Contribution of genetic variants associated with primary immunodeficiencies to childhood-onset systemic lupus erythematous.

BACKGROUND: A dysregulated immune response is a hallmark of autoimmune disorders. Evidence suggests that systemic autoimmune diseases and primary immunodeficiency disorders (PIDs) may be similar diseases with different clinical phenotypes. OBJECTIVE: This study aimed to investigate the burden of PID-associated genetic variants in patients with childhood-onset systemic lupus erythematosus (cSLE). METHODS: We enrolled 118 cSLE patients regularly followed at Chang Gung Memorial Hospital. Targeted next-generation sequencing identified PID genetic variants in patients versus 1475 unrelated healthy individuals, which were further filtered by allelic frequency and various functional scores. Customized immune assays tested the functions of the identified variants. RESULTS: On filtration, 36 patients (30.5%) harbored rare variants in PID-associated genes predicted to be damaging. One homozygous TREX1 (c.294dupA) mutation and 4 heterozygous variants with possible dominant PID traits, including BCL11B (c.G1040T), NFKB1 (c.T695G), and NFKB2 (c.G1210A, c.G1651A), were discovered. With recessive traits, variants were found across all PID types; one fifth involved phagocyte number or function defects. Predicted pathogenic PID variants were more predominant in those with a family history of lupus, regardless of infection susceptibility. Moreover, mutation loads were greater among cSLE patients than controls despite sex or age at disease onset. While greater mutation loads were observed among cSLE patients with peripubertal disease onset, no significant differences in sex or phenotype were noted among cSLE patients. CONCLUSION: cSLE is mostly not monogenic. Gene-specific analysis and mutation load investigations suggested that rare and predicted damaging variants in PID-related genes can potentially contribute to cSLE susceptibility.

Phenotype, genotype, and clinical outcome of Taiwanese with congenital nephrotic syndrome.

BACKGROUND/PURPOSE: Congenital nephrotic syndrome (CNS) is one of the important causes of end-stage kidney disease in children. Studies on the genotype, phenotype, and clinical outcome in infants with CNS caused by genetic mutations are scarce. METHODS: We analyzed the genetic background, clinical manifestations, treatment response, and prognosis of pediatric patients with CNS in Taiwan. RESULTS: Fifteen infants with CNS were enrolled, and 11 patients of median age 21 (interquartile range 3∼44) days caused by genetic mutations from 10 unrelated families were included in the study. Of the eleven patients, 9 had extra-renal manifestations including microcephaly, facial dysmorphism, and skeletal anomalies. More than two-thirds of the patients had disease onset before 1 month of age. Diffuse meningeal sclerosis was the most common histological characteristic. Whole exome sequencing followed by direct Sanger sequence revealed mutations in OSGEP (R247Q), WT1 (R366H and R467Q), LAMB2 (Q1209∗ and c. 5432-5451 19 bp deletion), NUP93 (D302V), and LAGE3 (c.188+1G > A). Three of the variants were novel. Corticosteroids and/or immunosuppressants were administered in 2 patients, but both were refractory to treatment. During the mean 3.5 years of follow-up, all but two died of uremia and sepsis. The two survivors reached end-stage kidney disease and required peritoneal dialysis, and one of them underwent uneventful renal transplantation. CONCLUSIONS: The majority of patients with CNS in Taiwan were caused by OSGEP followed by WT1 mutation. R247Q is the hotspot mutation of OSGEP in Taiwan. CNS patients in Taiwan suffer from significant morbidity and mortality.

Association of ITPKB, IL1R2 and COQ7 with Parkinson's disease in Taiwan.

