Gene Variants Research Articles

Exome Profiling Suggests Combined Effect of Myeloperoxidase, Toll-Like Receptors, and Metallopeptidase in Hidradenitis Suppurativa

Background: Hidradenitis suppurativa, also called acne inversa, is a chronic skin inflammatory condition involving hair follicles, sebaceous glands, and apocrine glands. Symptoms can be variable in intensity, ranging from mild to severe. The exact causes of hidradenitis suppurativa are not fully understood, but the etiology is presumed to be multifactorial, encompassing genetics and environmental factors. Methods: Two families presented with hidradenitis suppurativa with an autosomal dominant pattern. We performed whole-exome sequencing in two unrelated patients from the two families. Results: We identified two and three variants in the two families, respectively. Variants involved the TLR2 and MPO genes in the first family and the MMP2, GJB2, and TLR4 genes, some of which have already been previously reported as possible candidates for hidradenitis suppurativa. Conclusion: It is very likely that variants in a single gene only rarely cause the condition and that most cases, especially familial hidradenitis suppurativa cases, may more probably take the form of polygenic disorders.

Journey Through Autosomal-Recessive Spastic Ataxia of Charlevoix-Saguenay: Insights From a Case Series of Seven Patients-A Single-Center Study and Review of an Indian Cohort.

In this study, we describe the clinical and investigative profiles of 7 cases of autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). We performed a retrospective chart review of genetically proven cases of ARSACS from our database. Additionally, we reviewed the literature for reported cases of ARSACS from India. All 7 patients experienced disease onset within the first decade of life. According to the available data, all patients had walking difficulty (7/7), spastic ataxia (7/7), classical neuroimaging findings (7/7), sensory‒motor demyelinating polyneuropathy (6/6), abnormal evoked potentials (5/5), and a thickened retinal nerve fiber layer (3/3). Exome sequencing revealed 8 unique pathogenic/likely pathogenic variants (6 novel) in the SACS gene. An additional 21 cases (18 families) of ARSACS that could be identified from India had similar clinical and investigational findings. The most common c.8793delA variant may have a founder effect. Our series adds to the previously reported cases of ARSACS from India and expands the genetic spectrum by adding 6 novel variants.

Persistent renal dysfunction post-chemotherapy: a diagnostic conundrum in pediatric cancer survivorship – a case report

BackgroundLate-onset type II Bartter syndrome is an exceedingly rare condition, with only six documented cases presenting symptoms and signs beyond infancy. We report a unique case of late-onset type II Bartter syndrome with an atypical presentation and clinical course following chemotherapy treatment during childhood.Case presentationA 10-year-old boy, diagnosed with hepatoblastoma at age 2 and treated with cisplatin and epirubicin, presented with polyuria, polydipsia, failure to thrive, and electrolyte imbalances. He exhibited hypokalemia, metabolic alkalosis, and elevated urinary excretion of sodium, chloride, calcium, and magnesium. Whole exome sequencing and Sanger sequencing identified compound heterozygous variants in the KCNJ1 gene, confirming the diagnosis of type II Bartter syndrome. The patient’s clinical presentation was distinct from previously reported cases, with an absence of nephrocalcinosis, unusually small and hyperechoic kidneys, and a substantial decline in kidney function. Treatment included oral potassium supplementation, spironolactone, and angiotensin-converting enzyme inhibitors.ConclusionsThis case highlights the importance of considering late-onset Bartter syndrome in patients with a history of chemotherapy presenting with persistent electrolyte imbalances and ongoing renal dysfunction. The atypical features and rapid progression of chronic kidney disease in this patient may be attributed to the deleterious nature of the identified variants and the potential impact of previous chemotherapy on kidney susceptibility to damage. Careful monitoring and management of electrolyte imbalances and renal function are crucial in such cases.

