Non-genetic Causes Research Articles

P-997. Congenital Cytomegalovirus and Hearing Loss and Response to Treatment with Valganciclovir

Abstract Background Congenital cytomegalovirus (CMV) occurs in about 1 in 200 babies and is the leading non-genetic cause of sensorineural hearing loss (SNHL) in children in the United States. Approximately 50% of children with SNHL secondary to CMV have progression of their hearing loss. Data on the effectiveness of valganciclovir in the treatment of infants with congenital CMV with isolated hearing loss at birth is limited. Methods All newborns who did not pass their newborn hearing screening at birth between 2019-2023 were included and tested for CMV by a nucleic acid test from saliva and if positive confirmed from urine. All infants with CMV detected in urine had a Brainstem Auditory Evoked Response (BAER) test by 2-3 weeks of life and if hearing loss was confirmed, offered treatment with valganciclovir for 6 months. Infants who only had CMV detected in the saliva were not included. Results 204,680 newborns received hearing screens between 2019-2023. 7147 (3.5%) did not pass their hearing screening. 509 (7.1%) had hearing loss confirmed on BAER testing. 46 of the 7147 infants who did not pass their initial hearing screen had CMV detected in saliva and 17 of those had CMV detected in urine. 5 patients never received a urine test and were lost to follow-up. Among 17 cases with confirmed congenital CMV, 9 had confirmed hearing loss, 7 had normal hearing, and one lost to follow-up. 12 of the 17 cases were treated with valganciclovir, 8 with confirmed hearing loss, 3 with normal hearing, and one unknown. Among the 8 treated with hearing loss, 3 had progression of hearing loss, one improved, one was unchanged, and 3 lost to follow-up. Among the 7 with congenital CMV and normal hearing at birth, 3 were treated with valganciclovir and 2 remain with normal hearing with one to be determined. Among the 4 not treated, 3 remain with normal hearing and one was lost to follow-up. Among the 6638 with normal hearing on follow-up, 7-13 had congenital CMV (1 in 511-948). Among the 509 with confirmed hearing loss, there were 9 (1.8%) who had congenital CMV. Conclusion Congenital CMV was found in only 1.8% of newborns with hearing loss and about 0.15% of newborns without hearing loss. Treatment with valganciclovir did not appear to be beneficial in preventing the progression of hearing loss in some newborns but the numbers were too small to reach a conclusion. Disclosures All Authors: No reported disclosures

Congenital Cytomegalovirus Infection and Hearing Loss: It's Time to Screen.

Congenital CMV infection is the leading nongenetic cause of sensorineural hearing loss worldwide, yet most parents have never heard of it. The majority of infected newborns have no clinical signs of infection, although a substantial proportion may have hearing loss at birth or develop it later in life. As antiviral treatment with ganciclovir or valganciclovir initiated in the first month of age improves audiologic outcomes, there is an urgent need for timely identification of infected neonates. A targeted approach that tests neonates who refer on the newborn hearing screen has been implemented in many states and hospital programs, but it fails to identify about 40% of children who experience CMV-related hearing loss. A universal screening approach is optimal given the prevalence of congenital CMV infection, its associated sequelae, the availability of a simple saliva screening tool, the available antiviral treatment, and the directed therapies for hearing impairment.

Etiology of Cognitive Deficits in Schizophrenia: a Review of Studies Based on Polygenic Risk Scores

Background: cognitive deficits in schizophrenia have long been believed to reflect the influence of genetic predisposition to the disease. Schizophrenia genome-wide association studies of the last decade have made it possible to test this hypothesis. The aim: to analyze studies on the relationship between cognitive impairment in schizophrenia patients and polygenic risk scores for schizophrenia (SZ-PRS). Additionally, the associations of PRS for intelligence with cognitive deficits in patients and the associations of SZ-PRS with cognitive functions in healthy people were considered. Material and methods: the literature search was carried out in the PubMed database using the following terms: (schizophr* OR schizoaffective* OR psychosis) AND (cogn* OR intelligence OR IQ) AND (GWAS OR polygenic). Results and discussion: from papers published between January 2015 and February 2024, 40 publications met the inclusion criteria. Their analysis indicate that in schizophrenia patients, in contrast to healthy people, the correlation of SZ-PRS with cognitive deficits and premorbid cognitive abilities is absent. Cognitive functions of patients are associated with PRS of intelligence, however, the bulk of the variance in cognitive deficits in schizophrenia, except for the group with intellectual disability, appears to be associated with non-genetic causes. It can be assumed that disease process factors play the most important role. Future studies should be aimed at establishing whether they are directly related to the pathophysiology of the disease, to the influence of concomitant exposures (treatment, hospitalization, etc.) or cognitive reserve, which will contribute to the correction of cognitive deficits.

