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BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676.

The advent of clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated nuclease 9 (Cas9) technology has revolutionized the field of genetic engineering, offering unprecedented potential for the targeted manipulation of DNA sequences. Advances in the mechanism of action of the CRISPR-Cas9 system allowed potential applicability for the treatment of genetic diseases. CRISPR-Cas9's mechanism of action involves the use of an RNA guide molecule to target-specific DNA sequences and the Cas9 enzyme to induce precise DNA cleavage. In the context of the CRISPR-Cas9 system, this review covers nonviral delivery methods for gene editing based on peptide internalization. Here, we describe critical areas of discussion such as immunogenicity, emphasizing the importance of safety, efficiency, and cost-effectiveness, particularly in the context of treating single-mutation genetic diseases using advanced editing techniques genetics as prime editor and base editor. The text discusses the versatility of cell-penetrating peptides (CPPs) in forming complexes for delivering biomolecules, particularly ribonucleoprotein for genome editing with CRISPR-Cas9 in human cells. In addition, it emphasizes the promise of combining CPPs with DNA base editing and prime editing systems. These systems, known for their simplicity and precision, hold great potential for correcting point mutations in human genetic diseases. In summary, the text provides a clear overview of the advantages of using CPPs for genome editing with CRISPR-Cas9, particularly in conjunction with advanced editing systems, highlighting their potential impact on clinical applications in the treatment of single-mutation genetic diseases. [ABSTRACT FROM AUTHOR]

Human genetic disorders, arising from a range of genetic irregularities, can significantly affect human physiology, often with limited available treatment options. The development of the CRISPR system, facilitating precise editing of the genome, has opened new avenues for addressing a range of mutations found in various genetic disorders. However, there is currently a lack of comprehensive reviews that specifically address the application of CRISPR in genetic diseases. To bridge this gap, this review focuses on exploring the advancements in CRISPR technology and their utility in therapeutic approaches for various genetic disorders. This review introduces human genetic disorders, explains the fundamental mechanisms of CRISPR editing, and highlights the latest advancements in CRISPR technology. Additionally, it examines three CRISPR delivery techniques, including physical delivery, viral vectors, and nanocarriers. It further reviews CRISPR's applications in therapeutic approaches for genetic disorders. Finally, it identifies the primary hurdles associated with industrial development and ethics considerations that should be addressed before the application of CRISPR in a medical context. [ABSTRACT FROM AUTHOR]

Lipid nanoparticles (LNPs) have emerged as leading non-viral carriers for messenger RNA (mRNA) delivery in clinical applications. Overcoming challenges in safe and effective mRNA delivery to target tissues and cells, along with controlling release from the delivery vehicle, remains pivotal in mRNA-based therapies. This review elucidates the structure of LNPs, the mechanism for mRNA delivery, and the targeted delivery of LNPs to various cells and tissues, including leukocytes, T-cells, dendritic cells, Kupffer cells, hepatic endothelial cells, and hepatic and extrahepatic tissues. Here, we discuss the applications of mRNA–LNP vaccines for the prevention of infectious diseases and for the treatment of cancer and various genetic diseases. Although challenges remain in terms of delivery efficiency, specific tissue targeting, toxicity, and storage stability, mRNA–LNP technology holds extensive potential for the treatment of diseases. [ABSTRACT FROM AUTHOR]

Background: Ectodermal dysplasia (ED) is a rare genetic disorder that affects structures derived from the ectodermal germ layer. Results: In this study, we analyzed the genetic profiles of 27 Korean patients with ED. Whole exome sequencing (WES) was performed on 23 patients, and targeted panel sequencing was conducted on the remaining 4 patients. Among the patients in the cohort, 74.1% (20/27) tested positive for ED. Of these positive cases, EDA and EDAR mutations were found in 80% (16/20). Notably, 23.1% (3/13) of EDA-positive cases exhibited copy number variations. Among the 23 patients who underwent WES, we conducted a virtual panel analysis of eight well-known genes, resulting in diagnoses for 56.5% (13/23) of the cases. Additionally, further analysis of approximately 5,000 OMIM genes identified four more cases, increasing the overall positivity rate by approximately 17%. These findings underscore the potential of WES for improving the diagnostic yield of ED. Remarkably, 94.1% of the patients manifesting the complete triad of ED symptoms (hair/skin/dental) displayed detectable EDA/EDAR mutations. In contrast, none of the 7 patients without these three symptoms exhibited EDA/EDAR mutations. Conclusions: When conducting molecular diagnostics for ED, opting for targeted sequencing of EDA/EDAR mutations is advisable for cases with classical symptoms, while WES is deemed an effective strategy for cases in which these symptoms are absent. [ABSTRACT FROM AUTHOR]

