Phenotypic Features Research Articles

Biallelic NDC1 variants that interfere with ALADIN binding are associated with neuropathy and triple A-like syndrome

Nuclear pore complexes (NPC) regulate nucleocytoplasmic transport and are anchored in the nuclear envelope by the transmembrane nucleoporin NDC1. NDC1 is essential for post-mitotic NPC assembly and the recruitment of ALADIN to the nuclear envelope. While no human disorder has been associated to one of the three transmembrane nucleoporins, biallelic variants in AAAS, encoding ALADIN, cause Triple-A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints. In this report, diagnostic exome and/or RNA-sequencing was performed in 7 individuals from 4 unrelated consanguineous families with AAAS negative triple A syndrome. Molecular and clinical studies followed to elucidate the pathogenic mechanism. The affected individuals presented with intellectual disability, motor impairment, severe demyelinating with secondary axonal polyneuropathy, alacrima and achalasia.. None of the affected individuals has adrenal insufficiency. All individuals presented with biallelic NDC1 in-frame deletions or missense variants, that affect amino acids and protein domains required for ALADIN binding. No other significant variants associated with the phenotypic features were reported. Skin fibroblasts derived from affected individuals show decreased recruitment of ALADIN to the NE and decreased post-mitotic NPC insertion, confirming pathogenicity of the variants. Taken together, our results implicate biallelic NDC1 variants in the pathogenesis of polyneuropathy and a Triple-A-like disorder without adrenal insufficiency, by interfering with physiological NDC1 functions, including the recruitment of ALADIN to the NPC.

Differences of clinical phenotype between familial and sporadic Crohn’s disease in East China

PurposeFamily history is one of the strongest risk factors for inflammatory bowel diseases (IBD) while studies about the clinical phenotype of familial IBD are limited. This study aimed to compare the phenotypic features of familial Crohn’s disease (CD) with sporadic CD.MethodsFamilial CD was defined as CD patients having one or more first, second, third, fourth degree, or above relatives with CD. Sporadic CD patients hospitalized during the same period were matched 1:3 by age and gender. Differences in clinical characteristics, phenotype distribution, extraintestinal manifestations, and complications at diagnosis, as well as treatment regimen and surgery, were compared between familial and sporadic CD.ResultsThe familial CD was associated with a higher rate of past appendectomy history (P = 0.009), more intestinal perforation at onset (P = 0.012), more MRI results of anal lesion (P = 0.023), and gastrointestinal perforation (P = 0.040) at diagnosis, higher rate of past intestinal surgery history (P = 0.007), more number of intestinal surgeries (P = 0.037), longer duration of follow-up (P = 0.017), lower rate of taking biologicals for current maintenance (P = 0.043), lower tendency to upgrade to biologicals during follow-up (P = 0.013), higher possibility to experience gastrointestinal obstruction (P = 0.047), and abdominal abscess during follow-up (P = 0.045).ConclusionFamilial CD is associated with a more aggressive clinical phenotype.

Alström Syndrom: A Clinical Case

Background. Alström syndrome is a rare autosomal recessive disease characterized by multiple organ dysfunction. The prevalence in the population is less than one person per 1 million. Genomic mutation analysis study identified 109 new mutations increasing the number of known mutations of the ALMS1 protein to 239 which highlights the allelic heterogeneity of this disease and its phenotypic diversity.The aim of the work. Increasing awareness among medical professionals regarding Alström syndrome.Materials and methods. The analysis of the medical record of an outpatient patient, data from paraclinical research methods of the child of patient P., born in 2013, who was examined at the Children’s Regional Clinical Hospital (CRCH; Krasnodar).Results. The disease debuted with an acute respiratory infection at the age of 4 months, the primary clinical manifestations were acute respiratory failure, and therefore, the child was hospitalized at CRCH. The results of additional research methods revealed dilated cardiomyopathy with reduced global contractility of the left ventricle. For further disease diagnosis and treatment correction, the child was referred to the National Medical Research Center for Children’s Health (NMRCCH), where he was observed for several years by a multidisciplinary team of specialists. Based on results of molecular genetic studies (pathogenic homozygous mutation in the ALMS1 gene), the child was diagnosed with Alström syndrome at the age of 8 years.Discussion. This report illustrates difficulty diagnosis and lack of specific treatment.Conclusion. This clinical case demonstrates a wide range of phenotypic features of the rare hereditary Alström syndrome.

