RESUMEN
AIMS/HYPOTHESIS: Monogenic diabetes is estimated to account for 1-6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity. METHODS: Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing. RESULTS: A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes. CONCLUSIONS/INTERPRETATION: This unique single-centre study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Enfermedades del Recién Nacido , Masculino , Recién Nacido , Humanos , Niño , Anciano , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/diagnóstico , Consanguinidad , Estudios de Cohortes , Irak/epidemiología , Enfermedades del Recién Nacido/genética , Mutación/genética , Proteínas de Transporte de Nucleósidos/genéticaRESUMEN
Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across pancreas development, with > 21% of sites characterized as developmental differentially methylated positions (dDMPs) including many annotated to genes associated with monogenic diabetes. An analysis of DNA methylation in postnatal pancreas tissue showed that the dramatic temporal changes in DNA methylation occurring in the developing pancreas are largely limited to the prenatal period. Significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small proportion of sites showing sex-specific DNA methylation trajectories across pancreas development. Pancreas dDMPs were not distributed equally across the genome and were depleted in regulatory domains characterized by open chromatin and the binding of known pancreatic development transcription factors. Finally, we compared our pancreas dDMPs to previous findings from the human brain, identifying evidence for tissue-specific developmental changes in DNA methylation. This study represents the first systematic exploration of DNA methylation patterns during human fetal pancreas development and confirms the prenatal period as a time of major epigenomic plasticity.
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Metilación de ADN , Páncreas , Humanos , Páncreas/metabolismo , Páncreas/embriología , Femenino , Masculino , Regulación del Desarrollo de la Expresión Génica , Islas de CpG , Epigénesis Genética , Genoma Humano , Feto/metabolismoRESUMEN
EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.
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Proteínas de Unión al Calcio/genética , Trastornos Congénitos de Glicosilación/genética , Retículo Endoplásmico/genética , alfa-Manosidasa/genética , Adolescente , Alelos , Proteínas de Unión al Calcio/deficiencia , Línea Celular , Niño , Preescolar , Trastornos Congénitos de Glicosilación/sangre , Discapacidades del Desarrollo/genética , Femenino , Glicoproteínas/sangre , Glicosilación , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Mutación , Linaje , Polisacáridos/sangre , Deficiencias en la Proteostasis/genética , alfa-Manosidasa/deficienciaRESUMEN
Pathogenic FOXP3 variants cause immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a progressive autoimmune disease resulting from disruption of the regulatory T cell (Treg) compartment. Assigning pathogenicity to novel variants in FOXP3 is challenging due to the heterogeneous phenotype and variable immunological abnormalities. The number of cells with demethylation at the Treg cell-specific demethylated region (TSDR) is an independent biomarker of IPEX. We aimed to investigate if diagnosing IPEX at presentation with isolated diabetes could allow for effective monitoring of disease progression and assess whether TSDR analysis can aid FOXP3 variant classification and predict disease course. We describe a large genetically diagnosed IPEX cohort (n = 65) and 13 individuals with other monogenic autoimmunity subtypes in whom we quantified the proportion of cells with FOXP3 TSDR demethylation, normalized to the number with CD4 demethylation (%TSDR/CD4) and compare them to 29 unaffected controls. IPEX patients presenting with isolated diabetes (50/65, 77%) often later developed enteropathy (20/50, 40%) with a median interval of 23.5 weeks. %TSDR/CD4 was a good discriminator of IPEX vs. unaffected controls (ROC-AUC 0.81, median 13.6% vs. 8.5%, p < 0.0001) with higher levels of demethylation associated with more severe disease. Patients with other monogenic autoimmunity had a similar %TSDR/CD4 to controls (median 8.7%, p = 1.0). Identifying increased %TSDR/CD4 in patients with novel FOXP3 mutations presenting with isolated diabetes facilitates diagnosis and could offer an opportunity to monitor patients and begin immune modulatory treatment before onset of severe enteropathy.