BACKGROUND/PURPOSE: Genetic and environmental factors play significant roles in the pathogenesis of Parkinson's disease (PD). Recently, 17 novel risk loci of PD were identified in a meta-analysis of genome-wide association study (GWAS) in the European populations. In order to clarify if these risk loci are associated with PD in Taiwanese population, we conducted a case-control study including 14 of the novel risk loci and analyzed the genetic distribution and allele frequency. METHODS: A total of 2798 subjects were recruited in this study. Genotyping was performed in 672 PD patients and 609 healthy controls by using Mass ARRAY, and data of another 1517 healthy controls from Taiwan Biobank were also examined. RESULTS: Our results show that the dominant models of ITPKB rs4653767 (OR (95% CI) = 0.832 (0.699, 0.990), p = 0.038), IL1R2 rs34043159 (OR (95% CI) = 0.812 (0.665, 0.992), p = 0.041) and COQ7 rs11343 (OR (95% CI) = 0.304 (0.180, 0.512), p < 0.001) were associated with PD. In allelic analysis, the T allele of IL1R2 rs34043159 (OR (95% CI) = 0.873 (0.772, 0.987), p = 0.03) and T allele of COQ7 rs11343 (OR (95% CI) = 0.098 (0.040, 0.238), p < 0.001) showed lower risk of PD. After Bonferroni correction, only dominant model and T allele of COQ7 rs11343 showed significantly reduced the risk of PD. CONCLUSION: This study suggests that ITPKB, IL1R2 and COQ7 have influence on the risk of PD in Taiwan.

Integration of metagenomics-metabolomics reveals specific signatures and functions of airway microbiota in mite-sensitized childhood asthma.

BACKGROUND: Childhood asthma is a multifactorial inflammatory condition of the airways, associated with specific changes in respiratory microbiome and circulating metabolome. METHODS: To explore the functional capacity of asthmatic microbiome and its intricate connection with the host, we performed shotgun sequencing of airway microbiome and untargeted metabolomics profiling of serum samples in a cohort of children with mite-sensitized asthma and non-asthmatic controls. RESULTS: We observed higher gene counts and sample-to-sample dissimilarities in asthmatic microbiomes, indicating a more heterogeneous community structure and functionality among the cases than in controls. Moreover, we identified airway microbial species linked to changes in circulating metabolites and IgE responses of the host, including a positive correlation between Prevotella sp oral taxon 306 and dimethylglycine that were both decreased in patients. Several control-enriched species (Eubacterium sulci, Prevotella pallens, and Prevotella sp oral taxon 306) were inversely correlated with total and allergen-specific IgE levels. Genes related to microbial carbohydrate, amino acid, and lipid metabolism were differentially enriched, suggesting that changes in microbial metabolism may contribute to respiratory health in asthmatics. Pathway modules relevant to allergic responses were differentially abundant in asthmatic microbiome, such as enrichments for biofilm formation by Pseudomonas aeruginosa, membrane trafficking, histidine metabolism, and glycosaminoglycan degradation, and depletions for polycyclic aromatic hydrocarbon degradation. Further, we identified metagenomic and metabolomic markers (eg, Eubacterium sulci) to discriminate cases from the non-asthmatic controls. CONCLUSIONS: Our dual-omics data reveal the connections between respiratory microbes and circulating metabolites perturbed in mite-sensitized pediatric asthma, which may be of etiological and diagnostic implications.

A combined analysis of maximum standardized uptake value on FDG-PET, genetic markers, and clinicopathological risk factors in the prognostic stratification of patients with resected oral cavity squamous cell carcinoma.

OBJECTIVE: Clinical outcomes of patients with resected oral cavity squamous cell carcinoma (OCSCC) chiefly depend on the presence of specific clinicopathological risk factors (RFs). Here, we performed a combined analysis of FDG-PET, genetic markers, and clinicopathological RFs in an effort to improve prognostic stratification. METHODS: We retrospectively reviewed the clinical records of 2036 consecutive patients with first primary OCSCC who underwent surgery between 1996 and 2016. Of them, 345 underwent ultra-deep targeted sequencing (UDTS, between 1996 and 2011) and 168 whole exome sequencing (WES, between 2007 and 2016). Preoperative FDG-PET imaging was performed in 1135 patients from 2001 to 2016. Complete data on FDG-PET, genetic markers, and clinicopathological RFs were available for 327 patients. RESULTS: Using log-ranked tests based on 5-year disease-free survival (DFS), the optimal cutoff points for maximum standardized uptake values (SUV-max) of the primary tumor and neck metastatic nodes were 22.8 and 9.7, respectively. The 5-year DFS rates were as follows: SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7 (n = 77) versus SUVtumor-max < 22.8 and SUVnodal-max < 9.7 (n = 250), 32%/62%, P < 0.001; positive UDTS or WES gene panel (n = 64) versus negative (n = 263), 25%/62%, P < 0.001; pN3b (n = 165) versus pN1-2 (n = 162), 42%/68%, P < 0.001. On multivariate analyses, SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7, a positive UDTS/WES gene panel, and pN3b disease were identified as independent prognosticators for 5-year outcomes. Based on these variables, we devised a scoring system that identified four distinct prognostic groups. The 5-year rates for patients with a score from 0 to 3 were as follows: loco-regional control, 80%/67%/47%/24% (P < 0.001); distant metastases, 13%/23%/55%/92% (P < 0.001); DFS, 74%/58%/28%/7% (P < 0.001); and disease-specific survival, 80%/64%/35%/7% (P < 0.001) respectively. CONCLUSIONS: The combined assessment of tumor and nodal SUV-max, genetic markers, and pathological node status may refine the prognostic stratification of OCSCC patients.