C3 glomerulonephritis with genetically confirmed C3 deficiency in a pediatric patient: a case report

Complement component 3 glomerulonephritis (C3GN) is a rare kidney disease characterized by complement dysregulation that results in prominent complement component 3 (C3) deposition in the kidneys. The clinical course of C3GN varies from mild hematuria to progressive chronic kidney disease. In most patients, C3GN is driven by acquired factors, namely, autoantibodies that target C3 or C5 convertases. Genetic variations in complement-related genes are less frequent. We report the case of a 9-yearold Korean boy who presented with microscopic hematuria and a persistently low C3 level and had biopsy findings of C3GN, with the presence of a C3 gene mutation: a frameshift mutation associated with C3 deficiency. However, the patient did not exhibit any other symptoms of complement deficiency. Direct DNA sequencing of his family members revealed the same genetic mutation in his father and older brother. This case report is significant because there are very few such reports worldwide concerning gene mutations related to C3 deficiency to be discovered in patients with C3GN. Explaining C3GN pathogenesis is challenging; therefore, additional research is required in the future.

Wpływ polimorfizmu genetycznego na przebieg oraz ciężkość zakażenia wirusem SARS-CoV-2 oraz choroby COVID-19

COVID-19 is severe respiratory and systemic disease with complex pathogenesis and many clinical symptoms, including symptoms from respiratory system, immunology system, cardio-vascular system, haematopoietic system and neurological system. Severe character of the disease is associated with occurrence of respiratory failure, septic shock, multiple organ dysfunctions syndrome, which can lead to patients death due to cardiac arrest. Knowledge about interactions between the virus and human proteins as well as knowledge of immunological mechanisms against infection is a key to identifying the area of virus activity and severity factors of COVID-19. Multiple variants of genes encoding proteins involved in host cell invasion by SARS-CoV-2 virus have been identified: ACE2 i TMPRSS2, TMPRSS11A (HGNC:27954), ELANE (HGNC:3309) oraz CTSL (HGNC:2537), IL-6 rs1800795 variant associated with an increased risk of COVID-19, variant rs35705950:G>T located in the promoter of the MUC5B gene (11p15.5), encoding a protein that plays a key role in maintaining the proper function of the bronchoalveolar epithelium, having a protective effect against the form of the disease requiring hospitalization of the patient, as well as GC rs2282679 gene variant in the vitamin D binding protein associated with a more severe course of COVID-19. 48 of these variants were proved to be directly specific for some populations. Novel techniques of genome analysis enabled the research of the impact of specific polymorphism variants on the severity of various diseases including, COVID-19. Genetic factors analysis can permit understanding of disease pathogenesis, which is a chance to find effective treatment and prevention methods. Collected data from literature indicate that, in the case of COVID-19 disease, there are genes polymorphisms which affect the severity course.

CYP2C19 Genetic Variants and Major Depressive Disorder: A Systematic Review

Major depressive disorder (MDD) affects over 300 million people globally and has a multifactorial etiology. The CYP2C19 enzyme, involved in metabolizing certain antidepressants, can influence treatment response. Following the PRISMA protocol and PECOS strategy, this systematic review assessed the variation in common CYP2C19 gene variants’ frequencies across populations with MDD, evaluating their impact on clinical characteristics and treatment response. We comprehensively searched five databases, identifying 240 articles, of which only nine within the last decade met our inclusion criteria. Except for one study that achieved 74.28% of STROPS items, the rest met at least 75% of GRIPS and STROPS guidelines for quality and bias risk assessment. The CYP2C19’s *1 allele, the *1/*1 genotype, and the NM phenotype, considered as references, were generally more frequent. Other CYP2C19 polymorphism frequencies exhibit significant variability across different populations. Some studies associated variants with MDD development, a more extended history of depression, prolonged depressive episodes, and symptom severity, while others reported no such association. Some studies confirmed variants’ effects on escitalopram and citalopram metabolism but not that of other drugs, such as sertraline, venlafaxine, and bupropion. Treatment tolerability and symptom improvement also varied between studies. Despite some common findings, inconsistencies highlight the need for further research to clarify the role of these polymorphisms in MDD and optimize treatment strategies.