Generalized arterial calcification of infancy due to mutations of the ENPP1 and ABCC6 genes: phenotype features, bisphosphonate therapy

Generalized arterial calcification of infancy due to mutations of the ENPP1 and ABCC6 genes: phenotype features, bisphosphonate therapy

Allergen-specific B cell responses in oral immunotherapy-induced desensitization, remission, and natural outgrowth in cow's milk allergy.

Antigen-specific memory B cells play a key role in the induction of desensitization and remission to food allergens in oral immunotherapy and in the development of natural tolerance (NT). Here, we characterized milk allergen Bos d 9-specific B cells in oral allergen-specific immunotherapy (OIT) and in children spontaneously outgrowing cow's milk allergy (CMA) due to NT. Samples from children with CMA who received oral OIT (before, during, and after), children who naturally outgrew CMA (NT), and healthy individuals were received from Stanford biobank. Bos d 9-specific B cells were isolated by flow cytometry and RNA-sequencing was performed. Protein profile of Bos d 9-specific B cells was analyzed by proximity extension assay. Increased frequencies of circulating milk allergen Bos d 9-specific B cells were observed after OIT and NT. Milk-desensitized subjects showed the partial acquisition of phenotypic features of remission, suggesting that desensitization is an earlier stage of remission. Within these most significantly expressed genes, IL10RA and TGFB3 were highly expressed in desensitized OIT patients. In both the remission and desensitized groups, B cell activation-, Breg cells-, BCR-signaling-, and differentiation-related genes were upregulated. In NT, pathways associated with innate immunity characteristics, development of marginal zone B cells, and a more established suppressor function of B cells prevail that may play a role in long-term tolerance. The analyses of immunoglobulin heavy chain genes in specific B cells demonstrated that IgG2 in desensitization, IgG1, IgA1, IgA2, IgG4, and IgD in remission, and IgD in NT were predominating. Secreted proteins from allergen-specific B cells revealed higher levels of regulatory cytokines, IL-10, and TGF-β after OIT and NT. Allergen-specific B cells are essential elements in regulating food allergy towards remission in OIT-received and naturally resolved individuals.

Memory inflation: Beyond the acute phase of viral infection.

Memory inflation is confirmed as the most commonly dysregulation of host immunity with antigen-independent manner in mammals after viral infection. By generating large numbers of effector/memory and terminal differentiated effector memory CD8+ T cells with diminished naïve subsets, memory inflation is believed to play critical roles in connecting the viral infection and the onset of multiple diseases. Here, we reviewed the current understanding of memory inflated CD8+ T cells in their distinct phenotypic features that different from exhausted subsets; the intrinsic and extrinsic roles in regulating the formation of memory inflation; and the key proteins in maintaining the expansion and proliferation of inflationary populations. More importantly, based on the evidences from both clinic and animal models, we summarized the potential mechanisms of memory inflation to trigger autoimmune neuropathies, such as Guillain-Barré syndrome and multiple sclerosis; the correlations of memory inflation between tumorigenesis and resistance of tumour immunotherapies; as well as the effects of memory inflation to facilitate vascular disease progression. To sum up, better understanding of memory inflation could provide us an opportunity to beyond the acute phase of viral infection, and shed a light on the long-term influences of CD8+ T cell heterogeneity in dampen host immune homeostasis.

Undibacterium cyanobacteriorum sp. nov., an auxin-producing bacterium isolated from fresh water during cyanobacterial bloom period.

A novel Gram-negative, white-pigmented, and auxin-producing strain, 20NA77.5T, was isolated from fresh water during cyanobacterial bloom period. Pairwise comparison of the 16S rRNA gene sequences showed that strain 20NA77.5T belonged to the genus Undibacterium and exhibited the highest sequence similarity to the type strains of Undibacterium danionis (98.00%), Undibacterium baiyunense (97.93%), Undibacterium macrobrachii (97.92%), and Undibacterium fentianense (97.71%). The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain 20NA77.5T and its related type strains were below 79.93 and 23.80%, respectively. The predominant fatty acids (> 10% of the total fatty acids) were C16:0 and summed feature 3 (C16:1ω7c and/or C16:1ω6c). The genomic DNA G + C content of strain 20NA77.5T was found to be 48.61%. Based on the phylogenetic distinctness, chemotaxonomic features, and phenotypic features, strain 20NA77.5T is considered to represent a novel species of the genus Undibacterium, for which the name Undibacterium cyanobacteriorum sp. nov is proposed. The type strain is 20NA77.5T (= KCTC 8005T = LMG 33136T).