Combining single nucleotide polymorphisms and gene expression of LEP, FABP4, STAT5A and DGAT1 genes for improvement of body weight in Holstein calves

The objective of this study was to investigate the possible association of single nucleotide polymorphisms and gene expression of leptin (LEP), fatty acid binding protein (FABP4), signal transducer and activator of transcription 5A (STAT5A) and diacylglycerol acyltransferase (DGAT1) genes with body weight in Holstein calves. For the RNA extraction process, blood samples from 100 Holstein bull calves were taken. According to farm records, the acquired bull calves were weaned at a body weight of roughly 90 kg, with birth weights ranging from 31 to 38 kg and weaning ages ranging from 60 to 100 days. To account for the non-genetic causes, the dairy calves' body weight was changed to their 205-day body weight. Nucleotide sequence changes in the form of SNPs were found in the LEP, FABP4, STAT5A, and DGAT1 genes in the investigated Holstein calves. The identified SNPs and corrected 205-day body weight showed a significant correlation (P < 0.05). According to ΔCT values, a significant relationship between the mRNA levels of the LEP, FABP4, STAT5A, and DGAT1 genes and body weight was also found (P < 0.05). The effectiveness of the LEP, FABP4, STAT5A, and DGAT1 genes as proxies for growth qualities in Holstein dairy calves is highlighted by this study. Therefore, it was possible to select an animal with a high rate of growth.

Antiviral Therapy for Congenital Cytomegalovirus Infection: Does It Prevent Late-Onset Sensorineural Hearing Loss?

Abstract Background Congenital cytomegalovirus (CMV) infection is the leading non-genetic cause of sensorineural hearing loss (SNHL) in children. While SNHL is often present at birth, as many as 20% of infants with congenital CMV infection may develop late-onset hearing loss beyond the neonatal period. Antiviral therapy improves hearing outcomes, but its effect on the occurrence of late-onset SNHL is not fully known. The objective is to describe the prevalence of SNHL at birth and late SNHL among infants and children with congenital CMV infection and assess the impact of antiviral treatment on the occurrence of late-onset SNHL. Methods From 2013 to 2022, infants with congenital CMV infection referred to the NEO-ID Clinic at Nationwide Children’s Hospital (NCH), Columbus, OH underwent complete evaluation including hearing testing. Pertinent demographic, clinical, audiologic, laboratory, and radiographic data were obtained and stored using an electronic database (REDCap). Infants with SNHL at birth or who developed late-onset SNHL beyond a month of age were identified and compared with respect to receipt of antiviral therapy in the neonatal period. Results During the 10-year study period, we enrolled 204 infants with congenital CMV infection: 75% (154/204) had symptomatic disease, while 25% (50/204) had clinically inapparent infection (normal physical examination, growth parameters, and evaluation). Overall, 30% (n=62) had SNHL at birth or on follow-up audiologic evaluation with the majority (95%, 59/62) having symptomatic disease. Of the 62 infants with SNHL, 29% (n=18) had late-onset SNHL in one (n=10) or both (n=8) ears at a median age of 19 months (IQR, 8.5-42 months). Of the 122 infants who received antiviral therapy initiated in the first month of age, 12 (10%) developed late-onset SNHL in one (n=7) or both (n=5) ears. All 12 had symptomatic congenital CMV infection, and 2 received cochlear implants in one ear. Of the 82 infants who did not receive any antiviral therapy, 6 (7%) developed late-onset SNHL (3, unilateral [2, symptomatic]; 3, bilateral [1, symptomatic]) and 2 received cochlear implant. There was no difference in the occurrence of late-onset SNHL in treated (10%) vs. untreated (7%) infants with congenital CMV infection (p=0.6). Conclusion In this cohort of mostly symptomatic infants with congenital CMV infection, antiviral treatment did not reduce the occurrence of late-onset SNHL. Further study on the impact of early antiviral therapy on severity of the SNHL is urgently needed to inform optimal treatment management.

