included in the study. The clinical presentation, age at diagnosis, perinatal and family history, consanguinity, gender, hemoglobin A1c, C-peptide, insulin, insulin autoantibodies, genetic mutations, and response to treatment are retrospectively evaluated. The median age at diagnosis of diabetes was five months (4 days-18 months) although six patients with a confirmed genetic diagnosis were diagnosed >6 months. Three patients had mutations, six had mutations, three had mutations, and one had a mutation. All the permanent NDM patients with and mutations were started on sulfonylurea treatment resulting in a significant increase in C-peptide level, better glycemic control, and discontinuation of insulin. Although NDM is defined as diabetes diagnosed during the first six months of life, and a diagnosis of type 1 diabetes is more common between the ages of 6 and 24 months, in rare cases NDM may present as late as 12 or even 24 months of age. Molecular diagnosis in NDM is important for planning treatment and predicting prognosis. Therefore, genetic testing is essential in these patients.

The MNX1 gene encodes a homeobox transcription factor found to be important for pancreatic beta cell differentiation and development. Mutations of the MNX1 gene that cause permanent neonatal diabetes mellitus (PNDM) are rare and have been reported in only two cases. Both cases presented with hyperglycemia, with one case having isolated PNDM while the other had PNDM and multiple neurologic, skeletal, lung, and urologic congenital anomalies resulting in death in early infancy. We describe the genetic and clinical features of a preterm male infant with a homozygous [c.816C > A p.(Phe272Leu)] MNX1 mutation. Our proband is the first case to present in severe diabetic ketoacidosis (DKA), indicating severe insulin deficiency. Unlike the previously reported female case who had the same mutation and presented with isolated PNDM, our proband had hypospadias and congenital umbilical hernia and showed poor growth on follow up. Our case suggests that MNX1 mutations causing NDM can result in a range of extra‐pancreatic features and a variable phenotype, similar to other transcription factors causing NDM such as GATA6 and GATA4 mutations. We also cannot exclude the possibility of sex‐biased expression of MNX1 gene (which was recently reported for other monogenic/neonatal diabetes genes such as the NEUROD1 and HNF4A in humans) since the two male cases had associated multiple anomalies while the female case had isolated PNDM. Our report further defines the phenotype caused by recessive homozygous MNX1 mutations and explores potential new mechanisms regulating MNX1 gene expression which should be further explored. Our manuscript describes a male newborn with the rare MNX1 mutation with a novel presentation/phenotype of not only hyperglycemia but also severe diabetic ketoacidosis, hypospadias and congenital umbilical hernia. Thus, we expand on the phenotype presentation of MNX1 mutations associated with permanent neonatal diabetes. Since the two males who had MNX1 mutation and diabetes (our case and another previously reported case with a different mutation), had multiple congenital anomalies, whereas the female who had the same mutation as our patient had isolated diabetes, our report also raises the possibility of sex‐biased gene expression, which was recently reported for several monogenic diabetes genes. This is worth exploring further in the future especially as more cases are reported.

Neonatal diabetes mellitus (NDM) is a rare type of monogenic diabetes that presents in the first 6 months of life. Activating mutations in the KCNJ11 gene encoding for the Kir6.2 subunit of the ATP-sensitive potassium (K ) channel can lead to transient NDM (TNDM) or to permanent NDM (PNDM). A female infant presented on the 22 day of life with severe hyperglycemia and ketoacidosis (glucose: 907mg/dL, blood gas pH: 6.84, HCO : 6 mmol/L). She was initially managed with intravenous (IV) fluids and IV insulin. Ketoacidosis resolved within 48 hours and she was started on subcutaneous insulin injections with intermediate acting insulin NPH twice daily requiring initially 0.75-1.35 IU/kg/d. Pre-prandial C-peptide levels were 0.51 ng/mL (normal: 1.77-4.68). Insulin requirements were gradually reduced and insulin administration was discontinued at the age of 10 months with subsequent normal glucose and HbA1c levels. C-peptide levels normalized (pre-prandial: 1.6 ng/mL, postprandial: 2 ng/mL). Genetic analysis identified a novel missense mutation (p.Pro254Gln) in the KCNJ11 gene. We report a novel KCNJ11 mutation in a patient who presented in the first month of life with a phenotype of NDM that subsided at the age of 10 months. It is likely that the novel p.P254Q mutation results in mild impairment of the K channel function leading to TNDM.

Neonatal diabetes, defined as the onset of diabetes within the first six months of life, is very rarely caused by pancreatic agenesis. Homozygous truncating mutations in the PTF1A gene, which encodes a transcriptional factor, have been reported in patients with pancreatic and cerebellar agenesis, whilst mutations located in a distal pancreatic-specific enhancer cause isolated pancreatic agenesis. We report an infant, born to healthy non-consanguineous parents, with neonatal diabetes due to pancreatic agenesis. Initial genetic investigation included sequencing of KCNJ11, ABCC8 and INS genes, but no mutations were found. Following this, 22 neonatal diabetes associated genes were analyzed by a next generation sequencing assay. We found compound heterozygous mutations in the PTF1A gene: A frameshift mutation in exon 1 (c.437_462 del, p.Ala146Glyfs*116) and a mutation affecting a highly conserved nucleotide within the distal pancreatic enhancer (g.23508442A>G). Both mutations were confirmed by Sanger sequencing. Isolated pancreatic agenesis resulting from compound heterozygosity for truncating and enhancer mutations in the PTF1A gene has not been previously reported. This report broadens the spectrum of mutations causing pancreatic agenesis.

Neonatal diabetes mellitus is a rare form of monogenic diabetes which is diagnosed in the first six months of life. Here we report three patients with neonatal diabetes; two with isolated pancreas agenesis due to mutations in the pancreas-specific transcription factor 1A (PTF1A) enhancer and one with developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, due to a KCNJ11 mutation. The two cases with mutations in the distal enhancer of PTF1A had a homozygous g.23508363A>G and a homozygous g.23508437A>G mutation respectively. Previous functional analyses showed that these mutations can decrease expression of PTF1A which is involved in pancreas development. Both patients were born small for gestational age to consanguineous parents. Both were treated with insulin and pancreatic enzymes. One of these patients’ fathers was also homozygous for the PTF1A mutation, whilst his partner and the parents of the other patient were heterozygous carriers. In the case with DEND sydrome, a previosly reported heterozygous KCNJ11 mutation, p.Cys166Tyr (c.497G>A), was identified. This patient was born to nonconsanguineous parents with normal birth weight. The majority of neonatal diabetes patients with KCNJ11 mutations will respond to sulphonylurea treatment. Therefore Glibenclamide, an oral antidiabetic of the sulphonylurea group, was started. This treatment regimen relatively improved blood glucose levels and neurological symptoms in the short term. Because we could not follow the patient in the long term, we are not able to draw conclusions about the efficacy of the treatment. Although neonatal diabetes mellitus can be diagnosed clinically, genetic analysis is important since it is a guide for the treatment and for prognosis.

Andrew Hattersley, Noel Morgan, Juha Kere and colleagues identify de novo activating germline STAT3 mutations in five unrelated individuals with early-onset multi-organ autoimmune disease. Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.