Clinical features, genetic background, and outcome in infants with urinary tract infection and type IV renal tubular acidosis.

BACKGROUND: Type IV renal tubular acidosis (RTA) is a severe complication of urinary tract infection (UTI) in infants. A detailed clinical and molecular analysis is still lacking. METHODS: Infants with UTI who exhibited features of type IV RTA were prospectively enrolled. Clinical, laboratory, and image characteristics and sequencing of genes responsible for phenotype were determined with follow-up. RESULTS: The study cohort included 12 infants (9 males, age 1-8 months). All exhibited typical type IV RTA such as hyperkalemia with low transtubular potassium gradient, hyperchloremic metabolic acidosis with positive urine anion gap, hypovolemic hyponatremia with renal salt wasting, and high plasma renin and aldosterone levels. Seven had hyperkalemia-related arrhythmia and two of them developed life-threatening ventricular tachycardia. With prompt therapy, all clinical and biochemical abnormalities resolved within 1 week. Five had normal urinary tract anatomy, and three of them carried genetic variants on NR3C2. Three variants, c.1645T>G (S549A), c.538G>A (V180I), and c.1-2C>G, on NR3C2 were identified in four patients. During follow-up, none of them had recurrent type IV RTA, but four developed renal scaring. CONCLUSIONS: Genetic mutation on NR3C2 may contribute to the development of type IV RTA as a complication of UTI in infants without identifiable risk factors, such as urinary tract anomalies.

A CRYBB2 mutation in a Taiwanese family with autosomal dominant cataract.

BACKGROUND/PURPOSE: To identify the underlying genetic cause of a Taiwanese family with autosomal dominant cerulean cataract. METHODS: A three-generation cerulean cataract family with 13 affected and 13 normal was identified. Whole exome sequencing, whole genome single nucleotide polymorphism genotyping and haplotype analysis, and fine mapping using polymorphic short tandem repeat markers were used to identify the causative gene mutation. RESULTS: Whole genome single nucleotide polymorphism genotyping and haplotype analysis mapped the candidate disease loci to chromosome 18 and chromosome 22. Polymorphic short tandem repeat markers further narrowed down the disease interval to chromosome 22 between markers D22S1174 and D22S1163. Whole exome sequencing was performed on selected individuals. Polymorphisms detected were filtered based on their genomic positions, allele frequency (<1%), and segregation within the pedigree. Affected individuals were found to be heterozygous carrying a C to T mutation on exon 6 of the CRYBB2 gene (with SNP ID: rs74315489). The mutation was predicted to produce a premature stop mutation Q155X. The mutation is co-segregation across the pedigree and the disease "T" allele was not detected in healthy members of the family and in additional 50 normal controls (100 chromosomes). Phylogenic protein alignment was also performed for the CRYBB2 gene across 68 species ranging from fishes, Sauropsida, Placentalia, carnivores, rodents, and primates with total 56 orthologous genes. The Q155 residue is 100% conserved across the evolutionary tree, indicating its crucial function. CONCLUSION: Here we identify the first Taiwanese cerulean cataract family carrying a CRYBB2_Q155X mutation.

Genomic and transcriptomic analyses of the medicinal fungus Antrodia cinnamomea for its metabolite biosynthesis and sexual development.