Investigation of an MCM8 gene variant in women with premature ovarian insufficiency

Investigation of an MCM8 gene variant in women with premature ovarian insufficiency

The role of candidate pharmacogenetic variants in determining valproic acid efficacy, toxicity and concentrations in patients with epilepsy

BackgroundAntiseizure medications (ASM) exhibit considerable interindividual variability in terms of efficacy and adverse events. Genetic variation is thought to contribute to these differences in clinical outcomes. Specifically, the response to valproic acid (VPA), a widely used ASM, is influenced by multiple pharmacogenetic factors. However, and in contrast to other ASMs such as phenytoin and carbamazepine, there is a paucity of data on the association between VPA and various gene variants. The aim of this study was hence to evaluate the influence of candidate pharmacogenetic variants on VPA efficacy, toxicity and serum concentrations in a homogeneous cohort of patients newly diagnosed with genetic generalized epilepsies (GGE).MethodsIn this prospective cohort study, demographic, clinical and treatment outcomes of GGE patients were retrieved from their medical records. Whole exome sequencing was performed in collaboration with Epi25. Gene variants associated with VPA efficacy, metabolism and toxicities were retrieved from PharmGKB. An analysis was then conducted to explore potential associations between these gene variants and VPA clinical outcomes.ResultsOf the 166 patients included, 60 (36.1%) experienced treatment failure while 106 (63.9%) achieved treatment success. After adjusting for VPA maintenance dose, carriers of the rs3892097 (CYP2D6) variant were 2.5 times more likely to experience treatment failure compared to wildtype (p = 0.026). The rs1057910 variant (CYP2C9*3) was associated with increased serum VPA concentrations (p = 0.034). Moreover, the rs1137101 variant (LEPR gene, a metabolism regulator) was significantly associated with a higher risk of weight gain (regression coefficient of 3.430 [0.674; 6.186], p = 0.015) and a higher frequency of hair loss (OR = 3.394 [1.157; 9.956], p = 0.026), while the rs4480 variant (SOD2 gene, encoding for a mitochondrial scavenging enzyme) was correlated with a lower frequency of hair loss (OR = 0.276 [0.089; 0.858], p = 0.026).ConclusionThese findings highlight the role of genetic factors in VPA treatment and underscore the potential for developing therapeutic strategies to enhance patient outcomes and minimize adverse effects.

Variants that get straight to your heart – Cardiogenetic secondary findings in exome sequencing

BackgroundExome sequencing has been established as a fundamental tool in genetic diagnostics. It may also provide information about variants in genes unrelated to the primary purpose, so-called secondary findings. Especially, diagnoses of unnoticed inborn cardiac diseases are of high clinical relevance due to therapeutic options in context of prevention of sudden cardiac death. MethodsExome data of 9962 individuals was analysed for relevant cardiogenetic findings. Genes were selected according to ACMG recommendations for secondary findings (v.3.1). First, a filter for (likely) pathogenic variants, published in the ClinVar database, was used. Second, exome data was screened for loss of function (LoF) variants in genes in which LoF is a known disease pathomechanism. All variants were evaluated by geneticists regarding their pathogenicity. ResultsPathogenic or likely pathogenic variants were identified in 136 different individuals (136/9962, 1.4%), with the Low-Density Lipoprotein Receptor gene (LDLR, 24/136, 17.6%) and the Titin gene (TTN, 24/136, 17.6%), being the most frequently affected ones. 31.6% (43/136) of the identified variants had been reported beforehand, while 47.1% (64/136) had not been reported. The remaining cases (29/136, 21.3%) were part of research projects with no written reports. In 26.5% (36/136), the finding would have been missed, if only index patients and not their parents had been screened for secondary findings in case of trio ES. ConclusionAs demonstrated in our study, at least one or two out of one hundred people are likely to carry a pathogenic cardiogenetic variant. Counselling geneticist and clinicians need to be aware of these findings in exome and genome sequencing. Informed consent of the patient regarding the report of secondary findings should absolutely be obtained beforehand.

The potential clinical utility of Whole Genome Sequencing for patients with cancer: evaluation of a regional implementation of the 100,000 Genomes Project.

