Gene Variants Research Articles

Association of ESR1 Polymorphisms with Susceptibility to Migraine: A Meta-Analysis and Trial Sequential Analysis.

Migraine is a highly prevalent and incapacitating neurological disorder mostly characterised by recurring attacks of moderate to severe throbbing and pulsating pain on one side of the head. The role of estrogen in migraine has been well documented. Although genetic variations in the ESR1 gene have been associated with an increased risk of developing migraine, the findings are inconsistent. We performed a meta-analysis of previously published articles considering four important single nucleotide polymorphisms in the ESR1 gene (rs1801132, rs2228480, rs2234693, and rs9340799) to explore their possible association with the development of migraine and its clinical phenotypes. We thoroughly searched literature databases, including PubMed, Science Direct, and Scopus until March 14, 2024, to identify the relevant reports. We utilized GPower software v.3 to assess the power of each report included in the meta-analysis and Comprehensive Meta-analysis v4 for all meta-analysis-related analyses. We employed funnel plots and Egger's regression test to identify publication biases within each genetic comparison model. We used Cochrane Q statistics, probability value, and I2 to assess heterogeneity. After applying predefined criteria, a meta-analysis was conducted with 11 relevant studies comprising 3835 cases of migraine and 3655 healthy individuals. The analysis indicated a strong correlation between ESR1 polymorphisms (rs2228480 and rs9340799) and the likelihood of developing migraine. Furthermore, the subgroup analysis showed that rs2228480 is associated with susceptibility to migraine in both Caucasians and Asians. Additionally, rs2234693 variants were found to be linked with the development of migraine with aura. However, the trial sequential analysis suggested that more case-control studies are necessary to establish the definitive role of ESR1 variants in migraine. ESR1 variants (rs2228480, rs2234693, and rs9340799) are associated with an increased risk of migraine and related phenotypes. However, further studies are needed to establish a definitive conclusion.

Population-based, first-tier genomic newborn screening in the maternity ward.

The rapid development of therapies for severe and rare genetic conditions underlines the need to incorporate first-tier genetic testing into newborn screening (NBS) programs. A workflow was developed to screen newborns for 165 treatable pediatric disorders by deep sequencing of regions of interest in 405 genes. The prospective observational BabyDetect pilot project was launched in September 2022 in a maternity ward of a public hospital in the Liege area, Belgium. In this ongoing observational study, 4,260 families have been informed of the project, and 3,847 consented to participate. To date, 71 disease cases have been identified, 30 of which were not detected by conventional NBS. Glucose-6-phosphate dehydrogenase deficiency was the most frequent disorder detected, with 44 positive individuals. Of the remaining 27 cases, 17 were recessive disorders. We also identified one false-positive case in a newborn in whom two variants in the AGXT gene were identified, which were subsequently shown to be located on the maternal allele. Nine heterozygous variants were identified in genes associated with dominant conditions. Results from the BabyDetect project demonstrate the importance of integrating biochemical and genomic methods in NBS programs. Challenges must be addressed in variant interpretation within a presymptomatic population and in result reporting and diagnostic confirmation.

Utility of the C-peptide/insulin molar ratio for distinguishing type A insulin resistance syndrome from type 2 diabetes.