Antrodia cinnamomea, a polyporus mushroom of Taiwan, has long been used as a remedy for cancer, hypertension, and hangover, with an annual market of over $100 million (US) in Taiwan. We obtained a 32.15-Mb genome draft containing 9,254 genes. Genome ontology enrichment and pathway analyses shed light on sexual development and the biosynthesis of sesquiterpenoids, triterpenoids, ergostanes, antroquinonol, and antrocamphin. We identified genes differentially expressed between mycelium and fruiting body and 242 proteins in the mevalonate pathway, terpenoid pathways, cytochrome P450s, and polyketide synthases, which may contribute to the production of medicinal secondary metabolites. Genes of secondary metabolite biosynthetic pathways showed expression enrichment for tissue-specific compounds, including 14-α-demethylase (CYP51F1) in fruiting body for converting lanostane to ergostane triterpenoids, coenzymes Q (COQ) for antroquinonol biosynthesis in mycelium, and polyketide synthase for antrocamphin biosynthesis in fruiting body. Our data will be useful for developing a strategy to increase the production of useful metabolites.

Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation.

Severe cutaneous adverse reactions (SCARs), previously thought to be idiosyncratic or unpredictable, are a deadly form of adverse drug reactions with skin manifestations. Current pharmacogenomic studies of SCARs have made important strides, as the prevention of SCARs, to some extent, appears attainable with the identification of genetic variants for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). Despite the improvement of incidence, a treatment guideline for this devastating condition is still unavailable, highlighting the inadequacy of contemporary accepted therapeutic interventions. As such, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we discuss recent cutting-edge findings concerning the discovery of biomarkers for SCARs and their clinical utilities in the better prediction and early diagnosis of this disease. The knowledge compiled herein provides clues for future investigations on deciphering additional genetic markers for SCARs and the design of clinical trials for the prospective identification of subjects at genetic risk for this condition, ultimately personalizing the medicine.

Transcriptomic analyses of regenerating adult feathers in chicken.

BACKGROUND: Feathers have diverse forms with hierarchical branching patterns and are an excellent model for studying the development and evolution of morphological traits. The complex structure of feathers allows for various types of morphological changes to occur. The genetic basis of the structural differences between different parts of a feather and between different types of feather is a fundamental question in the study of feather diversity, yet there is only limited relevant information for gene expression during feather development. RESULTS: We conducted transcriptomic analysis of five zones of feather morphologies from two feather types at different times during their regeneration after plucking. The expression profiles of genes associated with the development of feather structure were examined. We compared the gene expression patterns in different types of feathers and different portions of a feather and identified morphotype-specific gene expression patterns. Many candidate genes were identified for growth control, morphogenesis, or the differentiation of specific structures of different feather types. CONCLUSION: This study laid the ground work for studying the evolutionary origin and diversification of feathers as abundant data were produced for the study of feather morphogenesis. It significantly increased our understanding of the complex molecular and cellular events in feather development processes and provided a foundation for future studies on the development of other skin appendages.

A New Phenotype of TUBB4A Mutation in a Family With Adult-Onset Progressive Spastic Paraplegia and Isolated Hypomyelination Leukodystrophy: A Case Report and Literature Review.

Tubulin beta 4A class IVa (TUBB4A) spectrum disorders include autosomal dominant dystonia type 4 or hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC syndrome). However, in rare cases, only mild hypomyelination in the cortex with no basal ganglia atrophy may be observed. We report a case of a family with TUBB4A mutation and complicated hereditary spasticity paraplegia (HSP). We performed quadro whole-exome sequencing (WES) on the family to identify the causative gene of progressive spastic paraparesis with isolated hypomyelination leukodystrophy. We identified a novel TUBB4A p.F341L mutation, which was present in all three affected patients but absent in the unaffected father. The affected patients presented with adult-onset TUBB4A disorder, predominant spastic paraparesis with/without ataxia, and brain hypomyelination with no cognitive impairment or extrapyramidal symptoms. In the literature, HSP is considered a TUBB4A spectrum disorder.

Long-Term Outcome of Neonatal Seizure with PACS2 Mutation: Case Series and Literature Review.

Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2)-related early infantile developmental and epileptic encephalopathy (EIDEE) is a rare neurodevelopmental disorder. EIDEE is characterized by seizures that begin during the first three months of life and are accompanied by developmental impairment over time. In this article, we present three patients with EIDEE who experienced neonatal-onset seizures that developed into intractable seizures during infancy. Whole exome sequencing revealed a de novo heterozygous missense variant in all three patients in the p.Glu209Lys variant of the PACS2 gene. We conducted a literature review and found 29 cases to characterize the seizure patterns, neuroimaging features, the usage of anticonvulsants, and the clinical neurodevelopmental outcomes of PACS2-related EIDEE. The seizures were characterized by brief, recurring tonic seizures in the upper limbs, sometimes accompanied by autonomic features. Neuroimaging abnormalities were observed in the posterior fossa region, including mega cisterna magna, cerebellar dysplasia, and vermian hypoplasia. The long-term prognosis ranges from low-average intelligence to severe developmental retardation, emphasizing the importance of early recognition and accurate diagnosis by pediatric neurologists to provide personalized patient management.

The abundances of LTF and SOD2 in amniotic fluid are potential biomarkers of gestational age and preterm birth.

Neonates who are born preterm (PT) are usually characterized by immature physiological development, and preterm birth (PTB) is the leading cause of neonatal morbidity and mortality if intensive medical care is not available to PTB neonates. Early prediction of a PTB enables medical personnel to make preparations in advance, protecting the neonate from the subsequent health risks. Therefore, many studies have worked on identifying invasive or noninvasive PT biomarkers. In this study, we collected amniocentesis-derived (at the second trimester of gestation) amniotic fluid (AF) samples. At delivery, AF samples were classified into PTB or full-term birth (FTB). We first applied protein mass spectrometry technology to globally screen AF proteins, followed by specific protein validation with ELISA. We identified four protein biomarkers of PTB, including lactotransferrin (LTF), glutathione-disulfide reductase (GSR), myeloperoxidase (MPO) and superoxide dismutase 2 (SOD2). Further analyses demonstrated that their abundances were negatively correlated with neonatal weight and gestational age. In addition, by mimicking survival rate analysis widely used in tumor biology, we found that LTF and SOD2 were prognostic factors of gestational age, with higher levels denoting shorter gestational age. Finally, using the abundances of the four protein biomarkers, we developed a prediction model of PTB with an auROC value of 0.935 (sensitivity = 0.94, specificity = 0.89, p value = 0.0001). This study demonstrated that the abundances of specific proteins in amniotic fluid were not only the prognostic factors of gestational age but also the predictive biomarkers of PTB. These four AF proteins enable identification of PTB early in the second trimester of gestation, facilitating medical intervention to be applied in advance.

Novel Compound Heterozygous Mutations in the SYNE1 Gene in a Taiwanese Family: A Case Report and Literature Review.

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene are associated with substantial clinical heterogeneity. Here, we report the first case of SYNE1 ataxia in Taiwan due to two novel truncating mutations. Our patient, a 53-year-old female, exhibited pure cerebellar ataxia with c.1922del in exon 18 and c. C3883T mutations in exon 31. Previous studies have indicated that the prevalence of SYNE1 ataxia among East Asian populations is low. In this study, we identified 27 cases of SYNE1 ataxia from 22 families in East Asia. Of the 28 patients recruited in this study (including our patient), 10 exhibited pure cerebellar ataxia, and 18 exhibited ataxia plus syndromes. We could not find an exact correlation between genotypes and phenotypes. Additionally, we established a precise molecular diagnosis in our patient's family and extended the findings on the ethnic, phenotypic, and genotypic diversity of the SYNE1 mutational spectrum.

Impact of Genomic Alterations on the Clinical Outcome of Patients With Hepatitis B-related Hepatocellular Carcinoma Receiving Curative Surgery: A Retrospective Cohort Study.

