Browse
Submit Data
Databases
API
Help

Dataset Information

23 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Case Report: Infantile-Onset Fulminant Type 1 Diabetes Mellitus Caused by Novel Compound Heterozygous LRBA Variants.

ABSTRACT: Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a subtype of common variable immune deficiency (CVID). Numerous case reports and cohort studies have described a broad spectrum of clinical manifestations and variable disease phenotypes, including immune dysregulation, enteropathy, and recurrent infections. Although LRBA deficiency is an autosomal recessive primary immunodeficiency resulting in a phenotype similar to CVID, it is a monogenic disease and separate from CVID. Recently, in a report of monogenic primary immunodeficiency disorder associated with CVID and autoimmunity, the most common mutated gene was LRBA. We report the case of a girl who presented with fulminant type 1 diabetes at age 7 months. She later experienced recurrent bacterial infections with neutropenia and idiopathic thrombocytopenic purpura. Clinical genome sequencing revealed compound heterozygosity of the LRBA gene, which bore two novel mutations. A genetic basis should be considered in the differential diagnosis for very young patients with fulminant autoimmunity, and the diagnostic work-up should include evaluation of markers of immunodeficiency.

SUBMITTER: Totsune E

PROVIDER: S-EPMC8072023 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Compound heterozygous variants in OTULIN are associated with fulminant atypical late-onset ORAS

Project description:Autoinflammatory diseases are a heterogenous group of disorders defined by fever and systemic inflammation suggesting involvement of genes regulating innate immune responses. Patients with homozygous loss-of-function variants in the OTU-deubiquitinase OTULIN suffer from neonatal-onset OTULIN-related autoinflammatory syndrome (ORAS) characterized by fever, panniculitis, diarrhea, and arthritis. Here, we describe an atypical form of ORAS with distinct clinical manifestation of the disease caused by two new compound heterozygous variants (c.258G>A (p.M86I)/c.500G>C (p.W167S)) in the OTULIN gene in a seven-year-old affected by a life-threatening autoinflammatory episode with sterile abscess formation. On the molecular level, we find binding of OTULIN to linear ubiquitin to be compromised by both variants, however, protein stability and catalytic activity is most affected by OTULIN variant p.W167S. These molecular changes together lead to increased levels of linear ubiquitin linkages in patient-derived cells triggering the disease. Our data indicate that the spectrum of ORAS patients is more diverse than previously thought and, thus, supposedly asymptomatic individuals might also be affected. Based on our results, we propose to subdivide the ORAS into classical and atypical entities.

| S-SCDT-EMM-2021-14901 | biostudies-other

Child-Onset Cerebellar Ataxia Caused by Two Compound Heterozygous Variants in ADPRS Gene: A Case Report.

Project description:Background: Gene variants of ADP-ribosylserine hydrosylase, also known as ADP-ribosylhydrolase-like 2 (ADPRS or ADPRLH2; OMIM: 610624), can cause stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS, OMIM: 618170), an ultra-rare neurodegenerative autosomal recessive disorder. ADPRS encodes ADP-ribosylhydrolase 3, which removes poly(ADP-ribose) polymers, whose posttranslational addition occurs under stressful conditions. Case Presentation: After a respiratory tract infection, a 30-month-old male patient presented with unsteady gait that rendered walking impossible without external help. Neurological examination revealed acute cerebellar ataxia, electroencephalogram results were abnormal, and brain magnetic resonance imaging revealed slightly widened cerebellar sulci. Laboratory tests showed decreased levels of thyroid-stimulating hormone, and increased levels of plasma lactic acid and serum cardiac enzymes. The cerebrospinal fluid glucose test was positive. Four months after onset, the patient died of sudden convulsions. Using whole exome sequencing, we identified two novel compound heterozygous ADPRS variants: NM_017825.3:c.580C>T (p.Gln194Ter) and NM_017825.3:c.803-1G>A. RNA sequencing indicated that the former mutation might cause nonsense-mediated mRNA decay. The c.803-1G>A variant was found to be a splice-site mutation that leads to the transcriptional retention of intron 5. According to the guidelines of the American College of Medical Genetics and Genomics, the two variants were classified as pathogenic. Conclusion: We present the first report of the existence of two compound heterozygous variants of ADPRS, which leads to CONDSIAS.

| S-EPMC9160522 | biostudies-literature

[Infantile hypophosphatasia caused by a novel compound heterozygous mutation: a case report and pedigree analysis].

Project description:This article reported the clinical features of one child with infantile hypophosphatasia (HPP) and his pedigree information. The proband was a 5-month-old boy with multiple skeletal dysplasia (koilosternia, bending deformity of both radii, and knock-knee deformity of both knees), feeding difficulty, reduction in body weight, developmental delay, recurrent pneumonia and respiratory failure, and a significant reduction in blood alkaline phosphatase. Among his parents, sister, uncle, and aunt (other family members did not cooperate with us in the examination), his parents and aunt had a slight reduction in alkaline phosphatase and his aunt had scoliosis; there were no other clinical phenotypes or abnormal laboratory testing results. His ALPL gene mutation came from c.228delG mutation in his mother and c.407G>A compound heterozygous mutation in his father. His aunt carried c.228delG mutation. The c.407G>A mutation had been reported as the pathogenic mutation of HPP, and c.228delG mutation was a novel pathogenic mutation. Hypophosphatasia is caused by ALPL gene mutation, and ALPL gene detection is an effective diagnostic method. This study expands the mutation spectrum of ALPL gene and provides a theoretical basis for genetic diagnosis of this disease.

| S-EPMC7389124 | biostudies-literature

Early-Onset Parkinson's Disease Caused by PLA2G6 Compound Heterozygous Mutation, a Case Report and Literature Review.