Anti-slit diaphragm antibodies on kidney biopsy identify pediatric patients with steroid-resistant nephrotic syndrome responsive to second-line immunosuppressants

Podocytopathies represent a group of glomerular disorders associated with minimal changes (MC) or focal segmental glomerulosclerosis (FSGS) lesion patterns at biopsy and heterogeneous responses to steroids. Anti-nephrin antibodies were previously found in such patients, suggesting an autoimmune form of podocytopathy. High resolution confocal microscopy on kidney biopsies of a cohort of 128 pediatric patients revealed localization of IgG along the slit diaphragm in 30% of patients with MC and 25% of those with FSGS, but not in other lesion patterns. Anti-nephrin IgG ELISA assay in the serum and stimulated emission depletion microscopy of kidney biopsies showed IgG-nephrin co-localization only in 77.8% of cases. Similar observations were obtained in a cohort of 48 adult patients with MC or FSGS at kidney biopsy, where IgG-nephrin colocalization was only 44.4%, suggesting the existence of autoantibodies binding to other slit proteins. Patients with anti-slit antibodies showed nephrotic syndrome at onset in 94.4% of cases. Patients with primary steroid-resistance had anti-slit antibodies in 27%, while those with secondary steroid-resistance in 87.5% of cases, irrespective of the histopathological lesion pattern. Steroid-resistant patients with anti-slit antibodies responded to second-line immunosuppressants in 92.3% vs. only 20% of patients that were anti-slit negative. No patient with anti-slit antibodies developed kidney failure vs. 51.7% of those negative for antibodies (66.7% with a genetic cause and 41.2% with a non-genetic cause). Thus, the detection of anti-slit antibodies can identify patients with an autoimmune podocytopathy responsive to treatment with second-line immunosuppressants, irrespective of the histopathological lesion pattern at biopsy.

Statins and the risk of colorectal cancer; a systematic review and meta-analysis of cohort and case-control studies

Introduction: Colorectal malignancy is the third furthermost frequent malignancy in the world, and approximately 80% of the cases are related to nongenetic causes, including high cholesterol levels. Accordingly, the present systematic review and meta-analysis aimed to investigate the relationship between statin treatment and the risk of colorectal cancer. Materials and Methods: The current study was a systematic review and meta-analysis designed based on PRISMA. International databases, including PubMed, Scopus, Web of Science, Cochrane, and Google Scholar search engine, were used to search for studies published until July 7, 2023. Data analysis was directed by STATA software version 14, and P values below than 0.05 (P<0.05) indicated the significance of statistical tests. Results: The results obtained from a combination of 30 studies with 2436650 samples indicated that statin use increased the risk of colorectal malignancy by 11% (OR: 0.89; 95% CI: 0.84, 0.95) and reduced the risk of rectal cancer by 16% (R: 0.84; 95% CI: 0.74, 0.94). Instead, statin administration reduced the hazard of colorectal cancer in individuals aged 50 to 59 by 22% (R: 0.78; 95% CI: 0.63, 0.95), 60 to 69 by 14% (OR: 0.86; 95% CI: 0.75, 0.98), and 70 to 79 by 8% (OR: 0.92; 95% CI: 0.87, 0.98). Utilization of statin in male (OR: 0.71; 95% CI: 0.58, 0.87) and female (OR: 0.84; 95% CI: 0.77, 0.92) patients reduced the risk of colorectal cancer by 29% and 16%, respectively. Furthermore, statin use in men (OR: 0.41; 95% CI: 0.26, 0.67) and women (OR: 0.64; 95% CI: 0.42, 0.97) reduced the risk of colon cancer by 59% and 36%, respectively. Conclusion: Statin administration reduced the risk of colorectal cancer, and the possibility of reduction in risk of colorectal cancer at lower ages was higher than in older adults and also higher in males compared with females. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (CRD42023450984) and Research Registry (UIN: reviewregistry1779) website.

Establishing a national linked database for Fetal Alcohol Spectrum Disorder (FASD) in the UK: multi-method public and professional involvement to determine acceptability and feasibility.