Type A insulin resistance syndrome (IRS), characterized by impaired insulin receptor function due to variants of the insulin receptor gene, manifests as severe insulin-resistant diabetes. Differentiation of type A IRS from type 2 diabetes on the basis of hyperinsulinemia can be challenging. Given the association between insulin receptor dysfunction and reduced insulin clearance, we evaluated the potential of the circulating C-peptide reactivity (CPR)/immunoreactive insulin (IRI) molar ratio, a marker of insulin clearance, for distinguishing type A IRS from type 2 diabetes. We retrospectively analyzed CPR and IRI levels measured during a 75-g oral glucose tolerance test (OGTT) in 18 individuals with type A IRS and 126 with type 2 diabetes. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic performance of the CPR/IRI molar ratio and IRI levels. IRI levels were significantly higher and the CPR/IRI molar ratio significantly lower in individuals with type A IRS compared with those with type 2 diabetes. The area under the ROC curve for the CPR/IRI molar ratio at baseline, 1 hour, and 2 hours after OGTT initiation was 0.997 (sensitivity 100%, specificity 99.2%), 0.999 (sensitivity 100%, specificity 97.6%), and 0.997 (sensitivity 100%, specificity 95.1%), respectively. The CPR/IRI molar ratio demonstrated robust diagnostic performance regardless of body mass index or hyperinsulinemia severity. The CPR/IRI molar ratio, both at baseline and during OGTT, exhibited higher sensitivity and specificity than IRI levels alone for distinguishing type A IRS from type 2 diabetes. This ratio may serve as a reliable clinical marker for early and accurate diagnosis of type A IRS.

Genomic profiling at a single center cracks the code in inborn errors of immunity.

Inborn errors of immunity (IEI) entail a diverse group of disorders resulting from hereditary or de novo mutations in single genes, leading to immune dysregulation. This study explores the clinical utility of next-generation sequencing (NGS) techniques in diagnosing monogenic immune defects. Eight patients attending the immunodeficiency clinic and with unclassified antibody deficiency were included in the analysis. Clinical records, immune characteristics, and family histories were reviewed, and a target gene panel (TGP) sequencing was performed to identify pathogenic variants. TGPs identified seven variants in TNFRSF13B (TACI), CARMIL2, STAT1, STAT3, and ORAI1 genes. These findings provided definitive diagnoses and proper prognostic assessment. Patients exhibited a wide range of clinical manifestations, including recurrent infections, autoimmune cytopenias, and organ-specific complications. The genetic diversity observed highlights the importance of genetic testing in diagnosing IEIs and tailoring treatments. This study underscores the role of TGPs in diagnosing IEIs, revealing significant genetic heterogeneity and phenotypic variability. They offer a precise tool for identifying underlying genetic defects, facilitating personalized medicine approaches, and eventually improving patient outcomes. The findings emphasize the need for comprehensive genetic testing to uncover novel pathogenic variants, enhancing our understanding of immune system dysfunction. NGS is a critical tool for the management of IEI, enabling precise diagnosis and personalized treatment strategies. Despite resource limitations, the progressive affordability is likely to expand its clinical utility, ultimately improving patient care and advancing the field of immunology. In the meantime, accurate phenotypic assessment is essential for resource optimization and case prioritization.

A Novel Pathogenic Variant in the KRT3 Gene in a Family with Meesmann Corneal Dystrophy

A Novel Pathogenic Variant in the KRT3 Gene in a Family with Meesmann Corneal Dystrophy