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Diabetes Mellitus , Enfermedades Genéticas Ligadas al Cromosoma X , Humanos , Linfocitos T Reguladores , Diarrea , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Factores de Transcripción Forkhead/genética , MutaciónRESUMEN
AIMS: The aim of this study is to elucidate the aetiology and clinical features of neonatal and early-onset diabetes in a large database for pediatric diabetes patients in Ukraine. METHODS: We established a Pediatric Diabetes Register to identify patients diagnosed with diabetes before 9 months of age. Genetic testing was undertaken for 66 patients from 65 unrelated families with diabetes diagnosed within the first 6 months of life (neonatal diabetes, n = 36) or between 6 and 9 months (early-onset diabetes, n = 30). RESULTS: We determined the genetic aetiology in 86.1% of patients (31/36) diagnosed before 6 months and in 20% (6/30) diagnosed between 6 and 9 months. Fourteen individuals (37.8% of those with a genetic cause identified) had activating heterozygous variants in ABCC8 or KCNJ11. An additional 10 individuals had pathogenic variants in the INS or GCK genes, while 4 had 6q24 transient neonatal diabetes. Rare genetic subtypes (including pathogenic variants in EIF2AK3, GLIS3, INSR, PDX1, LRBA, RFX6 and FOXP3) were identified in nine probands (24.3% of solved cases), 6 of whom died. In total, eight individuals died between infancy and childhood, all of them were diagnosed before 6 months and had received a genetic diagnosis. CONCLUSIONS: In the last decade, the increased availability of comprehensive genetic testing has resulted in increased recognition of the contribution of rare genetic subtypes within pediatric diabetes cohorts. In our study, we identified a high mortality rate among these patients.
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Diabetes Mellitus , Enfermedades del Recién Nacido , Recién Nacido , Humanos , Niño , Ucrania , Diabetes Mellitus/diagnóstico , Pruebas Genéticas , Enfermedades del Recién Nacido/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
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.
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Variaciones en el Número de Copia de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Algoritmos , Variaciones en el Número de Copia de ADN/genética , Exoma/genética , Humanos , Reacción en Cadena de la Polimerasa Multiplex , Secuenciación del ExomaRESUMEN
AIMS/HYPOTHESIS: A key unanswered question in type 1 diabetes is whether beta cells initiate their own destruction or are victims of an aberrant immune response (beta cell suicide or homicide?). To investigate this, we assessed islet autoantibodies in individuals with congenital beta cell defects causing neonatal diabetes mellitus (NDM). METHODS: We measured autoantibodies to GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) in 242 individuals with NDM (median age diagnosed 1.8 months [IQR 0.39-2.9 months]; median age collected 4.6 months [IQR 1.8-27.6 months]; median diabetes duration 2 months [IQR 0.6-23 months]), including 75 whose NDM resulted from severe beta cell endoplasmic reticulum (ER) stress. As a control cohort we also tested samples from 69 diabetes-free individuals (median age collected 9.9 months [IQR 9.0-48.6 months]) for autoantibodies. RESULTS: We found low prevalence of islet autoantibodies in individuals with monogenic NDM; 13/242 (5.4% [95% CI 2.9, 9.0%]) had detectable GADA, IA-2A and/or ZnT8A. This was similar to the proportion in the control participants who did not have diabetes (1/69 positive [1.4%, 95% CI 0.03, 7.8%], p=0.3). Importantly, monogenic individuals with beta cell ER stress had a similar rate of GADA/IA-2A/ZnT8A positivity to non-ER stress aetiologies (2.7% [95% CI 0.3, 9.3%] vs 6.6% [95% CI 3.3, 11.5%] p=0.4). We observed no association between islet autoimmunity and genetic risk, age at testing (including 30 individuals >10 years at testing) or diabetes duration (p>0.4 for all). CONCLUSIONS/INTERPRETATION: Our data support the hypothesis that beta cell stress/dysfunction alone does not lead to the production of islet autoantibodies, even in the context of high-risk HLA types. This suggests that additional factors are required to trigger an autoimmune response towards beta cells.
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Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Autoanticuerpos , Autoinmunidad/genética , Biomarcadores , Preescolar , Diabetes Mellitus Tipo 1/metabolismo , Glutamato Descarboxilasa , Humanos , Lactante , Recién Nacido , Células Secretoras de Insulina/metabolismo , Factores de RiesgoRESUMEN
We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.