Phagocytic Plasma Cells in Teleost Fish Provide Insights into the Origin and Evolution of B Cells in Vertebrates.

Teleost IgM+ B cells can phagocytose, like mammalian B1 cells, and secrete Ag-specific IgM, like mammalian B2 cells. Therefore, teleost IgM+ B cells may have the functions of both mammalian B1 and B2 cells. To support this view, we initially found that grass carp (Ctenopharyngodon idella) IgM+ plasma cells (PCs) exhibit robust phagocytic ability, akin to IgM+ naive B cells. Subsequently, we sorted grass carp IgM+ PCs into two subpopulations: nonphagocytic (Pha-IgM+ PCs) and phagocytic IgM+ PCs (Pha+IgM+ PCs), both of which demonstrated the capacity to secrete natural IgM with LPS and peptidoglycan binding capacity. Remarkably, following immunization of grass carp with an Ag, we observed that both Pha-IgM+ PCs and Pha+IgM+ PCs could secrete Ag-specific IgM. Furthermore, invitro concatenated phagocytosis experiments in which Pha-IgM+ PCs from an initial phagocytosis experiment were sorted and exposed again to beads confirmed that these cells also have phagocytic capabilities, thereby suggesting that all teleost IgM+ B cells have phagocytic potential. Additionally, we found that grass carp IgM+ PCs display classical phenotypic features of macrophages, providing support for the hypothesis that vertebrate B cells evolved from ancient phagocytes. These findings together reveal that teleost B cells are a primitive B cell type with functions reminiscent of both mammalian B1 and B2 cells, providing insights into the origin and evolution of B cells in vertebrates.

Quantifiable and reproducible phenotypic assessment of a constitutive knockout mouse model for congenital nephrotic syndrome of the Finnish type

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of childhood chronic kidney disease. Congenital nephrotic syndrome of the Finnish type (CNF) (MIM# 256300) is caused by biallelic variants in the gene NPHS1, encoding nephrin, an integral component of the kidney filtration barrier. No causal treatments exist, and children inevitably require kidney replacement therapy. In preparation for gene replacement therapy (GRT) in CNF, we established a quantifiable and reproducible phenotypic assessment of the nephrin-deficient CNF mouse model: 129/Sv-Nphs1tm1Rkl/J. We assessed the phenotypic spectrum of homozygous mice (Nphs1tm1Rkl/Nphs1tm1Rkl) compared to heterozygous controls (Nphs1tm1Rkl/Nphs1WT) by the following parameters: 1. cohort survival, 2. podocyte foot process (FP) density per glomerular basement membrane (GBM) using transmission electron microscopy, 3. tubular microcysts in brightfield microscopy, and 4. urinary albumin/creatinine ratios. Nphs1tm1Rkl/Nphs1tm1Rkl mice exhibited: 1. perinatal lethality with median survival of 1 day, 2. FP effacement with median FP density of 1.00 FP/µm GBM (2.12 FP/µm in controls), 3. tubular dilation with 65 microcysts per section (6.5 in controls), and 4. increased albumin/creatinine ratio of 238 g/g (4.1 g/g in controls). We here established four quantifiable phenotyping features of a CNF mouse model to facilitate future GRT studies by enabling sensitive detection of phenotypic improvements.

Novel genotypes and phenotypes in Snijders Blok-Campeau syndrome caused by CHD3 mutations.

Snijders Blok-Campeau syndrome (SNIBCPS) is a rare genetic disorder characterized by facial abnormalities, hypotonia, macrocephaly, and global developmental delay (GDD) caused by mutations in CHD3 gene. There is limited information on SNIBCPS and few studies on its pathogenic gene CHD3. We utilized whole-exome sequencing, in vitro minigene splicing assay analysis, and construction of protein models to validate the suspected pathogenic mutation. In addition, the PubMed database was searched using the keywords "Snijders Blok-Campeau syndrome," "CHD3," or "SNIBCPS" to summarize the gene mutations and clinical phenotypic characteristics of children with SNIBCPS. We identified a non-frameshift variant c.3592_c.3606delGCCAAGAGAAAGATG, a splice site variant c.1708-1G>T, and two missense variants, c. 2954G>C (p.Arg985Pro) and c.3371C>T (p.A1124V), in CHD3 variants with SNIBCPS. Importantly, the c.3592_c.3606delGCCAAGAGAAAGATG, c.1708-1G>T, and c.3371C > T (p.A1124V) loci were not reported, and the children in this study also had phenotypic features of unibrow, transverse palmar creases, tracheal bronchus, and hypomelanosis of Ito (HI). The c.1708-1G>T classical splicing mutation leads to abnormal shearing of mRNA, forming a truncated protein that ultimately affects gene function. Our findings have expanded the spectrum of genetic variants and clinical features in children with SNIBCPS. Splicing analysis of CHD3 is an important method to understand the pathogenesis of spliced cells.