Transthyretin variants impact blood-nerve barrier and neuroinflammation in amyloidotic neuropathy.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a neurodegenerative disease caused by mutations in the gene encoding transthyretin (TTR). Despite amyloid deposition being pathognomonic for diagnosis, this pathology in nervous tissues cannot fully account for nerve degeneration, implying additional pathophysiology for neurodegeneration, which, however, has not yet been fully elucidated. In this study, neuroinflammation in ATTRv-PN was investigated by examining nerve morphometry, the blood-nerve barrier, and macrophage infiltration in the sural nerves of ATTRv-PN patients and the sciatic nerves of a complementary mouse system, i.e. the humanized knock-in hTTRA97S mice. The direct effects of mutant TTR proteins were evaluated in these hTTRA97S mice and a human umbilical vein endothelial cell (HUVEC) model in vivo and in vitro, respectively. This case-control and cross-sectional study included 19 patients (17 men; 62.9 ± 3.9 years; FAP stage 1, n=11; FAP stage 2, n=7; FAP stage 3, n=1) with p.Ala117Ser (A97S) and 46 patients (39 men; 65.3 ± 11.4 years; FAP stage 1, n=31; FAP stage 2, n=12; FAP stage 3, n=3) with p.Val50Met (V30M). Both genotypes had elevated protein in the cerebrospinal fluid: 88.9% (16 cases in 18 patients) in A97S and 51.1% (23 cases in 45 patients) in V30M. The myelinated nerve fibers in sural nerves were markedly depleted in ATTRv-PN and the myelinated nerve fiber density was inversely correlated with CSF protein, implying leakage of the blood-nerve barrier. The tight junction ultrastructure of the endoneurial microvessels in sural nerves was impaired, as indicated by the reduced expression of zonula occludens-1 (ZO-1). The cultured HUVEC that were not transfected with any TTR gene variant presented reduced ZO-1 expression when exposed to mutant recombinant TTR of A97S or V30M compared to wild-type TTR. Increased infiltration of macrophage with expression of inflammasome maker, NLR family pyrin domain containing 3 (NLRP3), suggested polarization to proinflammatory M1 lineage were robust in the sural nerves of ATTRv-PN patients and the sciatic nerves of hTTRA97S mice compared with those of controls and wild-type mice. In parallel, the mRNA expression of interleukin 1β was greater in the sural nerves of ATTRv-PN than in those of the controls. In conclusion, the disrupted blood-nerve barrier due to mutant TTR protein resulting in increased CSF protein level was associated with nerve degeneration in ATTRv-PN via the infiltration of inflammatory macrophages and the production of inflammatory cytokines.

Association of BCHE gene SNP rs1803274 (K-variant) and rs3495 with obesity in Pakistani population group.

Obesity plays a crucial role in the development of metabolic disorders including diabetes, coronary and renal diseases. There are several factors involved in the pathology of obesity, including chronic inflammation and exposure to environmental contaminants. Recently, the cholinergic co-hydrolyzing enzyme BChE has been associated with clinical conditions such as diabetes and obesity. This study aims to investigate the levels of BChE and inflammatory markers in the serum, as well as the association between two specific BCHE gene variants (rs1803274 and rs3495) and the risk of obesity in the Pakistani population. The study recruited 350 people with obesity and 200 volunteers with no obesity. Proinflammatory cytokines (TNF-α, IL-6, and IL-1β) levels were quantified using ELISA kits, while the analysis of BCHE gene SNPs rs1803274 (K-variant) and rs3495 was conducted using the tetra-primer amplification refractory mutation-PCR (tetra-ARM-PCR) and PCR-restriction fragment length polymorphism (RFLP) methods, respectively. Additionally, clinico-pathological parameters HDL, LDL, BMI, Homa-IR, insulin, glucose, blood pressure was also assessed in subjects of current study. Results showed significantly higher levels of BChE, TNF-α, IL-1β, and IL-6 in the obesity group compared to the group without obesity. Furthermore, the obesity group exhibited higher blood pressure and LDL levels, as well as lower HDL levels when compared to group without obesity. Logistic regression analysis revealed a relationship between obesity and higher BChE activity, blood pressure, LDL, and lower HDL levels. The study also found a statistically significant association between the BCHE gene SNPs rs1803274 (K-variant) and rs3495 and the risk of obesity (OR = 2.01; CI = 1.21-3.33; p = 0.0063; OR = 1.80; CI = 1.09-2.96, respectively). In conclusion, the study suggests that BChE and inflammatory cytokines play a significant role in the development and pathogenesis of obesity and can also act as good diagnostic biomarkers for obesity and its related metabolic disorders.

Durable suppression of seizures in a preclinical model of KCNT1 genetic epilepsy with divalent small interfering RNA.