The 100,000 Genomes Project established infrastructure for Whole Genome Sequencing (WGS) in the United Kingdom. A retrospective study of cancer patients recruited to the 100,000 Genomes Project by the West Midlands Genomics Medicine Centre, evaluating clinical relevance of results. After excluding samples with no sequencing data (1678/4851; 34.6%), 3166 sample sets (germline and somatic) from 3067 participants were sequenced. Results of 1256 participants (41.0%) were interpreted (excluding participants who died (308/3067; 10.0%) or were clinically excluded (1503/3067; 49.0%)). Of these, 323 (25.7%) had no variants in genes which may alter management (Domain 1 genes). Of the remaining 933 participants, 552 (59.2%) had clinical recommendations made (718 recommendations in total). These included therapeutic recommendations (377/933; 40.4%), such as clinical trial, unlicensed or licensed therapies or high TMB recommendations, and germline variants warranting clinical genetics review (85/933; 9.1%). At the last follow up, 20.2% of all recommendations were followed (145/718). However, only a small proportion of therapeutic recommendations were followed (5.1%, 25/491). The 100,000 Genomes Project has established infrastructure and regional experience to support personalised cancer care. The majority of those with successful sequencing had actionable variants. Ensuring GTAB recommendations are followed will maximise benefits for patients.

Cancer Risks in Attenuated and Classical Familial Adenomatous Polyposis: A Nationwide Cohort with Matched, Non-Exposed Individuals: Cancer and surgery in AFAP and FAP patients.

Familial adenomatous polyposis (FAP) is caused by pathogenic variants in the APC gene. FAP is usually categorized according to phenotype: classical FAP (CFAP) and attenuated FAP (AFAP); the latter is considered to have a milder disease course. We aimed to assess the risk of overall and specific cancers in CFAP and AFAP patients compared to matched, non-exposed individuals. All known Danish FAP patients were classified as either CFAP or AFAP and assigned four matched, non-exposed individuals. The risk of overall and specific cancers, and mortality were analyzed. The analysis included 311 CFAP patients, 134 AFAP patients, and 1,600 non-exposed individuals. The overall cancer risk was significantly higher for both CFAP and AFAP patients than for non-exposed individuals, with hazard ratios (HR) of 4.77 (95% confidence interval (CI), 3.61-6.32; P<0.001) for CFAP and 3.22 (95% CI, 2.16-4.80; P<0.001) for AFAP. No significant difference was observed when comparing CFAP and AFAP (HR=1.48; 95% CI, 0.98-2.25; P=0.0646). The HR of colonic cancer was 2.16 (95% CI, 0.99-7.72; P=0.0522) and 2.72 (95% CI, 1.19-6.22; P=0.0177 for CFAP and AFAP), respectively compared to non-exposed and did not differ between CFAP and AFAP patients (HR=0.80; 95% CI, 0.32-2.00; P=0.6278). Mortality was significantly higher in CFAP (HR=2.96; 95% CI, 2.04-4.28; P<0.001), but not in AFAP (HR=1.40; 95% CI, 0.73-2.69; P=0.311). Nationwide data reveal differing risk profiles for specific cancers and mortality in AFAP and CFAP compared to non-exposed individuals. The cancer burden of AFAP necessitates consistent monitoring of these patients.

A New Case of Mitochondrial RNA Helicase SUPV3L1-Associated Neurodegenerative Disease: Ataxia, Spasticity, Optic Atrophy, and Skin Hypopigmentation (ASOASH)