Fetal Alcohol Spectrum Disorder (FASD) is one of the leading non-genetic causes of developmental disability worldwide and is thought to be particularly common in the UK. Despite this, there is a lack of data on FASD in the UK. To conduct public and professional involvement work to establish stakeholder views on the feasibility, acceptability, key purposes, and design of a national linked longitudinal research database for FASD in the UK. We consulted with stakeholders using online workshops (one for adults with FASD [and their supporters] N = 5; one for caregivers of people with FASD (N=7), 1:1/small-team video calls/email communication with clinicians, policymakers, data-governance experts, third-sector representatives, and researchers [N=35]), and one hybrid clinical workshop (N = 17). Discussions covered data availability, benefits, challenges, and design preferences for a national pseudonymised linked database for FASD. We derived key themes from the notes and recordings collected across all involvement activities. Our tailored, multi-method approach generated high levels of stakeholder engagement. Stakeholders expressed support for a pseudonymised national linked database for FASD. Key anticipated benefits were the potential for: increased awareness and understanding of FASD leading to better support; new insights into clinical profiles leading to greater diagnostic efficiency; facilitating international collaboration; and increased knowledge of the long-term impacts of FASD on health, social care, education, economic and criminal justice outcomes. Given the rich data infrastructure established in the UK, stakeholders expressed that a national linked FASD database could be world-leading. Common stakeholder concerns were around privacy and data-sharing and the importance of retaining space for clinical judgement alongside insights gained from quantitative analyses. Multi-method and multidisciplinary public and professional involvement activities demonstrated support for a national linked database for FASD in the UK. Flexible, diverse, embedded stakeholder collaboration will be essential as we establish this database.

Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a disorder of fatty acid oxidation and considered an inborn error of metabolism. In recent years, we have diagnosed an increasing number of patients where, despite extensive investigation, no disease-causing mutations have been found. We therefore investigated a cohort of consecutive patients, with the objective to detect possible non-genetic causes. We searched the patient records and the registry of muscle biopsies, for patients with MADD, diagnosed within the past 10 years. The patient records were reviewed regarding symptoms, clinical findings, comorbidities, drugs, diagnostic investigations, and response to treatment. In addition, complementary investigations of muscle tissue were performed. We identified 9 patients diagnosed with late-onset MADD. All presented with muscle weakness and elevated levels of creatine kinase. A lipid storage myopathy was evident in the muscle biopsies, as was elevated acylcarnitines in blood. Despite thorough genetic investigations, a probable genetic cause was found in only 2 patients. Remarkably, all 7 patients without disease-causing mutations were treated with sertraline. In some cases, a deterioration of symptoms closely followed dose increase, and discontinuation resulted in an improved acylcarnitine profile. All 9 patients responded to riboflavin treatment with normalization of creatine kinase and muscle biopsy findings, and in 8 patients the clinical symptoms clearly improved. Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients. Importantly, riboflavin treatment seems to be similarly effective as in genetic MADD, but discontinuation of sertraline is reasonably warranted. ANN NEUROL 2024;96:802-811.

Behind the Genetics: The Role of Epigenetics in Infertility-Related Testicular Dysfunction.

In recent decades, we have witnessed a progressive decline in male fertility. This is partly related to the increased prevalence of chronic diseases (e.g., obesity and diabetes mellitus) and risky lifestyle behaviors. These conditions alter male fertility through various non-genetic mechanisms. However, there is increasing evidence that they are also capable of causing sperm epigenetic alterations, which, in turn, can cause infertility. Furthermore, these modifications could be transmitted to offspring, altering their general and reproductive health. Therefore, these epigenetic modifications could represent one of the causes of the progressive decline in sperm count recorded in recent decades. This review focuses on highlighting epigenetic modifications at the sperm level induced by non-genetic causes of infertility. In detail, the effects on DNA methylation, histone modifications, and the expression profiles of non-coding RNAs are evaluated. Finally, a focus on the risk of transgenerational inheritance is presented. Our narrative review aims to demonstrate how certain conditions can alter gene expression, potentially leading to the transmission of anomalies to future generations. It emphasizes the importance of the early detection and treatment of reversible conditions (such as obesity and varicocele) and the modification of risky lifestyle behaviors. Addressing these issues is crucial for individual health, in preserving fertility, and in ensuring the well-being of future generations.

Human Cytomegalovirus Dysregulates Cellular Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases and Sonic Hedgehog Pathway Proteins in Neural Astrocyte and Placental Models.