Gain-of-function variants in the KCNT1 gene, which encodes a sodium-activated potassium ion channel, drive severe early onset developmental epileptic encephalopathies including epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. No therapy provides more than sporadic or incremental improvement. Here, we report suppression of seizures in a genetic mouse model of KCNT1 epilepsy by reducing Kcnt1 transcript with divalent small interfering RNA (siRNA), an emerging variant of oligonucleotide technology developed for the central nervous system. The ATL-201 molecule is two identical synthetic double-stranded siRNAs, covalently linked, with 100% nucleotide base pair match to sequence present in both human KCNT1 and mouse Kcnt1 that does not contain any known pathogenic variant. ATL-201 activity was tested in cortical neurons cultured from wild-type mice and in mice homozygous for Kcnt1-Y777H, the mouse ortholog to the human pathogenic KCNT1-Y796H missense variant. Seizures and nest-building behavior were measured in freely behaving Kcnt1-Y777H mice. The number and duration of seizures were measured by electrocorticography in mice dosed with ATL-201 or phosphate-buffered saline in a 6-month durability study and in a 2-month dose-efficacy study. In vitro, ATL-201 reduced KCNT1 transcript from whole-cell lysate and eliminated potassium currents from KCNT1 channels in heterologous expression. ATL-201 also eliminated sodium-activated potassium currents recorded from individual cortical neurons. Invivo, ATL-201 suppressed seizures in Kcnt1-Y777H homozygous mice in a dose-dependent manner with near-complete suppression from 2 weeks to at least 4 months. Kcnt1-Y777H mice had defects in nest building, whereas in ATL-201-treated mice nest building was equivalent to wild-type mice. Patients with KCNT1-driven epilepsy experience up to hundreds of seizures per day and have severe impairment in cognitive, motor, and language development and high mortality. The dose-dependent efficacy and long durability of ATL-201 in mice show promise for ATL-201 as a disease-modifying treatment of KCNT1 epilepsy.

The Novel Association of a Single Nucleotide Variant in the COL3A1 Gene with Diffuse Coronary Aneurysms

The Novel Association of a Single Nucleotide Variant in the COL3A1 Gene with Diffuse Coronary Aneurysms

Two Variants of the ANK1 Gene Associated with Hereditary Spherocytosis

Background Hereditary spherocytosis (HS) is an erythrocytic membranopathy that belongs to a group of rare genetic disorders. Mutations in five genes, including ANK1, cause clinical manifestations of the disease. Identified variations in individual families provide a better understanding of the molecular basis of the disease. Methods In this study, we used two sequencing methods, whole exome sequencing (WES) and Sanger sequencing, analyzing gDNA and cDNA as templates, to detect and verify the variants putatively responsible for the clinical symptoms observed in a Polish family diagnosed with HS. Results We detected two variants that occur in cis in the ANK1 gene, a known missense mutation (NP_000028.3:p.V463I) and a novel frameshift mutation (NP_000028.3: p.V1626fs*64) that appears to be crucial for the probands. As shown by transcriptome studies, the mutant allele is not present at a detectable level. Conclusions We conclude that the molecular basis of this case is related to an unstable transcript of the mutant allele and that the direct cause of the HS is a deficiency of erythrocyte ankyrin leading to a disruption of the AE1-erythrocyte ankyrin-spectrin complex in the erythrocyte membrane.

P-20 EARLY ZOLEDRONIC ACID TREATMENT IN A PEDIATRIC CASE OF OSTEOGENESIS IMPERFECTA TYPE V: CLINICAL OUTCOMES AND THE ROLE OF IFITM5 (BRIL) MUTATION