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Discapacidades del Desarrollo/etiología , Holoprosencefalia/etiología , Enfermedades del Recién Nacido/etiología , Mutación , Enfermedades del Sistema Nervioso/etiología , Páncreas/anomalías , Enfermedades Pancreáticas/congénito , Factores de Transcripción/genética , Secuencia de Aminoácidos , Animales , Discapacidades del Desarrollo/patología , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , Femenino , Holoprosencefalia/patología , Humanos , Lactante , Recién Nacido , Enfermedades del Recién Nacido/patología , Masculino , Ratones , Ratones Noqueados , Enfermedades del Sistema Nervioso/patología , Páncreas/patología , Enfermedades Pancreáticas/etiología , Enfermedades Pancreáticas/patología , Linaje , Fenotipo , Homología de Secuencia , SíndromeRESUMEN
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life, and in utero obstruction to urine flow is a frequent cause of secondary upper urinary tract malformations. Here, using whole-exome sequencing, we identified three different biallelic mutations in CHRNA3, which encodes the α3 subunit of the nicotinic acetylcholine receptor, in five affected individuals from three unrelated families with functional lower urinary tract obstruction and secondary CAKUT. Four individuals from two families have additional dysautonomic features, including impaired pupillary light reflexes. Functional studies in vitro demonstrated that the mutant nicotinic acetylcholine receptors were unable to generate current following stimulation with acetylcholine. Moreover, the truncating mutations p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. Although the importance of acetylcholine signaling in normal bladder function has been recognized, we demonstrate for the first time that mutations in CHRNA3 can cause bladder dysfunction, urinary tract malformations, and dysautonomia. These data point to a pathophysiologic sequence by which monogenic mutations in genes that regulate bladder innervation may secondarily cause CAKUT.
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Enfermedades del Sistema Nervioso Autónomo/etiología , Riñón/anomalías , Mutación , Receptores Nicotínicos/genética , Sistema Urinario/anomalías , Anomalías Urogenitales/etiología , Adulto , Enfermedades del Sistema Nervioso Autónomo/genética , Enfermedades del Sistema Nervioso Autónomo/patología , Femenino , Estudios de Seguimiento , Humanos , Riñón/patología , Masculino , Linaje , Pronóstico , Sistema Urinario/patología , Anomalías Urogenitales/genética , Anomalías Urogenitales/patología , Adulto JovenRESUMEN
We report a second patient with intrauterine growth retardation, congenital polycystic kidney disease, infancy-onset diabetes, microcephaly, and liver fibrosis caused by a homozygous PDIA6 loss-of-function variant. Our study further defines the genetic and clinical features of this rare syndromic form of infancy-onset diabetes.
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Diabetes Mellitus , Microcefalia , Enfermedades Renales Poliquísticas , Diabetes Mellitus/genética , Femenino , Retardo del Crecimiento Fetal/genética , Homocigoto , Humanos , Microcefalia/genética , Enfermedades Renales Poliquísticas/genética , Proteína Disulfuro Isomerasas/genéticaRESUMEN
We report the case of a consanguineous couple who lost four pregnancies associated with skeletal dysplasia. Radiological examination of one fetus was inconclusive. Parental exome sequencing showed that both parents were heterozygous for a novel missense variant, p.(Pro133Leu), in the SLC35D1 gene encoding a nucleotide sugar transporter. The affected fetus was homozygous for the variant. The radiological features were reviewed, and being similar, but atypical, the phenotype was classified as a 'Schneckenbecken-like dysplasia.' The effect of the missense change was assessed using protein modelling techniques and indicated alterations in the mouth of the solute channel. A detailed biochemical investigation of SLC35D1 transport function and that of the missense variant p.(Pro133Leu) revealed that SLC35D1 acts as a general UDP-sugar transporter and that the p.(Pro133Leu) mutation resulted in a significant decrease in transport activity. The reduced transport activity observed for p.(Pro133Leu) was contrasted with in vitro activity for SLC35D1 p.(Thr65Pro), the loss-of-function mutation was associated with Schneckenbecken dysplasia. The functional classification of SLC35D1 as a general nucleotide sugar transporter of the endoplasmic reticulum suggests an expanded role for this transporter beyond chondroitin sulfate biosynthesis to a variety of important glycosylation reactions occurring in the endoplasmic reticulum.