Human cytomegalovirus (CMV) infection is the leading non-genetic cause of congenital malformation in developed countries, causing significant fetal injury, and in some cases fetal death. The pathogenetic mechanisms through which this host-specific virus infects then damages both the placenta and the fetal brain are currently ill-defined. We investigated the CMV modulation of key signaling pathway proteins for these organs including dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and Sonic Hedgehog (SHH) pathway proteins using human first trimester placental trophoblast (TEV-1) cells, primary human astrocyte (NHA) brain cells, and CMV-infected human placental tissue. Immunofluorescence demonstrated the accumulation and re-localization of SHH proteins in CMV-infected TEV-1 cells with Gli2, Ulk3, and Shh re-localizing to the CMV cytoplasmic virion assembly complex (VAC). In CMV-infected NHA cells, DYRK1A re-localized to the VAC and DYRK1B re-localized to the CMV nuclear replication compartments, and the SHH proteins re-localized with a similar pattern as was observed in TEV-1 cells. Western blot analysis in CMV-infected TEV-1 cells showed the upregulated expression of Rb, Ulk3, and Shh, but not Gli2. In CMV-infected NHA cells, there was an upregulation of DYRK1A, DYRK1B, Gli2, Rb, Ulk3, and Shh. These in vitro monoculture findings are consistent with patterns of protein upregulation and re-localization observed in naturally infected placental tissue and CMV-infected ex vivo placental explant histocultures. This study reveals CMV-induced changes in proteins critical for fetal development, and identifies new potential targets for CMV therapeutic development.

Chromosomal abnormalities in primary and secondary amenorrhea

Background: Menstruation is an important physiological function of the female reproductive system. The absence of menstruation is called amenorrhea. Many genetic and nongenetic causes are responsible for primary or secondary amenorrhea. This study aimed to determine the types chromosomal abnormalities among patients with primary or secondary amenorrhea. Methods: It was a cross-sectional study conducted in the Department of Pathology, Bangabandhu Sheikh Mujib Medical University, Dhaka, from September 2019 to August 2021. A total of 115 women who had come for a karyotype test with complaints of pathological amenorrhea were purposively selected. One hundred five cases presented with primary amenorrhea, and 10 cases presented with secondary amenorrhea. Karyotype analysis in peripheral blood by G-banding was carried out using the standard method. Results: Among the 105 patients with primary amenorrhea, 53.3% of patients had a normal karyotype (46, XX), and 46.6% had chromosomal abnormalities (numerical or structural). Turner syndrome classic, 45, XO (16.2%) and 46, XY DSD (Disorders of Sexual Development) (11.4%) were the two most frequent chromosomal abnormalities found in the patients with primary amenorrhea. Among the 10 cases with secondary amenorrhea, seven patients had normal karyotype, and three patients had chromosomal abnormalities (2 had sex chromosomal abnormalities, and 1 had a structural abnormality of autosome). Conclusion: The study of chromosomal abnormalities will help in the early and accurate diagnosis of the underlying aetiology of primary or secondary amenorrhea. It will also help in the management and proper counselling of cases.

Effects of prenatal alcohol exposure on the olfactory system development.

Fetal Alcohol Spectrum Disorders (FASD), resulting from maternal alcohol consumption during pregnancy, are a prominent non-genetic cause of physical disabilities and brain damage in children. Alongside common symptoms like distinct facial features and neurocognitive deficits, sensory anomalies, including olfactory dysfunction, are frequently noted in FASD-afflicted children. However, the precise mechanisms underpinning the olfactory abnormalities induced by prenatal alcohol exposure (PAE) remain elusive. Utilizing rodents as a model organism with varying timing, duration, dosage, and administration routes of alcohol exposure, prior studies have documented impairments in olfactory system development caused by PAE. Many reported a reduction in the olfactory bulb (OB) volume accompanied by reduced OB neuron counts, suggesting the OB is a brain region vulnerable to PAE. In contrast, no significant olfactory system defects were observed in some studies, though subtle alterations might exist. These findings suggest that the timing, duration, and extent of fetal alcohol exposure can yield diverse effects on olfactory system development. To enhance comprehension of PAE-induced olfactory dysfunctions, this review summarizes key findings from previous research on the olfactory systems of offspring prenatally exposed to alcohol.