BACKGROUND/AIM: The aim of the current study was to obtain comprehensive genomic information on viral hepatitis B (HBV)-related hepatocellular carcinoma (HCC) and identify potential biomarkers of early recurrence in patients receiving curative surgery. PATIENTS AND METHODS: A total of 104 patients with HBV-related HCC receiving curative surgery at Kaohsiung Chang Gung Memorial Hospital between January 2017 and December 2020 were identified, including 52 patients each with and without recurrence. Next-generation sequencing was performed to investigate genomic alterations caused by surgical resection of specimens. The Kaplan-Meier method was used to estimate disease-free survival and overall survival. RESULTS: The landscape of gene mutations in HCC patients of our cohort showed a median number of single nucleotide variants of 250, a median number of insertions and deletions of 22, and a median number of protein-coding mutations of 185. The 10 most frequently mutated genes were TP53 (43%), TTN (39%), MUC16 (28%), PCLO (25%), OBSCN (22%), ADGRV1 (19%), ALB (18%), SYNE1 (18%), DNAH17 (17%), and RYR1 (17%). The tumour mutation burden was 4.8 mutations per megabase, and high microsatellite instability was reported in only three patients. In addition, the mutational signatures showed that aristolochic acid exposure was highly implicated in our HCC cohort. Five mutant genes, TBC1D4, ITGA4, RPS6KA3, VWA8, and FMN2, were more frequent in the recurrence group than that in the non-recurrence group. CONCLUSION: Our results present an in-depth genomic analysis of HBV-related HCC. The study findings provide an improved understanding of the related molecular mechanisms and identify potential biomarkers associated with early tumour recurrence after curative resection.

Association of AXIN1 With Parkinson's Disease in a Taiwanese Population.

OBJECTIVE: A meta-analysis of locus-based genome-wide association studies recently identified a relationship between AXIN1 and Parkinson's disease (PD). Few studies of Asian populations, however, have reported such a genetic association. The influences of rs13337493, rs758033, and rs2361988, three PD-associated genetic variants of AXIN1, were investigated in the present study because AXIN1 is related to Wnt/ß-catenin signaling. METHODS: A total of 2,418 individuals were enrolled in our Taiwanese cohort for analysis of the genotypic and allelic frequency. Polymerase chain reaction-restriction fragment length polymorphism analysis was employed for rs13337493 genotyping, and the Agena MassARRAY platform (Agena Bioscience, San Diego, CA, USA) was used for rs758033 and rs2361988 genotyping in 672 patients with PD and 392 controls. Taiwan Biobank data of another 1,354 healthy controls were subjected to whole-genome sequencing performed using Illumina platforms at approximately 30× average depth. RESULTS: Our results revealed that rs758033 {odds ratios [OR] (95% confidence interval [CI]) = 0.267 [0.064, 0.795], p = 0.014} was associated with the risk of PD, and there was a trend toward a protective effect of rs2361988 (OR [95% CI] = 0.296 [0.071, 0.884], p = 0.026) under the recessive model. The TT genotype of rs758033 (OR [95% CI] = 0.271 [0.065, 0.805], p = 0.015) and the CC genotype of rs2361988 (OR [95% CI] = 0.305 [0.073, 0.913], p = 0.031) were less common in the PD group than in the non-PD group. CONCLUSION: Our findings indicate that the rs758033 and rs2361988 polymorphisms of AXIN1 may affect the risk of PD in the Taiwanese population.

Characteristics and genetic analysis of patients suspected with early-onset systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is rarely diagnosed before 5-years-old. Those with disease onset at a very young age are predicted by a higher genetic risk and a more severe phenotype. We performed whole-exome sequencing to survey the genetic etiologies and clinical manifestations in patients fulfilling 2012 SLICC SLE classification criteria before the age of 5. CASE PRESENTATION: Among the 184 childhood-onset SLE patients regularly followed in a tertiary medical center in Taiwan, 7 cases (3.8%) of which onset ≦ 5 years of age were identified for characteristic review and genetic analysis. Compared to those onset at elder age, cases onset before the age of 5 are more likely to suffer from proliferative glomerulonephritis, renal thrombotic microangiopathy, neuropsychiatric disorder and failure to thrive. Causative genetic etiologies were identified in 3. In addition to the abundance of autoantibodies, patient with homozygous TREX1 (c.292_293 ins A) mutation presented with chilblain-like skin lesions, peripheral spasticity, endocrinopathy and experienced multiple invasive infections. Patient with SLC7A7 (c.625 + 1 G > A) mutation suffered from profound glomerulonephritis with full-house glomerular deposits as well as hyperammonemia, metabolic acidosis and episodic conscious disturbance. Two other cases harbored variants in lupus associating genes C1s, C2, DNASE1 and DNASE1L3 and another with CFHR4. Despite fulfilling the classification criteria for lupus, many of the patients required treatments beyond conventional therapy. CONCLUSIONS: Genetic etiologies and lupus mimickers were found among a substantial proportion of patients suspected with early-onset SLE. Detail clinical evaluation and genetic testing are important for tailored care and personalized treatment.