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Enfermedades Fetales/genética , Proteínas de Transporte de Monosacáridos/genética , Osteocondrodisplasias/genética , Alelos , Animales , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Femenino , Enfermedades Fetales/metabolismo , Enfermedades Fetales/patología , Heterocigoto , Humanos , Mutación con Pérdida de Función , Masculino , Ratones , Proteínas de Transporte de Monosacáridos/metabolismo , Mutación Missense , Osteocondrodisplasias/embriología , Osteocondrodisplasias/metabolismoRESUMEN
Neonatal diabetes is diagnosed before the age of 6 months and is usually caused by single-gene mutations. More than 30 genetic causes of neonatal diabetes have been described to date, resulting in severely reduced ß-cell number or function. Seven of these genes are known to cause neonatal diabetes through disrupted development of the whole pancreas, resulting in diabetes and exocrine pancreatic insufficiency. Pathogenic variants in five transcription factors essential for ß-cell development cause neonatal diabetes without other pancreatic phenotypes. However, additional extra-pancreatic features are common. This review will focus on the genes causing neonatal diabetes through disrupted ß-cell development, discussing what is currently known about the genetic and phenotypic features of these genetic conditions, and what discoveries may come in the future.
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Diabetes Mellitus Tipo 1/genética , Enfermedades del Recién Nacido/genética , Mutación , Páncreas/metabolismo , Factores de Transcripción/genética , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Recién Nacido , Enfermedades del Recién Nacido/metabolismo , FenotipoRESUMEN
Heterozygous mutations in GCK result in a persistent, mildly raised glucose from birth, but it is usually diagnosed in adulthood as maturity-onset diabetes of the young (MODY), where hyperglycemia is often an incidental finding. The hyperglycemia of GCK-MODY is benign and does not require treatment, but is important to be aware of, particularly in females where it has implications for managing pregnancy. We present three cases of neonatal hyperglycemia resulting from a heterozygous mutation in GCK, illustrating its clinical presentation and evolution in early life. In summary, as with adults, neonatal hyperglycemia is an incidental finding, does not require treatment and has no adverse consequences for health. Neonates and their parents should be referred for genetic testing to confirm the diagnosis, avoid a label of diabetes and enable pregnancy counseling for females found to be affected.
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Diabetes Mellitus Tipo 2/diagnóstico , Glucoquinasa/genética , Hiperglucemia/genética , Diabetes Mellitus Tipo 2/genética , Femenino , Humanos , Lactante , Recién Nacido , Masculino , LinajeRESUMEN
The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the ß-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.
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Hiperinsulinismo Congénito/genética , Diabetes Mellitus/genética , Células Secretoras de Insulina/metabolismo , Mutación , Canales de Potasio de Rectificación Interna/genética , Receptores de Sulfonilureas/genética , Hiperinsulinismo Congénito/diagnóstico , Diabetes Mellitus/diagnóstico , Mutación con Ganancia de Función , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , Mutación con Pérdida de FunciónRESUMEN
AIMS/HYPOTHESIS: Diabetes diagnosed at <6 months of age is usually monogenic. However, 10-15% of affected infants do not have a pathogenic variant in one of the 26 known neonatal diabetes genes. We characterised infants diagnosed at <6 months of age without a pathogenic variant to assess whether polygenic type 1 diabetes could arise at early ages. METHODS: We studied 166 infants diagnosed with type 1 diabetes at <6 months of age in whom pathogenic variants in all 26 known genes had been excluded and compared them with infants with monogenic neonatal diabetes (n = 164) or children with type 1 diabetes diagnosed at 6-24 months of age (n = 152). We assessed the type 1 diabetes genetic risk score (T1D-GRS), islet autoantibodies, C-peptide and clinical features. RESULTS: We found an excess of infants with high T1D-GRS: 38% (63/166) had a T1D-GRS >95th centile of healthy individuals, whereas 5% (8/166) would be expected if all were monogenic (p < 0.0001). Individuals with a high T1D-GRS had a similar rate of autoantibody positivity to that seen in individuals with type 1 diabetes diagnosed at 6-24 months of age (41% vs 58%, p = 0.2), and had markedly reduced C-peptide levels (median <3 pmol/l within 1 year of diagnosis), reflecting rapid loss of insulin secretion. These individuals also had reduced birthweights (median z score -0.89), which were lowest in those diagnosed with type 1 diabetes at <3 months of age (median z score -1.98). CONCLUSIONS/INTERPRETATION: We provide strong evidence that type 1 diabetes can present before the age of 6 months based on individuals with this extremely early-onset diabetes subtype having the classic features of childhood type 1 diabetes: high genetic risk, autoimmunity and rapid beta cell loss. The early-onset association with reduced birthweight raises the possibility that for some individuals there was reduced insulin secretion in utero. Comprehensive genetic testing for all neonatal diabetes genes remains essential for all individuals diagnosed with diabetes at <6 months of age. Graphical abstract.