Inositol Restores Appropriate Steroidogenesis in PCOS Ovaries Both In Vitro and In Vivo Experimental Mouse Models.

Androgen excess is a key feature of several clinical phenotypes of polycystic ovary syndrome (PCOS). However, the presence of FSH receptor (FSHR) and aromatase (CYP19A1) activity responses to physiological endocrine stimuli play a critical role in the pathogenesis of PCOS. Preliminary data suggest that myo-Inositol (myo-Ins) and D-Chiro-Inositol (D-Chiro-Ins) may reactivate CYP19A1 activity. We investigated the steroidogenic pathway of Theca (TCs) and Granulosa cells (GCs) in an experimental model of murine PCOS induced in CD1 mice exposed for 10 weeks to a continuous light regimen. The effect of treatment with different combinations of myo-Ins and D-Chiro-Ins on the expression of Fshr, androgenic, and estrogenic enzymes was analyzed by real-time PCR in isolated TCs and GCs and in ovaries isolated from healthy and PCOS mice. Myo-Ins and D-Chiro-Ins, at a ratio of 40:1 at pharmacological and physiological concentrations, positively modulate the steroidogenic activity of TCs and the expression of Cyp19a1 and Fshr in GCs. Moreover, in vivo, inositols (40:1 ratio) significantly increase Cyp19a1 and Fshr. These changes in gene expression are mirrored by modifications in hormone levels in the serum of treated animals. Myo-Ins and D-Chiro-Ins in the 40:1 formula efficiently rescued PCOS features by up-regulating aromatase and FSHR levels while down-regulating androgen excesses produced by TCs.

Using a new analytic approach for genotyping and phenotyping chromosome 9p deletion syndrome.

Using a new analytic method ("unique non-overlapping region" (UNOR) analysis), we characterized the genotypes and phenotypes of a large cohort of individuals diagnosed with chromosome 9p deletion syndrome (9PMS) and defined critical genomic regions. We extracted phenotypic information from 48 individuals with 9PMS from medical records and used a guided interview with caregivers to clarify ambiguities. Using high-resolution whole-genome sequencing for breakpoint definition, we aligned deletions and drew virtual breakpoints to obtain UNORs associated with phenotypic characteristics. We next extracted genotype and phenotype data for 57 individuals identified from a systematic review of the 9PMS literature and analyzed these as above. Common phenotypic features included developmental delay/intellectual disability, dysmorphic features, hypotonia, genital defects in XY individuals, psychiatric diagnoses, chronic constipation, atopic disease, vision problems, autism spectrum disorder, gastroesophageal reflux disease, trigonocephaly, congenital heart disease, and neonatal hypoglycemia. Our approach confirmed previous literature reports of an association of FREM1 with trigonocephaly and suggested a possible modifier element for this phenotype. In conclusion, the UNOR approach delineated phenotypic characteristics for 9PMS and confirmed the critical role of FREM1 and a possible long-distance regulatory element in pathogenesis of trigonocephaly that will need to be replicated in future studies.

Monogenic interferon-mediated diseases: novel phenotype and genotype characteristics from a Saudi population.