Risk Factors for Intracerebral Hemorrhage: Genome-Wide Association Study and Mendelian Randomization Analyses.

The genetic and nongenetic causes of intracerebral hemorrhage (ICH) remain obscure. The present study aimed to uncover the genetic and modifiable risk factors for ICH. We meta-analyzed genome-wide association study data from 3 European biobanks, involving 7605 ICH cases and 711 818 noncases, to identify the genomic loci linked to ICH. To uncover the potential causal associations of cardiometabolic and lifestyle factors with ICH, we performed Mendelian randomization analyses using genetic instruments identified in previous genome-wide association studies of the exposures and ICH data from the present genome-wide association study meta-analysis. We performed multivariable Mendelian randomization analyses to examine the independent associations of the identified risk factors with ICH and evaluate potential mediating pathways. We identified 1 ICH risk locus, located at the APOE genomic region. The lead variant in this locus was rs429358 (chr19:45411941), which was associated with an odds ratio of ICH of 1.17 (95% CI, 1.11-1.20; P=6.01×10-11) per C allele. Genetically predicted higher levels of body mass index, visceral adiposity, diastolic blood pressure, systolic blood pressure, and lifetime smoking index, as well as genetic liability to type 2 diabetes, were associated with higher odds of ICH after multiple testing corrections. Additionally, a genetic increase in waist-to-hip ratio and liability to smoking initiation were consistently associated with ICH, albeit at the nominal significance level (P<0.05). Multivariable Mendelian randomization analysis showed that the association between body mass index and ICH was attenuated on adjustment for type 2 diabetes and further that type 2 diabetes may be a mediator of the body mass index-ICH relationship. Our findings indicate that the APOE locus contributes to ICH genetic susceptibility in European populations. Excess adiposity, elevated blood pressure, type 2 diabetes, and smoking were identified as the chief modifiable cardiometabolic and lifestyle factors for ICH.

On the Hunt for the Missed Genetic Causes of Multiple Primary Tumors.

Improved cancer screening and treatment programs have led to an increased survivorship of patients with cancer, but consequently also to the rise in number of individuals with multiple primary tumors (MPT). Germline testing is the first approach investigating the cause of MPT, as a positive result provides a diagnosis and proper clinical management to the affected individual and their family. Negative or inconclusive genetic results could suggest non-genetic causes, but are negative genetic results truly negative? Herein, we discuss the potential sources of missed genetic causes and highlight the trove of knowledge MPT can provide. See related article by Borja et al., p. 209.

Genetic aspects of ataxias in a cohort of Turkish patients

IntroductionAtaxia is one of the clinical findings of the movement disorder disease group. Although there are many underlying etiological reasons, genetic etiology has an increasing significance thanks to the recently developing technology. The aim of this study is to present the variants detected in WES analysis excluding non-genetic causes, in patients with ataxia.MethodsThirty-six patients who were referred to us with findings of ataxia and diagnosed through WES or other molecular genetic analysis methods were included in our study. At the same time, information such as the onset time of the complaints, consanguinity status between parents, and the presence of relatives with similar symptoms were evaluated. If available, the patient’s biochemical and radiological test results were presented.ResultsThirty-six patients were diagnosed through WES or CES. The rate of detected autosomal recessive inheritance disease was 80.5%, while that of autosomal dominant inheritance disease was 19.5%. Abnormal cerebellum was detected on brain MRI images in 26 patients, while polyneuropathy was detected on EMG in eleven of them. While the majority of the patients were compatible with similar cases reported in the literature, five patients had different/additional features (variants in MCM3AP, AGTPBP1, GDAP2, and SH3TC2 genes).ConclusionsThe diagnosis of ataxia patients with unknown etiology is made possible thanks to these clues. Consideration of a genetic approach is recommended in patients with ataxia of unknown etiology.

What Causes Premature Coronary Artery Disease?