Background: The SUPV3L1 gene encodes ATP-dependent RNA helicase SUPV3L1, which is a part of the mitochondrial degradosome complex or SUV3. SUPV3L1 unwinds secondary structures of mitochondrial RNA (mtRNA) and facilitates the degradation of mtRNA molecules. A nonsense homozygous variant in the SUPV3L1 gene was recently associated with mitochondrial disease. Our study presents the second documented case of SUPV3L1 pathology in humans. Methods: Whole-genome sequencing was performed on the NovaSeq 6000 platform using pair-end reading. Data analysis was performed with an in-house developed pipeline. Results: The 17-year-old female patient exhibited a diverse array of symptoms, including ataxia, spastic paraparesis, cognitive deficit, optic atrophy, and horizontal gaze-evoked nystagmus. Early onset of symptoms, such as ataxic gait and nystagmus, was noted, with subsequent progression of neurological manifestations. At the time of the observation, the proband had extensive regions of hypopigmented skin patches on the body and extremities, which have progressed over time. Whole-genome sequencing revealed compound heterozygous variants in the SUPV3L1 gene: c.272-2A&gt;G and c.1924A&gt;C; p.(Ser642Arg). RNA analysis demonstrated splicing changes attributable to the c.272-2A&gt;G variant. ELISA assay showed increased Complex I content in the patient’s fibroblasts. This case underscores the phenotypic diversity associated with SUPV3L1 mutations, emphasizing the importance of considering mitochondrial RNA helicase dysfunction in the differential diagnosis of neurodegenerative disorders. Further elucidation of the molecular mechanisms underlying SUPV3L1-associated pathology may provide valuable insights into targeted therapeutic interventions.

Clinical phenotype and functional influence of GRIN2A variants in epilepsy-aphasia syndrome.

N-methyl-D-aspartate receptors are glutamate-gated ion channels that play a crucial role in brain function. Numerous inherited or de novo variants in the GRIN2A gene, encoding the GluN2A subunit of the receptor, have been identified in patients with epilepsy. In addition, it is worth noting that GRIN2A variants exhibit a strong correlation with epilepsy-aphasia syndromes, a group of age-dependent epileptic, cognitive, and language disorders with a characteristic electroencephalographic pattern. Whole exome sequencing was conducted in enrolled patients with epilepsy-aphasia syndromes, and GRIN2A variants were screened. The conservation of substituted residues, conformational changes of mutant subunits, and in silico predictions of pathogenicity were thoroughly assessed in our study. Functional alterations of the variants were examined using whole-cell voltage-clamp current recordings while the relative surface expression levels of subunit proteins were assessed via immunofluorescence assays. A summary of previously published GRIN2A missense variants was conducted to investigate the genotypic-phenotypic-functional correlations. Two missense GRIN2A variants (c. 2482A >G/p. M828V, c.2627 T >C/p. I876T) were identified, which are located in the transmembrane helix M4 and C-terminus domain of the GluN2A subunit, respectively. Both variants exhibited reduced current density of NMDARs and surface/total expression levels of GluN2A subunits, while M828V showed a decreased extent of desensitization as well. A further summary of the previously reported GRIN2A variants demonstrated that more variable phenotypes were observed for variants situated in the C-terminus domain or those with loss-of-function effects. Our study expands the phenotypic and functional range of GRIN2A-related disorders. In order to optimally establish the domain-function-phenotype correlations in GRIN2A variants, it is imperative to gather a more extensive set of clinical and functional data. This study has identified two genetic variants of the GRIN2A gene in patients with epilepsy-aphasia syndrome. We assess the variants' harmfulness through a variety of functional experiments, including evaluating the expression level of the mutated protein and the resulting changes in electrophysiological activities. Also, we reviewed previously published papers about GRIN2A variants in epilepsy to learn more about the correlations between their locations, functional changes, and clinical manifestations.

Cutaneous Metastasis of Rectal Cancer as a Diagnostic Challenge: A Clinical Case and Literature Review

Background/Objectives: Metastatic colorectal cancer remains a fatal disease, with a 5-year survival rate lower than 15%. The most common metastatic sites are the lungs and the liver, while skin metastases are very rare and often indicate a poor prognosis with a lower survival rate. Methods. Herein, we present the clinical case of a 62-year-old female patient with rectal cancer metastases to the skin of the anogenital and abdominal regions, diagnosed 2 years after completion of treatment of the underlying disease. Results: Histological examination of the skin lesions revealed adenocarcinoma, and expression of the same immunohistochemical markers was also found in the primary tumor and in the cutaneous metastases. However, next-generation sequencing demonstrated differences in the mutational profiles of the primary tumor and metastasis to the skin. Somatic mutations in the APC, TP53, and PTPN11 genes were revealed in primary rectal adenocarcinoma, but another pathogenic TP53 mutation and a frameshift variant in the DYNC1I1 gene were found in cutaneous metastases. The patient underwent several courses of FOLFOX6 chemotherapy in combination with bevacizumab, but the treatment was unsuccessful. An analysis of 50 clinical cases from the literature concerning various manifestations of cutaneous metastases of rectal cancer showed a median survival of 8.5 months from the time of detection of the skin lesions. Conclusions: In this regard, careful skin examination of patients with rectal cancer and timely detection of cutaneous metastases are essential steps in the follow-up of patients who have undergone treatment of the primary tumor.