Abstract Introduction Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility, low bone mass, and frequent fractures. OI is typically associated with mutations in the COL1A1 and COL1A2 genes, but a subset of cases, such as OI type V, is linked to mutations in the IFITM5 gene, also known as BRIL (bone-restricted IFITM-like). Clinical Case This report presents a case of a 2-year-old boy diagnosed with OI type V, a rare form of the disease caused by a mutation in BRIL. The patient exhibited multiple recurrent bone fractures beginning in infancy, though there was no family history of bone disease or consanguineous marriage. Physical examination revealed that the patient was of normal weight and height for his age, with neurodevelopmental milestones met. Laboratory tests showed elevated alkaline phosphatase (ALP) levels, indicative of increased bone turnover, while other values were within normal ranges. Radiological evaluations confirmed an active fracture in the left tibia but showed no additional pathological involvement. Genetic testing identified a de novo C>T variant in the IFITM5 gene, confirming the diagnosis of OI type V. The patient was treated with intravenous zoledronic acid (ZA), a bisphosphonate therapy, which is currently being tested in infants and toddlers for OI treatment. The treatment led to a significant reduction in fracture recurrence and a decrease in ALP levels, demonstrating its efficacy in managing the disease. Despite these positive outcomes, certain hallmark features of OI type V, such as hyperplastic callus formation and new periosteal bone growth, were not observed during follow-up, possibly due to the early initiation of ZA therapy. OI type V is distinguished from other forms of OI by hyperplastic callus formation and increased osteoblast activity, often accompanied by elevated ALP levels. Radiographic and histological findings specific to this type include periosteal bone growth and a reticular lamellation pattern in the bone matrix. Although ZA has shown promise in reducing fracture risk and improving clinical outcomes, its long-term efficacy in preventing other disease manifestations, such as intramembranous ossification, remains uncertain. The underlying pathological mechanisms of OI type V, particularly the role of BRIL, are not yet fully understood. Further research into the activation of BRIL in osteoblasts could lead to the development of targeted therapies that address the root cause of the disease. While ZA therapy has been effective in managing the immediate symptoms of OI type V, a deeper understanding of the disease's genetic and molecular basis is crucial for improving long-term treatment outcomes. In conclusion, the IFITM5 (BRIL) mutation is recognized as the genetic cause of OI type V. Early intervention with ZA has shown positive effects in managing the disease, but further research is needed to fully understand the pathological mechanisms and to develop treatments that can address all aspects of the disease.Table 1:Lab workout (age 2)ALP = alkaline phosphatase; AST = aspartate transaminase; BUN = blood urea nitrogen; GGT = gamma-glutamyl transferase; CBC: complete blood count

Thick skin and thicker arteries: case report on a rare cause of hypertension.

Renovascular hypertension is the second leading cause of hypertension. Twenty-seven genes have been attributed to monogenic renovascular hypertension at present. We present a 15-year-old boy with facial dysmorphism, thick skin and renovascular hypertension with a novel gain-of-function variant in SMAD4 gene suggesting Myhre syndrome. Hypertension was controlled with three anti-hypertensive agents and vascular intervention is planned. It is characterized by a multisystem connective tissue disorder associated with progressive fibrosis of skin, cardiovascular, musculoskeletal, gastrointestinal and respiratory systems. This case highlights the need for recognizing syndromic features in children with renovascular hypertension.

Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series

BackgroundApparent Mineralocorticoid Excess (AME) is a rare autosomal recessive disorder, characterized by a notably complex diagnostic process. To date, the majority of documented cases have been presented as individual case reports. This article aims to enhance the understanding of the course and prognosis of AME, by detailing the management protocols employed for patients with genetically confirmed diagnoses.MethodsAn analysis comprising three cases and a review of relevant literature were conducted to synthesize the insights and experiences derived from gathering clinical and laboratory data on patients.ResultsAll three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria. The glomerular filtration rate was normal in all cases. One patient experienced complications related to hypertension. Genetic analysis revealed biallelic recessive variations in the HSD11B2 gene in all three patients. Treatment with oral spironolactone and potassium chloride resulted in the normalization of both blood pressure and serum potassium levels in all patients.ConclusionThis study presents the diagnostic and treatment experiences of three Chinese pediatric patients with AME type I. Through our analysis, four novel variants of the HSD11B2 gene were identified, thereby enhancing the genotype-phenotype spectrum associated with AME. Early genetic testing in patients suspected of having AME is beneficial for facilitating prompt diagnosis and the implementation of standardized treatment protocols. Such measures are essential for the prevention or mitigation of target organ damage, as well as for the reduction of associated morbidity and mortality

Exocrine pancreatic insufficiency as an unusual extrarenal manifestation of proximal renal tubular acidosis associated with a novel SLC4A4 mutation.