IFN-mediated diseases are mendelian innate immunodysregulatory disorders that present early in life with fevers, sterile organ inflammation, and a high type-I IFN-response gene signature in peripheral blood cells. To date, monumental discoveries of novel genetic variants with various phenotypic features have been recognised. We aimed to describe the genotype and phenotype findings in Saudi children diagnosed with autoinflammatory interferonopathy and to report novel findings. This is a descriptive retrospective cohort study of children with genetically confirmed type I interferonopathies. Medical records were reviewed for demographic, family history, clinical and laboratory data. All patients underwent genetic testing. A total of 20 patients (11 females) were included in the study. Sixteen patients (80%) presented within the first 2 years. The median age of disease onset was 0.87 years (IQR: 0.5-2) and the median age of diagnosis was 4.5 years (IQR: 2-7.5). The rates of consanguinity and family history of affected members were high (88% and 47%, respectively). Among the cohort of patients, whole exome sequencing was conducted for 15 patients. Three patients underwent targeted gene tests, and 2 patients had a leukoencephalopathy genetic panel. Eight patients were diagnosed with Aicardi-Goutières syndrome, attributed to variants in the RNASEH2A, RNASEH2C, and IFIH1 genes. Additionally, 2 patients were identified with STING-associated vasculopathy with onset in infancy linked to the TMEM173 variant. One patient exhibited chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature due to PSMB8, and another patient had DNase II. Moreover, 8 patients presented with rare interferonopathy conditions, including three with ISG15, 3 with ZNFX1, 1 with the SOCS1 variant, and 1 the STAT1 variant. Of 12 variants, six (50%) found to have novel genetic variants. The most frequent features were fever (75%), neurology (70%), mucocutaneous (60%), gastrointestinal (50%), and pulmonary (50%). Hypogammaglobinaemia and recurrent infections were seen in (45%) and (20%), respectively. Fifteen patients (75%) had elevated inflammatory markers. The majority of patients received intensive treatment, including corticosteroids, JAK inhibitors, IVIG, and various immunosuppressive agents. Despite these interventions, a partial response to treatment was observed, and cumulative disease damage primarily manifested as growth failure and developmental delay. Our findings support the previous reports; early-onset fever, neurology, and respiratory features should raise the suspicion of interferonopathies. However, there is eminent evidence of phenotypic variability. Our data also expanded the spectrum of clinical findings in relation to novel genetic variants.

Automated Phenotypic Trait Extraction for Rice Plant Using Terrestrial Laser Scanning Data.

To quickly obtain rice plant phenotypic traits, this study put forward the computational process of six rice phenotype features (e.g., crown diameter, perimeter of stem, plant height, surface area, volume, and projected leaf area) using terrestrial laser scanning (TLS) data, and proposed the extraction method for the tiller number of rice plants. Specifically, for the first time, we designed and developed an automated phenotype extraction tool for rice plants with a three-layer architecture based on the PyQt5 framework and Open3D library. The results show that the linear coefficients of determination (R2) between the measured values and the extracted values marked a better reliability among the selected four verification features. The root mean square error (RMSE) of crown diameter, perimeter of stem, and plant height is stable at the centimeter level, and that of the tiller number is as low as 1.63. The relative root mean squared error (RRMSE) of crown diameter, plant height, and tiller number stays within 10%, and that of perimeter of stem is 18.29%. In addition, the user-friendly automatic extraction tool can efficiently extract the phenotypic features of rice plant, and provide a convenient tool for quickly gaining phenotypic trait features of rice plant point clouds. However, the comparison and verification of phenotype feature extraction results supported by more rice plant sample data, as well as the improvement of accuracy algorithms, remain as the focus of our future research. The study can offer a reference for crop phenotype extraction using 3D point clouds.

Concordance of phenotypic characteristics among patients with familial Crohn's disease in China.

Familial Crohn's disease (CD) accounts for approximately 1.5%-22.5% of all CD cases worldwide. We aimed to assess the concordance in disease subtype and phenotypic features among patients with CD and their relatives based on data from a large, well-characterized, referral center-based cohort in China. A retrospective study was conducted on patients with familial CD who were admitted to the Sixth Affiliated Hospital of Sun Yat-sen University between January 2012 and June 2022. We analyzed the disease characteristics and performed a concordance analysis within the same family among patients with familial CD. Among 5150 patients, 70 (1.4%) had a family history of Crohn's disease. The median age of the patients at initial diagnosis did not differ significantly between the probands and successors of family members with CD (p = 0.25). At the initial diagnosis, 54 first-degree relatives showed moderate concordance in age (κ = 0.50) and disease location (κ = 0.44). At the last follow-up visit, all family members and first-degree relatives showed good concordance in upper gastrointestinal involvement (κ = 0.67 and 0.62) and stricturing or penetrating behavior (κ = 0.69 and 0.77), respectively. Patients with familial CD within the same family showed moderate agreement regarding anti-tumor necrosis factor α monoclonal antibody use and treatment efficacy (κ = 0.44 and 0.42) and mild agreement regarding the efficacy and adverse reactions of thiopurine (κ = 0.26 and 0.35). The proportion of patients with familial CD in China may be relatively low. The consistency of certain disease features in familial CD may be associated with the degree of kinship and convergence with longer follow-up duration.

