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Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10−4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10−5) and Finnish (n = 80, odds ratio = 22, P = 1 × 10−6) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance., published version, peerReviewed

BACKGROUND: Maturity-onset diabetes of the young (MODY) is uncommon; however, accurate diagnosis facilitates personalized management and informs prognosis in probands and relatives. OBJECTIVE: The objective of the study was to highlight that the appropriate use of genetic and nongenetic investigations leads to the correct classification of diabetes etiology. CASE DISCUSSION: A 30-year-old European female was diagnosed with insulin-treated gestational diabetes. She discontinued insulin after delivery; however, her fasting hyperglycemia persisted. β-Cell antibodies were negative and C-peptide was 0.79 nmol/L. Glucokinase (GCK)-MODY was suspected and confirmed by the identification of a GCK mutation (p.T206M). METHODS: Systematic clinical and biochemical characterization and GCK mutational analysis were implemented to determine the diabetes etiology in five relatives. Functional characterization of GCK mutations was performed. RESULTS: Identification of the p.T206M mutation in the proband's sister confirmed a diagnosis of GCK-MODY. Her daughter was diagnosed at 16 weeks with permanent neonatal diabetes (PNDM). Mutation analysis identified two GCK mutations that were inherited in trans-p. [(R43P);(T206M)], confirming a diagnosis of GCK-PNDM. Both mutations were shown to be kinetically inactivating. The proband's mother, other sister, and daughter all had a clinical diagnosis of type 1 diabetes, confirmed by undetectable C-peptide levels and β-cell antibody positivity. GCK mutations were not detected. CONCLUSIONS: Two previously misclassified family members were shown to have GCK-MODY, whereas another was shown to have GCK-PNDM. A diagnosis of type 1 diabetes was confirmed in three relatives. This family exemplifies the importance of careful phenotyping and systematic evaluation of relatives after discovering monogenic diabetes in an individual.

Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.

Context Approximately 39% of cases with permanent neonatal diabetes (PNDM) and about 11% with maturity onset diabetes of the young (MODY) have an unknown genetic aetiology. Many of the known genes causing MODY and PNDM were identified as being critical for beta cell function before their identification as a cause of monogenic diabetes. Objective We used nominations from the EU beta cell consortium EURODIA project partners to guide gene candidacy. Subjects Seventeen cases with permanent neonatal diabetes and 8 cases with maturity onset diabetes of the young. Main outcome measures The beta cell experts within the EURODIA consortium were asked to nominate 3 "gold", 3 "silver" and 4 "bronze" genes based on biological or genetic grounds. We sequenced twelve candidate genes from the list based on evidence for candidacy. Results Sequencing ISL1, LMX1A, MAFA, NGN3, NKX2.2, NKX6.1, PAX4, PAX6, SOX2, SREBF1, SYT9 and UCP2 did not identify any pathogenic mutations. Conclusion Further work is needed to identify novel causes of permanent neonatal diabetes and maturity onset diabetes of the young utilising genetic approaches as well as further candidate genes. Image: Peninsula Medical School logo. Exeter, United Kingdom., JOP. Journal of the Pancreas, Vol 11, N° 1 (2010): January - P. 1-94

Aims An early genetic diagnosis of neonatal diabetes guides clinical management and results in improved treatment in ~ 40% of patients. In the offspring of individuals with neonatal diabetes, a prenatal diagnosis allows accurate estimation of the risk of developing diabetes and, eventually, the most appropriate treatment for the baby. In this study, we performed non‐invasive prenatal genetic testing for a fetus at risk of inheriting a paternal KCNJ11 p.R201C mutation causing permanent neonatal diabetes. Methods A droplet digital polymerase chain reaction assay was used to detect the presence of the mutation in cell‐free circulating DNA (cfDNA) extracted from maternal plasma at 12 and 16 weeks’ gestation. Results The mutation was not detected in the cfDNA samples, suggesting that the fetus had not inherited the KCNJ11 mutation. The fetal DNA fraction was estimated at 6.2% and 10.7%, which is above the detection limit of the assay. The result was confirmed by Sanger sequencing after the baby's birth, confirming that the baby's risk of developing neonatal diabetes was reduced to that of the general population. Conclusions We report the first case of non‐invasive prenatal testing in a family with neonatal diabetes. A prenatal diagnosis in families at high risk of monogenic diabetes informs both prenatal and postnatal management. Although the clinical impact of this novel technology still needs to be assessed, its implementation in clinical practice (including cases at risk of inheriting mutations from the mother) will likely have a positive impact upon the clinical management of families affected by monogenic diabetes., What's new? This article describes the first case of non‐invasive prenatal diagnosis using cell‐free fetal DNA in a family with neonatal diabetes.The test showed that the baby had not inherited the neonatal diabetes mutation, providing reassurance to the parents at mid‐gestation that this baby was not at high risk of neonatal diabetes and informing management of the pregnancy, delivery and neonate accordingly.