Autosomal recessive proximal renal tubular acidosis (AR-pRTA) with ocular abnormalities is a rare syndrome caused by variants in the SLC4A4 gene, which encodes Na/HCO3 cotransporter (NBCe1). The syndrome primarily affects the kidneys, but also causes extra-renal manifestations. Pancreatic type NBCe1 is located at the basolateral membrane of the pancreatic ductal cells and together with CFTR chloride channel, it is involved in bicarbonate secretion. In vitro models have demonstrated that mutations inthe pancreatic type NBCe1 lead to a reduction inpancreatic bicarbonate secretion. Although elevated amylase levels have been observed in some cases, there is no evidence of symptomatic pancreas involvement in children with AR-pRTA. This report presents the case of a seven-year-old girl with AR-pRTA and exocrine pancreatic insufficiency. This novel presentation with a novel mutation in SLC4A4 expands the extra-renal involvement in this rare disease. We recommend that these children be screened for exocrine pancreatic insufficiency.

A novel X-linked variant c.1772delG (p.G591fs*20) in IRS4 in two related patients with central hypothyroidism

Introduction: Central hypothyroidism (CeH) is characterized by thyroid hormone deficiency due to impairment of pituitary thyroid stimulating hormone (TSH) or hypothalamic TRH biosynthesis. It is extremely rare and affects approximately 1:16,000-100,000 individuals. Diagnosis, especially of isolated CeH, may be challenging. CeH is often seen as a part of multiple pituitary hormone deficiencies, but it can also be seen as isolated CeH. To date, some variants that can cause CeH have been identified; although in a number of patients the cause has not been clarified. Recently, variants of the insulin receptor substrate 4 (IRS4) gene have been reported to be the cause of isolated CeH. Herein, we report two related patients and their family with carriers with a novel X-linked frameshift variant in the IRS4 gene. It has also been shown that thyroid function may be slightly affected in the heterozygous female carriers in our study. Case Presentation: Herein, we reported two Turkish male patients with CeH due to a hemizygous variant in IRS4. The index case was a 15-year-and-2-month male who presented with a low serum free thyroxin level, which was incidentally detected. Conclusion: Isolated CeH should kept in mind in insistent low fT4 levels without an increase in TSH levels. Genetic testing can aid in identifying the underlying cause of CeH in such cases. This report demonstrates the significance of providing comprehensive laboratory and molecular features of the patients and carriers with the IRS4 variants.

P-08 OLD ETIOLOGY, NEW CHALLENGES: MANAGING WATERHOUSE FRIDERICHSEN SYNDROME IN A PEDIATRIC PATIENT WITH SIGNIFICANT COMORBIDITIES