Breed of origin analysis in genome-wide association studies: enhancing SNP-based insights into production traits in a commercial Brangus population

BackgroundCarcass weight (HCW) and marbling (MARB) are critical for meat quality and market value in beef cattle. In composite breeds like Brangus, which meld the genetics of Angus and Brahman, SNP-based analyses have illuminated some genetic influences on these traits, but they fall short in fully capturing the nuanced effects of breed of origin alleles (BOA) on these traits. Focus on the impacts of BOA on phenotypic features within Brangus populations can result in a more profound understanding of the specific influences of Angus and Brahman genetics. Moreover, the consideration of BOA becomes particularly significant when evaluating dominance effects contributing to heterosis in crossbred populations. BOA provides a more comprehensive measure of heterosis due to its ability to differentiate the distinct genetic contributions originating from each parent breed. This detailed understanding of genetic effects is essential for making informed breeding decisions to optimize the benefits of heterosis in composite breeds like Brangus.ObjectiveThis study aims to identify quantitative trait loci (QTL) influencing HCW and MARB by utilizing SNP and BOA information, incorporating additive, dominance, and overdominance effects within a multi-generational Brangus commercial herd.MethodsWe analyzed phenotypic data from 1,066 genotyped Brangus steers. BOA inference was performed using LAMP-LD software using Angus and Brahman reference sets. SNP-based and BOA-based GWAS were then conducted considering additive, dominance, and overdominance models.ResultsThe study identified numerous QTLs for HCW and MARB. A notable QTL for HCW was associated to the SGCB gene, pivotal for muscle growth, and was identified solely in the BOA GWAS. Several BOA GWAS QTLs exhibited a dominance effect underscoring their importance in estimating heterosis.ConclusionsOur findings demonstrate that SNP-based methods may not detect all genetic variation affecting economically important traits in composite breeds. BOA inclusion in genomic evaluations is crucial for identifying genetic regions contributing to trait variation and for understanding the dominance value underpinning heterosis. By considering BOA, we gain a deeper understanding of genetic interactions and heterosis, which is integral to advancing breeding programs. The incorporation of BOA is recommended for comprehensive genomic evaluations to optimize trait improvements in crossbred cattle populations.

Genotype-histotype-phenotype correlations in hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in ABCC8 or KCNJ11. Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal ABCC8/KCNJ11 mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to MEN1 mutations. MAFA mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.

Assessment of clinical phenotypic characteristics of patients with angioedema without wheals in a turkish population.

Background: Angioedema (AE) is defined as localized, self-limited swelling of subcutaneous tissues and mucosa. Objective: The aim of this study was to compare the phenotypic characteristics of patients with AE without wheals. Methods: This prospective study included adult patients with recurrent AE without wheals. Demographic and laboratory data of the patients were recorded in the patient file when they presented to the outpatient clinic between August 2018 and August 2020. The patients were contacted by phone to evaluate whether their AE had gone into remission between October 2023 and January 2024. The phenotypic characteristics of AE subtypes were compared. Results: The study included a total of 143 patients. The average age, age of onset of AE, rates of diabetes mellitus, hypertension and coronary artery disease were higher in the patients with angiotensin-converting enzyme inhibitor (ACEI) use related acquired AE (AAE) (AAE-ACEI). The rates of allergic rhinitis, drug allergy, atopy, and aeroallergen sensitivity, and the median total immunoglobulin E level were higher in patients with idiopathic histaminergic AAE (AAE-IH). The rate of face and/or perioral AE attacks was higher in the patients with AAE-ACEI, AAE-IH, and idiopathic non-histaminergic AAE. The rate of AE attacks in limbs, abdominal, genital and other parts of the body was higher in patients with hereditary AE (HAE). The baseline AE activity score was lower in the patients with AAE-IH and higher in the patients with HAE. In long-term follow-up, the remission rate of AE attacks was significant higher in patients with AAE-ACEI and AAE-IH. Conclusion: The phenotypic characteristic features of Turkish patients with AE without wheals may vary, depending on the underlying AE pathogenesis. C1 inhibitor level and function, complement C4 and C1q, and genetic tests contributed to the diagnosis; other laboratory tests did not contribute to the diagnosis.