Epilepsy in Loeys-Dietz Syndrome: The Rare Concurrence of a Connective Tissue and Neuronal Migration Disorder

We present a 7-year-old girl who presented to our emergency department in active status epilepticus. Seizures responded to standard antiepileptic medications; however, baseline work-up for seizure etiology remained unremarkable. Her new-onset seizures were further investigated via EEG and MRI brain, which revealed focal epileptiform discharges and periventricular nodular heterotopia, respectively. Concurrently, the clinical evaluation revealed extensive marfanoid features, and a personal history of eczema and asthma. Her family history was pertinent for aortic valve disease, asthma, and tall stature. Given the peculiar skeletal features, allergic propensities and coexistent weighty family history, a molecular genetic panel analysis for Marfan Syndrome and Loeys-Dietz Syndrome (LDS) were sought. Genetic testing revealed an underlying heterozygous variant in the TGFBR-1 gene; thereby confirming the presence of LDS. The child had responded well to single antiepileptic agent therapy and was discharged in good condition with regular outpatient cardiac and neurology follow-up. This is a unique case reported of a child with genetically diagnosed LDS concurring with an underlying neuronal migration disorder, manifesting in an acute, severe, and lifethreatening fashion.

Molecular Variation and Phylogeny of Thymidylate Kinase Genes of Candidatus Phytoplasma ziziphi from Different Resistant and Susceptible Jujube Cultivars in China

The thymidylate kinase (tmk) gene is indispensable for the proliferation and survival of phytoplasma. To reveal the molecular variation and phylogeny of the tmk genes of Candidatus phytoplasma ziziphi, in this study, the tmk genes of 50 phytoplasma strains infecting different resistant and susceptible jujube cultivars from different regions in China were amplified and analyzed. Two sequence types, tmk-x and tmk-y, were identified using clone-based sequencing. The JWB phytoplasma strains were classified into three types, type-X, type-Y, and type-XY, based on the sequencing chromatograms of the tmk genes. The type-X and type-Y strains contained only tmk-x and tmk-y genes, respectively. The type-XY strain contained both tmk-x and tmk-y genes. The type-X, type-Y, and type-XY strains comprised 42%, 12%, and 46% of all the strains, respectively. The type-X and type-XY strains were identified in both susceptible and resistant jujube cultivars, while type-Y strain was only identified in susceptible cultivars. Phylogenetic analysis indicated that the tmk genes of the phytoplasmas were divided into two categories: phylo-S and phylo-M. The phylo-S tmk gene was single-copied in the genome, with an evolutionary pattern similar to the 16S rRNA gene; the phylo-M tmk gene was multi-copied, related to PMU-mediated within-genome transposition and between-genome transfer. Furthermore, the phylogenetic tree suggested that the tmk genes shuttled between the genomes of the Paulownia witches’ broom phytoplasma and JWB phytoplasma. These findings provide insights into the evolutionary and adaptive mechanisms of phytoplasmas.