This review provides an overview of genetic and non-genetic causes of premature coronary artery disease (pCAD). pCAD refers to coronary artery disease (CAD) occurring before the age of 65years in women and 55years in men. Both genetic and non-genetic risk factors may contribute to the onset of pCAD. Recent advances in the genetic epidemiology of pCAD have revealed the importance of both monogenic and polygenic contributions to pCAD. Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with atherosclerotic pCAD. However, clinical overreliance on monogenic genes can result in overlooked genetic causes of pCAD, especially polygenic contributions. Non-genetic factors, notably smoking and drug use, are also important contributors to pCAD. Cigarette smoking has been observed in 25.5% of pCAD patients relative to 12.2% of non-pCAD patients. Finally, myocardial infarction (MI) associated with spontaneous coronary artery dissection (SCAD) may result in similar clinical presentations as atherosclerotic pCAD. Recognizing the genetic and non-genetic causes underlying pCAD is important for appropriate prevention and treatment. Despite recent progress, pCAD remains incompletely understood, highlighting the need for both awareness and research.

Large-scale gene expression changes in APP/PSEN1 and GFAP mutation models exhibit high congruence with Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with both genetic and non-genetic causes. Animal research models are available for a multitude of diseases and conditions affecting the central nervous system (CNS), and large-scale CNS gene expression data exist for many of these. Although there are several models specifically for AD, each recapitulates different aspects of the human disease. In this study we evaluate over 500 animal models to identify those with CNS gene expression patterns matching human AD datasets. Approaches included a hypergeometric based scoring system that rewards congruent gene expression patterns but penalizes discordant gene expression patterns. The top two models identified were APP/PS1 transgenic mice expressing mutant APP and PSEN1, and mice carrying a GFAP mutation that is causative of Alexander disease, a primary disorder of astrocytes in the CNS. The APP/PS1 and GFAP models both matched over 500 genes moving in the same direction as in human AD, and both had elevated GFAP expression and were highly congruent with one another. Also scoring highly were the 5XFAD model (with five mutations in APP and PSEN1) and mice carrying CK-p25, APP, and MAPT mutations. Animals with the APOE3 and 4 mutations combined with traumatic brain injury ranked highly. Bulbectomized rats scored high, suggesting anosmia could be causative of AD-like gene expression. Other matching models included the SOD1G93A strain and knockouts for SNORD116 (Prader-Willi mutation), GRID2, INSM1, XBP1, and CSTB. Many top models demonstrated increased expression of GFAP, and results were similar across multiple human AD datasets. Heatmap and Uniform Manifold Approximation Plot results were consistent with hypergeometric ranking. Finally, some gene manipulation models, including for TYROBP and ATG7, were identified with reversed AD patterns, suggesting possible neuroprotective effects. This study provides insight for the pathobiology of AD and the potential utility of available animal models.

Case of Autoimmune Haemolytic Anaemia (Aiha) in an Immunocompetent 1-Month-Old Child with Congenital Cytomegalovirus (cCMV) Infection

Here we report a case of congenital CMV infection with rare presentation as haemolytic anaemia in a 50-day-old infant. Clinical manifestations of our patient were pallor, jaundice, hepatosplenomegaly, and a deranged coagulation profile. Congenital CMV being the most common viral congenital infection should be suspected in every neonate and infant presenting with haemolytic anaemia. It is also the most common non-genetic cause of SNHL and not much is yet there for its prevention except for primary prevention as the role of immunoglobulin is still under trial.

Molecular Pathways and Animal Models of Tetralogy of Fallot and Double Outlet Right Ventricle.

Tetralogy of Fallot and double-outlet right ventricle are outflow tract (OFT) alignment defects situated on a continuous disease spectrum. A myriad of upstream causes can impact on ventriculoarterial alignment that can be summarized as defects in either i) OFT elongation during looping morphogenesis or ii) OFT remodeling during cardiac septation. Embryological processes underlying these two developmental steps include deployment of second heart field cardiac progenitor cells, establishment and transmission of embryonic left/right information driving OFT rotation and OFT cushion and valve morphogenesis. The formation and remodeling of pulmonary trunk infundibular myocardium is a critical component of both steps. Defects in myocardial, endocardial, or neural crest cell lineages can result in alignment defects, reflecting the complex intercellular signaling events that coordinate arterial pole development. Importantly, however, OFT alignment is mechanistically distinct from neural crest-driven OFT septation, although neural crest cells impact indirectly on alignment through their role in modulating signaling during SHF development. As yet poorly understood nongenetic causes of alignment defects that impact the above processes include hemodynamic changes, maternal exposure to environmental teratogens, and stochastic events. The heterogeneity of causes converging on alignment defects characterizes the OFT as a hotspot of congenital heart defects.