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Diabetes Mellitus Tipo 1/inmunología , Autoinmunidad/inmunología , Autoinmunidad/fisiología , Biomarcadores/metabolismo , Péptido C/metabolismo , Femenino , Pruebas Genéticas , Humanos , Lactante , Recién Nacido , Células Secretoras de Insulina/metabolismo , MasculinoRESUMEN
Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability.
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Ribonucleoproteínas Nucleares Heterogéneas/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Adolescente , Adulto , Niño , Preescolar , Epilepsia/genética , Femenino , Genes Ligados a X/genética , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Síndrome , Adulto JovenRESUMEN
The original version of this Article contained an error in the top left of Figure 2: the number 1 on the y-axis had been changed to 0 during the typesetting process. This has now been corrected in both the PDF and HTML versions of the Article.
RESUMEN
PURPOSE: One of the greatest challenges currently facing those studying Mendelian disease is identifying the pathogenic variant from the long list produced by a next-generation sequencing test. We investigate the predictive ability of homozygosity mapping for identifying the regions likely to contain the causative variant. METHODS: We use 179 homozygous pathogenic variants from three independent cohorts to investigate the predictive power of homozygosity mapping. RESULTS: We demonstrate that homozygous pathogenic variants in our cohorts are disproportionately likely to be found within one of the largest regions of homozygosity: 80% of pathogenic variants are found in a homozygous region that is in the ten largest regions in a sample. The maximal predictive power is achieved in patients with <8% homozygosity and variants >3 Mb from a telomere; this gives an area under the curve (AUC) of 0.735 and results in 92% of the causative variants being in one of the ten largest homozygous regions. CONCLUSION: This predictive power can be used to prioritize the list of candidate variants in gene discovery studies. When classifying a homozygous variant the size and rank of the region of homozygosity in which the candidate variant is located can also be considered as supporting evidence for pathogenicity.
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Mapeo Cromosómico/métodos , Enfermedades Genéticas Congénitas/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Femenino , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/patología , Homocigoto , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido Simple/genética , Análisis de Secuencia de ADNRESUMEN
AIMS/HYPOTHESIS: Identifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet- and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise individuals for gene discovery studies. METHODS: We studied 79 individuals with diabetes and at least one additional autoimmune disease diagnosed before the age of 5 years. We screened all participants for the seven genes known to cause monogenic autoimmunity that can include diabetes (AIRE, IL2RA, FOXP3, LRBA, STAT1, STAT3, STAT5B). We genotyped the top ten risk alleles for type 1 diabetes, including HLA and non-HLA loci, to generate a type 1 diabetes GRS. RESULTS: Of the 79 individuals studied, 37 (47%) had mutations in the monogenic autoimmunity genes. The type 1 diabetes GRS was lower in these individuals than in those without mutations in these genes (median 9th vs 49th centile of type 1 diabetes controls, p < 0.0001). Age of diabetes diagnosis and type 1 diabetes GRS combined to be highly discriminatory of monogenic autoimmunity (receiver operating characteristic AUC: 0.88). Most individuals without a mutation in a known gene had a high type 1 diabetes GRS, suggesting that they have polygenic clustering of type 1 diabetes and additional autoimmunity and should not be included in gene discovery studies. CONCLUSIONS/INTERPRETATION: We have shown that the type 1 diabetes GRS can identify individuals likely to have monogenic autoimmunity, helping both diagnostic testing and novel monogenic autoimmunity gene discovery. Individuals with monogenic autoimmunity have a different clinical course to those with polygenic type 1 diabetes and can respond well to therapies targeting the underlying genetic defect.
Asunto(s)
Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Alelos , Autoanticuerpos/inmunología , Preescolar , Análisis por Conglomerados , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Antígenos HLA/inmunología , Humanos , Lactante , Recién Nacido , Islotes Pancreáticos/inmunología , Masculino , Mutación , Curva ROC , Riesgo , Sensibilidad y EspecificidadRESUMEN
AIMS/HYPOTHESIS: Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B1) in a cohort of individuals with TRMA-related diabetes. METHODS: We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire. RESULTS: We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3-24]) and median age at diabetes onset was 10 months (IQR 5-27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3-10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day. CONCLUSIONS/INTERPRETATION: In TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent. DATA AVAILABILITY: SLC19A2 mutation details have been deposited in the Decipher database ( https://decipher.sanger.ac.uk/ ).