Abstract Introduction Waterhouse-Friderichsen syndrome (WFS) is a rare but life-threatening condition characterized by bilateral adrenal hemorrhage, typically precipitated by severe systemic infection. This syndrome can lead to chronic primary adrenal insufficiency, a condition that poses significant management challenges, particularly when accompanied by major comorbidities. Clinical Case We report the case of a young boy who developed Neisseria meningitidis type B meningitis at 3 months of age, followed by purpura fulminans, septic shock and coma, necessitating orotracheal intubation and mechanical ventilation. Acute phase management included fluid resuscitation, antibiotics, osmotic diuretics, immunoglobulins, antipyretics and plasma. During hospitalization, the development of progressive generalized skin hyperpigmentation raised the suspicion of adrenal insufficiency, confirmed by cortisol (4.60 µg/dL) and ACTH (330 pg/mL) levels. Glucocorticoid replacement therapy was initiated, with a favorable recovery and no neurological deficits at discharge. Several months later, the patient began experiencing recurrent seizures, subsequently diagnosed as focal generalized epilepsy. Treatment with valproic acid was initiated, with the dosage gradually increased due to inadequate seizure control and lack of responsiveness to initial therapy. Despite appropriate glucocorticoid replacement therapy, the patient experiences nausea, vomiting, and apathy for several hours following each epileptic episode. Further complicating the clinical picture, the patient associates generalized epi-metaphyseal dysplasia, limb-length discrepancy and other skeletal deformities (Figure). Given these clinical features, genetic testing was performed using a panel of genes associated with skeletal dysplasia. This revealed a heterozygous variant in the TCIRG1 gene (c.907+4A>T), associated with autosomal recessive osteopetrosis. However, since both alleles must be mutated for the condition to manifest, the patient is considered a healthy carrier, which does not account for the observed phenotype. Subsequent genetic testing for Beckwith-Wiedemann syndrome revealed no pathological findings, leaving the etiology of the skeletal dysplasia currently unexplained, highlighting the complexity of the case. Conclusion In 21st century, when most cases of adrenal insufficiency are of autoimmune etiology, we are facing a rare cause of adrenal insufficiency with potentially fatal prognosis in a 3 month-old infant. While the therapeutic approach of WFS is difficult, the added neuropsychiatric complications further challenges the management of chronic adrenal insufficiency, especially in the absence of established guidelines for glucocorticoid dose adjustments in epileptic patients. Complex cases require enhanced interdisciplinary collaboration and further research to develop evidence-based guidelines for managing adrenal insufficiency with comorbid neurological conditions.Figure 1:Generalized lesional hyperpigmentationThe image shows an infant patient recovering from an episode of meningitis, complicated by disseminated purpura and adrenal insufficiency. These conditions have caused darkening of the skin and hyperpigmentation of healing purpuric lesions.

P-28 A CASE OF MODY TYPE 9 WITH C.89T>C MUTATION IN PAX4 GENE

Abstract Introduction Maturity-onset diabetes (MODY) is a rare type of diabetes mellitus (DM) with autosomal dominant inheritance that occurs at a young age, constituting 1-2% of all DM cases. Most MODY cases are misdiagnosed as type 1 or type 2 DM. MODY9 is a rare type caused by a mutation in the Paired box gene 4 (PAX4). We aimed to present a case that had been followed for eight years, initially diagnosed as type 1 DM, but later diagnosed with MODY type 9 after a PAX4 gene mutation was detected as a result of genetic analysis. Clinical Case A 23-year-old male patient had been followed up for eight years with a diagnosis of type 1 DM. In the evaluation, his body mass index was normal, fasting glucose level was 143 mg/dl, HbA1c was 9.5%, C peptide level was 607 pmol/L (370-1470 pmol/L), low-density lipoprotein was 112 mg/dl, and triglyceride was 60 mg/dl. He did not show signs of diabetic neuropathy or retinopathy and had no history of hospitalization due to diabetic ketoacidosis. His father also had DM. Because the patient was diagnosed at a young age, type 1 DM was accepted without checking insulin autoantibodies at the time of diagnosis, and intensive insulin therapy was started. Due to the patient's age, normal body mass index, normal C peptide level, family history and genetic evaluation was requested for monogenic diabetes diseases. As a result of the analysis performed in the patient's genetic laboratory, the C.89T>C missense variant in the PAX4 gene was detected. As a result of clinical findings and gene analysis, the patient was diagnosed with MODY type 9. Conclusion PAX4-MODY typically presents between ages 6 to 44 and is more common in men. The severity of diabetes may vary, with some patients experiencing diabetic ketoacidosis (DKA), impaired glucose tolerance, and potential complications such as renal or retinal issues, or end-stage renal failure. Treatment for MODY9 primarily involves a diabetic diet, physical activity, insulin therapy, and possibly oral hypoglycemic agents, tailored to the individual's disease progression.