This narrative review explores the potential, complexities, and consequences of using artificial intelligence (AI) to screen large government-held facial image databases for the early detection of rare genetic diseases. Government-held facial image databases, combined with the power of artificial intelligence, offer the potential to revolutionize the early diagnosis of rare genetic diseases. AI-powered phenotyping, as exemplified by the Face2Gene app, enables highly accurate genetic assessments from simple photographs. This and similar breakthrough technologies raise significant privacy and ethical concerns about potential government overreach augmented with the power of AI. This paper explores the concept, methods, and legal complexities of AI-based phenotyping within the EU. It highlights the transformative potential of such tools for public health while emphasizing the critical need to balance innovation with the protection of individual privacy and ethical boundaries. This comprehensive overview underscores the urgent need to develop robust safeguards around individual rights while responsibly utilizing AI's potential for improved healthcare outcomes, including within a forensic context. Furthermore, the intersection of AI and sensitive genetic data necessitates proactive cybersecurity measures. Current and future developments must focus on securing AI models against attacks, ensuring data integrity, and safeguarding the privacy of individuals within this technological landscape. [ABSTRACT FROM AUTHOR]

Genetic testing is the gold standard for diagnosing different epidermolysis bullosa (EB) subtypes; however, testing rates are low. We conducted a pilot study to test feasibility of a novel, home‐based registry that involved patients with EB submitting self‐reported clinical symptoms using secure, online surveys (REDCap) and submitting buccal swabs for exome sequencing of EB‐related genes (GeneDx). In total, 50 EB participants were enrolled, with an average age of 17 years and an average distance of 198 miles from EB specialty centers. All buccal swabs (N = 24) provided sufficient DNA for sequencing without causing mucosal trauma and 80% of participants were found to have pathogenic variants in COL7A1, the gene mutated in DEB. Participants with recessive dystrophic EB (RDEB) reported a higher prevalence of esophageal dilations (65.7% vs. 0%, p =.009) and mitten deformities of the feet (57.1% vs. 0%, p =.047) compared to non‐RDEB participants. [ABSTRACT FROM AUTHOR]

Objectives: Root resorption in permanent teeth is a common pathological process that often follows dental trauma or orthodontic treatment. More rarely, root resorption is a feature of genetic disorders and can help with diagnosis. Thus, the present review aims to determine which genetic disorders could induce pathological root resorptions and thus which mutated genes could be associated with them. Methods: We conducted a systematic review following the PRISMA guidelines. Articles describing root resorptions in patients with genetic disorders were included from PubMed, Embase, Web of Science, and Google Scholar. We synthesized the genetic disorder, the type, severity, and extent of the resorptions, as well as the other systemic and oral symptoms and histological features. Results: The synthetic analysis included 25 studies among 937 identified records. We analyzed 21 case reports, three case series, and one cohort study. Overall, we highlighted 14 different pathologies with described root resorptions. Depending on the pathology, the sites of resorption, their extent, and their severity showed differences. Conclusion: With 14 genetic pathologies suspected to induce root resorptions, our findings are significant and enrich a previous classification. Among them, three metabolic disorders, three calcium–phosphorus metabolism disorders, and osteolysis disorders were identified. [ABSTRACT FROM AUTHOR]

Genotype-phenotype associations in recessive dystrophic epidermolysis bullosa (RDEB) have been difficult to elucidate. To investigate RDEB genotype-phenotype associations and explore a functional approach to genotype classification. Clinical examination and genetic testing of RDEB subjects, including assessment of clinical disease by RDEB subtype and extent of blistering. Genotypes were evaluated according to each variant's effect on type VII collagen function per updated literature and subsequently categorized by degree of impact on VII collagen function as low-impact (splice/missense, missense/missense), medium-impact (premature termination codon [PTC]/missense, splice/splice), and high-impact (PTC/PTC, PTC/splice). Genotype-phenotype associations were investigated using Kruskal-Wallis and Fisher's exact tests, and age-adjusted regressions. Eighty-three participants were included. High-impact variants were associated with worse RDEB subtype and clinical disease, including increased prevalence of generalized blistering (55.6% for low-impact vs 72.7% medium-impact vs 90.4% high-impact variants, P =.002). In age-adjusted regressions, participants with high-impact variants had 40.8-fold greater odds of squamous cell carcinoma compared to low-impact variants (P =.02), and 5.7-fold greater odds of death compared to medium-impact variants (P =.05). Cross-sectional design. Functional genotype categories may stratify RDEB severity; high-impact variants correlated with worse clinical outcomes. Further validation in larger cohorts is needed. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions PTC518 is an orally administered, centrally and peripherally distributed huntingtin (HTT) pre‐mRNA splicing modifier being developed for the treatment of Huntington's disease (HD) for which there is a high unmet medical need as there are currently no approved disease‐modifying treatments. This first‐in‐human study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PTC518 in healthy volunteers.This phase 1, single‐centre, randomized study in 77 healthy male and female volunteers evaluated the safety and tolerability and PK of PTC518 following single ascending doses and multiple ascending doses, PD as assessed by HTT mRNA and HTT protein levels after single and multiple doses, and food effects.PTC518 demonstrated a favourable safety profile. The majority of treatment‐emergent adverse events were mild and transient. PTC518 Tmax was reached at 6–7 h and the terminal T1/2 was 54.0–75.3 h following a single oral dose. Exposure increased with dose though less than dose proportionally. The PTC518 concentrations in cerebrospinal fluid were approximately 2.6‐fold higher than the unbound free‐drug concentrations in plasma. A significant dose‐dependent reduction of up to approximately 60% in HTT mRNA and a significant dose‐dependent, time‐dependent and sustained reduction in HTT protein levels of up to 35% were observed after PTC518 treatment.PTC518 was well tolerated, and proof of mechanism of this novel splicing modifier was demonstrated by the dose‐dependent decrease in systemic HTT mRNA and HTT protein levels. Results from this first‐in‐human study support further studies in patients with HD and demonstrate the potential for PTC518 as a breakthrough treatment for HD. [ABSTRACT FROM AUTHOR]