Project description:PLA2G6 has been certified as a causative gene in patients with autosomal recessive early-onset Parkinson's disease (EOPD). We reported an EOPD case caused by PLA2G6 gene mutation, and performed neurological examination, genetic analysis, and multimodal neuroimaging to describe this phenotype. A compound heterozygous mutation c.991G>T/c.1472+1G>A was detected in this patient. Heterozygous for the c.991G>T and c.1472+1G>A were separately detected in his parents. Pathogenicity of these two mutations were predicted according to the American college of medical genetics and genomics (ACMG) guideline. MRI assessment showed absence of bilateral "swallow tail sign" and cerebellar atrophy in this patient, while no obvious difference in brain iron accumulation between PLA2G6 mutant PD patient and healthy controls. Cerebellar abnormalities may be a marker for diagnosis and evaluation of PLA2G6 mutation Parkinsonism. However, the iron accumulation in PD may not be the result of PLA2G6 mutation.

| S-EPMC6712964 | biostudies-literature

Novel Compound Heterozygous Variants in TBCD Gene Associated with Infantile Neurodegenerative Encephalopathy.

Project description:Mutations in tubulin-specific chaperon D (TBCD), the gene encoding one of the co-chaperons required for the assembly and disassembly of the α/β-tubulin heterodimers, have been reported to cause perturbed microtubule dynamics, resulting in debilitating early-onset progressive neurodegenerative disorder. Here, we identified two novel TBCD variants, c.1340C>T (p.Ala447Val), and c.817+2T>C, presented as compound heterozygotes in two affected siblings born to unaffected carrier parents. Clinical features included early-onset neurodegeneration, failure to thrive, respiratory failure, hypotonia, muscle weakness and atrophy and seizures. We established the genotype-phenotype relationship of these TBCD pathogenic variants and provided insight into the protein structural alteration that may contribute to this chaperone-associated tubulinopathy.

| S-EPMC8699832 | biostudies-literature

MCAD deficiency caused by compound heterozygous pathogenic variants in ACADM.

Project description:Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is an autosomal recessive disease caused by biallelic pathogenic ACADM variants. We report a case of an asymptomatic Japanese girl with MCAD deficiency caused by compound heterozygous pathogenic variants (NM_000016.5:c.1040G > T (p.Gly347Val) and c.449_452delCTGA (p.Thr150ArgfsTer4)). Because the MCAD residual activity in lymphocytes of the patient was below the limit of quantification, both variants are likely to cause complete loss of MCAD enzymatic activity.

| S-EPMC8761748 | biostudies-literature

De novo heterozygous variants in POLR2A cause a neurodevelopmental syndrome with infantile-onset hypotonia

Project description: ABSTRACT POLR2A encodes RPB1, the largest subunit of the RNA polymerase II (pol II) complex, which is responsible for transcription of all ~21,000 protein-encoding genes. Here we describe the first fifteen patients harboring de novo heterozygous variants in POLR2A. The majority presents with profound infantile onset hypotonia and developmental delay. Missense variants that were expected to exert only mild structural effects, lead to malfunctioning RPB1, thereby inducing a dominant negative effect on pol II function. Intriguingly, these patients presented with a severe clinical phenotype. Conversely, variants expected to result in loss-of-function, leading to reduced availability of RPB1 were better tolerated: these patients exhibited the mildest phenotypes.

2019-09-02 | PXD011355 | Pride

Novel compound heterozygous variants in XYLT1 gene caused Desbuquois dysplasia type 2 in an aborted fetus: a case report.

Project description:BackgroundDesbuquois dysplasia type 2 (DBQD2) is an infrequent dysplasia with a wide range of symptoms, including facial deformities, growth retardation and short long bones. It is an autosomal recessive disorder caused by mutations in the XYLT1 gene that encodes xylosyltransferase-1.Case presentationWe studied an aborted fetus from Iranian non-consanguineous parents who was therapeutically aborted at 19 weeks of gestation. Ultrasound examinations at 18 weeks of gestation revealed growth retardation in her long bones and some facial problems. Whole-exome sequencing was performed on the aborted fetus which revealed compound heterozygous XYLT1 mutations: c.742G>A; p.(Glu248Lys) and c.1537 C>A; p.(Leu513Met). Sanger sequencing and segregation analysis confirmed the compound heterozygosity of these variants in XYLT1.ConclusionThe c.1537 C>A; p.(Leu513Met) variant has not been reported in any databases so far and therefore is novel. This is the third compound heterozygote report in XYLT1 and further supports the high heterogeneity of this disease.

| S-EPMC8790879 | biostudies-literature

Basal laminar drusen caused by compound heterozygous variants in the CFH gene.

Project description:Age-related macular degeneration (AMD) is a multifactorial disease that is strongly associated with the Tyr402His variant in the complement factor H (CFH) gene. Drusen are hallmark lesions of AMD and consist of focal-inflammatory and/or immune-mediated depositions of extracellular material at the interface of the retinal pigment epithelium (RPE) and the Bruch membrane. We evaluated the role of CFH in 30 probands with early-onset drusen and identified heterozygous nonsense, missense, and splice variants in five families. The affected individuals all carried the Tyr402His AMD risk variant on the other allele. This supports an autosomal-recessive disease model in which individuals who carry a CFH mutation on one allele and the Tyr402His variant on the other allele develop drusen. Our findings strongly suggest that monogenic inheritance of CFH variants can result in basal laminar drusen in young adults, and this can progress to maculopathy and severe vision loss later in life.

| S-EPMC2427272 | biostudies-literature

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia.

Project description:The RNA polymerase II complex (pol II) is responsible for transcription of all ?21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.

| S-EPMC6699192 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data