Coinheritance of HNF1A and glucokinase variants in maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a group of monogenic forms of diabetes mellitus characterized by early-onset diabetes with dominant inheritance of beta-cell dysfunction. There are few reports of the coinheritance of glucokinase (GCK) and hepatocyte nuclear factor 1 alpha gene (HNF1A) variants underlying MODY in patients. Herein, we describe a case involving combinations of monoallelic GCK and HNF1A variants associated with MODY. A 10-year-old Japanese girl with a three-generation family history of diabetes without obesity showed high levels of urinary glucose during a school screening test. Her glucose metabolism profile revealed 124 mg/dL of fasting glucose, 6.9% glycated hemoglobin (HbA1c), and 2.78 ng/mL of C-peptide immunoreactivity levels. In a 75-g oral glucose tolerance test, her base glucose, peak glucose, insulin resistance, and homeostasis model assessment of beta cell function levels were 124 mg/dL, 210 mg/dL (120 min), 1.71, and 33%, respectively. Based on the clinical phenotype of GCK-MODY, alimentary and exercise therapy without oral hypoglycemic agents were used to maintain her fasting glucose and HbA1c levels. We explored the coinheritance of MODY with GCK and HNF1A variants in this and past cases and found that careful clinical follow-up is required to firmly establish phenotypic features. Moreover, the accumulation of data on genetically confirmed MODY associated with the coinheritance of GCK and HNF1A variants will be useful for understanding genotype-phenotype correlations. MODY is a group of monogenic forms of diabetes mellitus characterized by early-onset diabetes with the dominant inheritance of beta-cell dysfunction. MODY2 and MODY3 caused by heterozygous loss-of-function variants in the glucokinase (GCK) and hepatocyte nuclear factor 1 alpha (HNF1A) genes, respectively, are the most common forms of the disease. Few cases of MODY have previously been reported as being associated with the coinheritance of GCK and HNF1A variants. Careful clinical follow-up is required to firmly establish phenotypic features in the coinheritance of MODY with GCK and HNF1A variants. The accumulation of data on genetically confirmed MODY associated with the coinheritance of GCK and HNF1A variants will be useful for understanding genotype-phenotype correlations.

Confirmation and pathogenicity of small copy number variations incidentally detected via a targeted next-generation sequencing–based preimplantation genetic testing for aneuploidy platform

ObjectiveTo evaluate the technical accuracy, inheritance, and pathogenicity of small copy number variants (CNVs) detected by a targeted next-generation sequencing (NGS)-based PGT-A platform. DesignRetrospective observational study performed between 2020-2022. Subjects12,157 patients who underwent clinical PGT-A performed by targeted NGS for whole chromosome and large segmental aneuploidies. ExposureAn incidental finding was reported when a CNV gain/loss of at least three consecutive amplicons appeared in at least two embryos from the same IVF cycle. Main Outcome MeasuresThe primary outcome measures were the specificity, incidence, inheritance, and pathogenicity of small CNVs detected by the PGT-A platform. Accuracy of the PGT-A platform CNV calls was assessed via concordance with the CNV calls (size and genomic location) on chromosomal microarray of the gamete provider(s). Parental origin of the CNV and pathogenicity classifications were also reported. ResultsIn 75 of 12,157 unique PGT-A patients (0.62%;95%CI:0.5-0.8%), an incidental finding that met reporting criteria was identified. Chromosomal microarray follow-up was requested for all cases and results were received for one or both members of 65 reproductive couples. In all cases, one of the gamete providers was confirmed to have the CNV identified in the embryos (100.0%: N=65/65 95%CI:94.5-100). The identified CNV was of maternal origin in 34 cases (52.3%) and of paternal origin in 31 cases (47.7%). A significant correlation was identified between PGT-A-predicted CNV sizes and chromosomal microarray detected sizes (r=0.81) and genomic coordinates on parental DNA. Twenty-six (40%) of the CNVs were classified as benign/likely benign, 30 (46.2%) as a variant of uncertain significance (VUS), and 9 (13.8%) as pathogenic/likely pathogenic. ConclusionCertain PGT-A platforms may enable the detection of inherited, small CNVs with extremely high specificity without prior knowledge of parental status. The majority of CNVs in this data set were confirmed to be benign/likely benign or a VUS; however, pathogenic/likely pathogenic CNVs associated with a broad range of phenotypic features may also be detected, although a reliable negative predictive value for small CNVs with current PGT-A technologies is unknown due to the many technical challenges.