Epigenetic modulation of social cognition: exploring the impact of methylation in brain-derived neurotrophic factor and oxytocin receptor genes across sex

Social cognition, which ranges from recognizing social cues to intricate inferential reasoning, is influenced by environmental factors and epigenetic mechanisms. Notably, methylation variations in stress-related genes like brain-derived neurotrophic factor (BDNF) and the oxytocin receptor (OXTR) are linked to distinct social cognitive functions and exhibit sex-specific differences. This study investigates how these methylation differences affect social cognition across sexes, focusing on both perceptual and inferential cognitive levels. Social cognitive abilities were assessed using the Korean version of the Reading the Mind in the Eyes Test (K-RMET) and Brune’s story-based Theory of Mind tasks (ToM-PST). DNA methylation levels in BDNF and OXTR were analyzed for correlations with performance on these cognitive tasks in a cohort of male and female participants. A moderation model was applied to determine if sex moderates the relationship between social cognition and DNA methylation. No significant overall correlation was found between social cognition and DNA methylation across participants. However, sex-specific correlations were identified, including a negative impact of BDNF methylation on K-RMET scores in males, and a similar effect of OXTR methylation on ToM-PST scores in females. The findings underscore the complex relationship between epigenetic modifications and social cognition, revealing sex-specific effects and highlighting the importance of considering sex in epigenetic studies of social cognition. This research contributes to understanding how epigenetic factors, influenced by sex, shape social cognitive processes and supports the need for sex-specific therapeutic approaches.

A prospective pragmatic evaluation of automatic trial matching tools in a molecular tumor board

Publicly available trial matching tools can improve the access to therapeutic innovations, but errors may expose to over-solicitation and disappointment. We performed a pragmatic non-interventional prospective evaluation on sequential patients at the Molecular Tumor Board of Centre Leon Berard. During 10 weeks in 2024, we analysed 157 patients with four clinical trial matching tools from the 19 screened: Klineo, ScreenAct, Trialing and DigitalECMT. Each patient had 2.19 trials proposed on average, and 38% had no trials suggested. The mean performances were precision = 0.33, recall = 0.32, AP@3 = 0.45, and NDCG@3 = 0.34. Using all the tools can increase to 26% the clinical trial options. The most frequent error concerned the type of gene variants required by the selection criteria. We showed that using a Large Language Model on the patients’ molecular reports could improve the performance by up to 5%. We recommend that experts supervise the results and we advocate for improved technologies.

An augmented transformer model trained on protein family specific variant data leads to improved prediction of variants of uncertain significance.

Variants of uncertain significance (VUS) represent variants that lack sufficient evidence to be confidently associated with a disease, thus posing a challenge in the interpretation of genetic testing results. Here we report an improved method for predicting the VUS of Arylsulfatase A (ARSA) gene as part of the Critical Assessment of Genome Interpretation challenge (CAGI6). Our method uses a transfer learning approach that leverages a pre-trained protein language model to predict the impact of mutations on the activity of the ARSA enzyme, whose deficiency is known to cause a rare genetic disorder, metachromatic leukodystrophy. Our innovative framework combines zero-shot log odds scores and embeddings from the ESM, an evolutionary scale model as features for training a supervised model on gene variants functionally related to the ARSA gene. The zero-shot log odds score feature captures the generic properties of the proteins learned due to its pre-training on millions of sequences in the UniProt data, while the ESM embeddings for the proteins in the ARSA family capture features specific to the family. We also tested our approach on another enzyme, N-acetyl-glucosaminidase (NAGLU), that belongs to the same superfamily as ARSA. Our results demonstrate that the performance of our family models (augmented ESM models) is either comparable or better than the ESM models. The ARSA model compares favorably with the majority of state-of-the-art predictors on area under precision and recall curve (AUPRC) performance metric. However, the NAGLU model outperforms all pathogenicity predictors evaluated in this study on AUPRC metric. The improved AUPRC has relevance in a diagnostic setting where variant prioritization generally entails identifying a small number of pathogenic variants from a larger number of benign variants. Our results also indicate that genes that have sparse or no experimental variant impact data, the family variant data can serve as a proxy training data for making accurate predictions. Attention analysis of active sites and binding sites in ARSA and NAGLU proteins shed light on probable mechanisms of pathogenicity for positions that are highly attended.