Incomplete penetrance of NOD2 C483W mutation underlining Blau syndrome.

BACKGROUND: Blau syndrome (BS) is a rare autoinflammatory disorder with NOD2 gain-of-function mutation and characterized by autoactivation of the NFκB pathway. Classically considered a disease of high penetrance, reports on NOD2 mutations underlining BS with incomplete penetrance is limited. CASE PRESENTATION: The proband is a 9-year-old girl presented with brownish annular infiltrative plaques and symmetric boggy polyarthritis over bilateral wrists and ankles. Her skin biopsy revealed noncaseating granulomas inflammation with multinucleated giant cells. A novel C483W NOD2 mutation was identify in the proband and her asymptomatic father. Functional examinations including autoactivation of the NFκB pathway demonstrated by in vitro HEK293T NOD2 overexpression test as well as intracellular staining of phosphorylated-NFκB in patient's CD11b+ cells were consistent with BS. CONCLUSIONS: We reported a novel C483W NOD2 mutation underlining BS with incomplete penetrance. Moreover, a phosphorylated-NFκB intracellular staining assay of CD11b+ was proposed to assist functional evaluation of NFκB autoactivation in patient with BS.

Rare Occurrence of Aristolochic Acid Mutational Signatures in Oro-Gastrointestinal Tract Cancers.

BACKGROUND: Aristolochic acids (AAs) are potent mutagens commonly found in herbal plant-based remedies widely used throughout Asian countries. PATIENTS AND METHODS: To understand whether AA is involved in the tumorigenesis of the oro-gastrointestinal tract, we used whole-exome sequencing to profile 54 cases of four distinct types of oro-gastrointestinal tract cancer (OGITC) from Taiwan. RESULTS: A diverse landscape of mutational signatures including those from DNA mismatch repair and reactive oxygen species was observed. APOBEC mutational signatures were observed in 60% of oral squamous cell carcinomas. Only one sample harbored AA mutational signatures, contradictory to prior reports of cancers from Taiwan. The metabolism of AA in the liver and urinary tract, transient exposure time, and high cell turnover rates at OGITC sites may explain our findings. CONCLUSION: AA signatures in OGITCs are rare and unlikely to be a major contributing factor in oro-gastrointestinal tract tumorigenesis.

NOTCH1 mutations as prognostic marker in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity with poor prognosis. The dysregulation of Notch signaling pathway has been implicated in the OSCC tumorigenesis. However, the clinical implication of NOTCH1 mutation status in OSCC remains unelucidated. We extracted the NOTCH1 gene mutations from a whole exome sequencing dataset of 168 frozen OSCC tumor specimens and validated these NOTCH1 gene mutations by Sanger sequencing. We also assessed these NOTCH1 gene mutations and its pathological significance in our OSCC tumor tissues using immunohistochemistry. Univariate and multivariate analyses were also used to determine whether the association between NOTCH1 mutation status and prognostic factors was independent of other parameters. In this study, we have identified 44 (26.19 %) NOTCH1 gene mutations from a whole-exome sequencing of 168 OSCC formalin-fixed, paraffin-embedded (FFPE) tissue specimen. These mutations distributed in different NOTCH1 function domains, including the EGF-like repeats region, negative regulatory region, and Ankyrin repeats region. The immunohistochemical staining analysis revealed that NOTCH1 expression was increased in oral cancer tissues. In addition, of the 43 OSCC tumors with NOTCH1 mutations, we observed that the majority were negative for NOTCH1 intracellular domain 1 (NICD1) staining (76.74 %), and 10 tumors were positive for NICD1 staining (23.26 %). In conclusion, our study suggested that NOTCH1 expression is associated with the progression of OSCC. We also demonstrated that presence of a mutated NOTCH1 gene will help prognostic stratification in OSCC when combined with other clinicopathologic parameters.