Case report: Double mutations in a patient with early-onset Alzheimer’s disease in China, PSEN2 and IDE variants

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by gradual cognitive decline. Early-onset Alzheimer’s disease (EOAD) is defined as AD occurring before age 65. The main pathogenic gene variants associated with EOAD include PSEN1, PSEN2, and APP. IDE gene has been identified as a risk factor in the pathogenesis of AD. In this study, we report a 33-year-old male with mutations in the PSEN2 gene (c.640G &amp;gt; T, p.V214L) and IDE gene (c.782G &amp;gt; A, p.R261Q). PSEN2 V214L has been reported in five previous cases, and no reported cases have carried IDE R261Q. He had progressive memory decline, his sister carried the same gene mutations but had no clinical manifestations. Neuroimaging revealed mild cortical atrophy. The concentration of Aβ42 in cerebrospinal fluid (CSF) was obviously decreased. In silico predictive models suggested that these mutations are damaging. Our findings indicate that mutations in the PSEN2 and IDE genes may disrupt the normal functioning of their respective proteins, contributing to the pathogenesis of AD.

Adverse effects of CXCR2 deficiency in mice reared under non-gnotobiotic conditions

The family of pro-inflammatory and pro-angiogenic chemokines including Interleukin-8 (IL-8, aka CXCL8) and its homologues (CXCL1,2,3,5,6, and 7) exhibit promiscuous binding and activation of several G-protein-coupled receptors (i.e., CXCR2, CXCR1, and the atypical chemokine receptor (ACKR1)). A high proportion of their biological activity is attributed to CXCR2 activation, thus many CXCR2 inhibitors are in clinical trials for several chronic diseases. However, CXCR2 inhibition is often only investigated acutely in these trials or in Cxcr2−/− mice grown in gnotobiotic conditions. Since humans do not live in germ-free environments, our first goal is to highlight novel retinal and systemic observations in Cxcr2−/− mice grown in non-gnotobiotic conditions that suggest potential harmful consequences of long-term CXCR2 deficiency or blockade. Beyond confirmation of circulating blood/immune cell-related phenotypes, we report novel findings in Cxcr2−/− mice including: (1) delayed dye transit to the retinal vasculature, (2) alterations in the density and distribution of retinal vessels, astrocytes and microglia, (3) decreased electroretinogram a- and b-wave amplitudes, (4) reduced visual acuity, and (5) increased polymorphonuclear cell accumulation in vascular lumina abutting venular walls in the retina and in vital non-ocular tissues (lung and liver). Furthermore, PheWAS of CXCR2 CXCR1, and ACKR1 gene variants using data from UK Biobank participants suggest clinical associations with both retinal and vascular disease phenotypes. We conclude that chronic CXCR2 deficiency in mice contributes to functional damage to the retina and that the long-term safety of CXCR1/2 inhibitors designed for chronic use in humans should be explored before clinical adoption to safeguard sight and overall vascular health.

Association of ACE2 Gene Variants with Adverse Perinatal Outcomes in COVID-19 Infected Pregnant Women in Kazakhstan

SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors located on membranes to enter host cells. Nevertheless, the ACE2 gene primarily encodes for a zinc metalloproteinase, which is a part of the renin–angiotensin system (RAS). ACE2 downregulation results in the deregulation of RAS in favor of pro-fibrosis, pro-apoptosis, oxidative stress, pro-inflammation, aldosterone production and release, and blood vessel contraction axis. ACE2 is highly expressed in the placenta. There are both axes of the RAS system in the placenta. This study aims to assess the perinatal outcomes with ACE2 receptor polymorphisms in pregnant women infected with SARS-CoV-2 during pregnancy. The case-control study was conducted to determine the association of ACE2 single-nucleotide polymorphisms in 171 COVID-19-positive pregnant subjects and 112 control subjects. The recessive mutations of rs2158082 and rs4830974 were associated with an increased risk of low birthweight and preterm birth, whereas the dominant mutation of rs2285666 (CT + TT) was associated with decreased odds of low birthweight. COVID-19 was not a significant factor contributing to the adverse perinatal outcomes in our sampling. These findings may help to clarify the controversy regarding the increased risk of adverse perinatal outcomes observed during COVID-19 as well as provide new perspectives for research on the genetic factors associated with a higher risk of adverse perinatal outcomes.

Analysis of the genetic etiology of CDH23 gene variation in a child with hearing loss.

Analysis of the genetic etiology of CDH23 gene variation in a child with hearing loss.