Background: Congenital hyperinsulinism (CHI) has not been studied in the Ukraine. Objective and hypotheses: We investigated the genetic aetiology and treatment of patients with CHI. Method: Routine clinical and laboratory investigations were performed in children with hypoglycaemia. Genetic testing was undertaken for seven patients with CHI from 9 families. KCNJ11, ABCC8, HNF4A genes were sequenced in all patients. For those who were negative in the initial screening, were also tested for GLUD1 gene, as well as tNGS of all known CHI genes was performed. 18F-DOPA PET-CT (and 68Ga-DOTA PET-CT) scans were performed in selected cases. Results: In seven patients hypoglycaemia (glucose 0,8 [0,5; 1,2] mmol/l) with detectable insulin (43,1 [1,2; 45,9] mIU/l) and/or C-peptide (6,9 [1,1; 9,9] ng/ml) confirmed CHI. The median age at diagnosis was 55,4 [1,0; 330] days and the median birth weight was 4078 [2850; 5200] g. The incidence of CHI in the Ukraine was calculated at 1 in 258,650 births. Mutations were detected in 6/7 patients. In one patient without a mutation, 18F-DOPA and 68Ga-DOTA PET-CT scanning revealed diffuse disease. All patients showed a poor response to medication and had varying degrees of developmental delay and seizures. 5/7 were surgically treated. Postoperative complications included transient fasting hyperglycaemia (1), cicatricial hernia development after convulsions (1) and persistent subclinical exocrine insufficiency (1). Conclusion: Children with hypoglycaemia and unsuppressed insulin and C-peptide levels should undergo genetic and eventual PET CT scan for characterization of the type of CHI. Further studies to identify novel CHI genes are required. (Table Presented).

Background: Congenital hyperinsulinism (CHI) is a common cause of hypoglycaemia in neonates, infants and children. CHI is a heterogeneous disease in terms of clinical presentation, genetics and histology. Objective and hypotheses: The aim of this study was to describe the clinical characteristics, genotype-phenotype correlations and treatment outcome of Russian patients with CHI. Method: A total of 90 children with CHI were identified from 2009 till 2015 in Russia, of which 64 (71.1%) responded to the medical therapy (diazoxide and/or octreotide) and 26 (28.9%) were resistant and underwent subtotal or partial pancreatectomy. Results: Mutations in ABCC8 and KCNJ11 genes were found in 28/86 patients (32.5%); 3/86 patients (3.4%) were found to carry heterozygous GCK mutations; 3/86 (3.4%) - GLUD1 mutations and one patient (1.1%) had HADH mutation. Among medically resistant cases, 17/26 patients (65.4%) had KATP genes mutations, of which nine were paternally inherited and represent focal HI, what was confirmed histologically and eight had diffuse disease (four heterozygous de-novo mutations and four homozygous and compound heterozygous mutations); one patient (3.8%) had severe GCK mutation; 8/26 patients had WT genes. Among medically responsive cases, 11/64 patients (17%) had mutations in KATP genes, interesting that two of them (both with heterozygous intronic mutations) spontaneously recovered during 6 months after diagnosis; 2/64 (3.1%) - in GCK, 3/64 (4.6%) - in GLUD1 and 1/64 (1.5%) - in HADH gene. Genotype-phenotype correlation revealed that mutations in KATP genes were associated with an increased birth weight and early age of presentation. Follow up studies showed high prevalence of severe developmental delay, cerebral palsy, and optic neuropathy (40, 26, and 7.5% respectively). Conclusion: A genetic cause was detected in 26 and 69%, of children with mild, and severe CHI, respectively, in Russia. Mutations in ABCC8 and KCNJ11 were found to be the most common cause and associated with severe course of the disease and poor neurologic outcome.

Context:Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.Objective:To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.Design:This was an observational, longitudinal study conducted over 7 years.Setting:International collaborative study conducted at referral centers for pituitary diseases.Participants:FIPA families (n = 216) and sporadic young-onset (≤30 y) pituitary adenoma patients (n = 404) participated in the study.Interventions:We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant.Main Outcome Measure(s):We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis.Results:Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.Conclusions:A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

Background Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined.Methods and Results We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known.Conclusions The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome inaddition to the established beta cell phenotype.

The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ∼400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease. Fil: Weedon, M. N.. University of Exeter; Reino Unido Fil: Cebola, I.. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Imperial College London; Reino Unido Fil: Patch, A. M.. University of Exeter; Reino Unido Fil: Flanagan, S.. University of Exeter; Reino Unido Fil: De Franco, E.. University of Exeter; Reino Unido Fil: Caswell, R.. University of Exeter; Reino Unido Fil: Rodríguez Seguí, Santiago Andrés. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Shaw Smith, C.. University of Exeter; Reino Unido Fil: Cho, C.. Anne McLaren Laboratory for Regenerative Medicine; Reino Unido Fil: Allen, H. L.. University of Exeter; Reino Unido Fil: Houghton, J.. University of Exeter; Reino Unido Fil: Roth, C. L.. Seattle Children’s Hospital Research Institute; Estados Unidos Fil: Chen, R.. King’s College London; Reino Unido Fil: Hussain, K.. University College London; Reino Unido Fil: Marsh, P.. King’s College London; Reino Unido Fil: Vallier, L.. Anne McLaren Laboratory for Regenerative Medicine; Reino Unido Fil: Murray, A.. University of Exeter; Reino Unido Fil: International Pancreatic Agenesis Consortium. No especifica; Fil: Ellard, S.. University of Exeter; Reino Unido Fil: Ferrer, J.. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Imperial College London; Reino Unido Fil: Hattersley, A. T.. University of Exeter; Reino Unido

Aim To describe the clinical and radiological features of four new families with a childhood presentation of COL4A1 mutation. Method We retrospectively reviewed the clinical presentation. Investigations included radiological findings and COL4A1 mutation analysis of the four cases. Affected family members were identified. COL4A1 mutation analysis was performed in all index cases and, where possible, in affected family members. Results The three male and one female index cases presented with recurrent childhood-onset stroke, infantile hemiplegia/spastic quadriplegia, and infantile spasms. Additional features such as congenital cataracts and anterior segment dysgenesis were present. Microcephaly and developmental delay/learning difficulties were present in three cases. Three cases had one or more family member affected in multiple generations, with a total of 11 such individuals identified. The clinical features showed a wide intrafamilial variation. Magnetic resonance imaging (MRI) showed bilateral white matter change in all cases, except in one mutation-positive family member. Unilateral or bilateral porencephaly was present in cases with infantile hemiplegia, and a diagnosis of clinical stroke was supported by the presence of intracerebral haemorrhage. The age at diagnosis was between 1year and 6years for the children with presentation in infancy and 12months after stroke in a 14-year-old male. Three new pathogenic mutations were identified in the COL4A1 gene. Interpretation COL4A1 mutations can present in children with infantile hemiplegia/quadriplegia, stroke or epilepsy, and a motor disorder. The presence of eye features and white matter change on MRI in childhood can help point towards the diagnosis. Once the diagnosis is made, a careful search can identify affected family members. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

We identified a novel heterozygous mutation, W68R, in the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, in a patient with transient neonatal diabetes. This tryptophan is absolutely conserved in mammalian Kir channels. The functional effects of mutations at residue 68 of Kir6.2 were studied by heterologous expression in Xenopus oocytes, and by homology modelling. We found the Kir6.2-W68R mutation causes a small reduction in ATP inhibition in the heterozygous state and an increase in the whole-cell KATP current. This can explain the clinical phenotype of the patient. The effect of the mutation was not charge or size dependent, the order of potency for ATP inhibition being W

Understanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreatic agenesis, however, most instances of this disorder are of unknown origin. We report de novo heterozygous inactivating mutations in GATA6 in 15/27 (56%) individuals with pancreatic agenesis. These findings define the most common cause of human pancreatic agenesis and establish a key role for the transcription factor GATA6 in human pancreatic development.

opisuju se strukturne varijacije hemoglobina i genetika hemoglobinopatija