Introduction and Purpose: In last years gene modification technologies such as CRISPR/Cas9 has had a revolutionary impact on the treatment of inherited diseases. Technologies developed from bacterial defense mechanisms, has become a basic tools in scientific research and medical therapies. In our article we provided an overview of applications of gene modifications technologies, directly focusing on CRISPR/Cas9, in genetic disease treatment. State of Knowledge: New applications of CRISPR/Cas9 are still being explored. Treating inherited diseases such as cystic fibrosis, Duchenne muscular dystrophy, thalassemia, hemophilia, Huntington's disease, Crigler-Najjar syndrome, sickle cell anemia, Marfan syndrome, and phenylketonuria, is feasible with this novel technique. A comparative analysis with other gene editing methods highlights CRISPR/Cas9's efficacy, ease of use, and multiplexing capabilities. Summary: CRISPR/Cas9 is a groundbreaking technology with broad applications in genetic research and therapy. Its ease of use, cost-effectiveness, and ability to target multiple genes simultaneously position it as a preferred method. However, there are some challenges associated with precision issues and ethical considerations in human embryo gene editing. As CRISPR/Cas9 continues to evolve, responsible application and ethical considerations are important for maximizing its potential in treatment of genetic diseases. [ABSTRACT FROM AUTHOR]

Transmembrane and tetratricopeptide repeat 4 (Tmtc4) is a deafness gene in mice. Tmtc4-KO mice have rapidly progressive postnatal hearing loss due to overactivation of the unfolded protein response (UPR); however, the cellular basis and human relevance of Tmtc4-associated hearing loss in the cochlea was not heretofore appreciated. We created a hair cell-specific conditional KO mouse that phenocopies the constitutive KO with postnatal onset deafness, demonstrating that Tmtc4 is a hair cell-specific deafness gene. Furthermore, we identified a human family in which Tmtc4 variants segregate with adult-onset progressive hearing loss. Lymphoblastoid cells derived from multiple affected and unaffected family members, as well as human embryonic kidney cells engineered to harbor each of the variants, demonstrated that the human Tmtc4 variants confer hypersensitivity of the UPR toward apoptosis. These findings provide evidence that TMTC4 is a deafness gene in humans and further implicate the UPR in progressive hearing loss.

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.

Osteogenesis imperfecta (OI), or brittle bone disease, is a disorder characterized by bone fragility and increased fracture incidence. All forms of OI also feature short stature, implying an effect on endochondral ossification. Using the Aga2+/- mouse, which has a mutation in type I collagen, we show an affected growth plate primarily due to a shortened proliferative zone. We used single-cell RNA-Seq analysis of tibial and femoral growth plate tissues to understand transcriptional consequences on growth plate cell types. We show that perichondrial cells, which express abundant type I procollagen, and growth plate chondrocytes, which were found to express low amounts of type I procollagen, had ER stress and dysregulation of the same unfolded protein response pathway as previously demonstrated in osteoblasts. Aga2+/- proliferating chondrocytes showed increased FGF and MAPK signaling, findings consistent with accelerated differentiation. There was also increased Sox9 expression throughout the growth plate, which is expected to accelerate early chondrocyte differentiation but reduce late hypertrophic differentiation. These data reveal that mutant type I collagen expression in OI has an impact on the cartilage growth plate. These effects on endochondral ossification indicate that OI is a biologically complex phenotype going beyond its known impacts on bone to negatively affect linear growth.

Background. Within the framework of the regional pilot project on selective exome screening of newborn children, which is carried out on the basis of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, we conducted molecular genetic testing of children who meet the criteria for inclusion in the increased group of hereditary diseases. We examine not only children with suspected genetic etiology of the condition, but also children with borderline clinical and laboratory manifestations and minor developmental anomalies.The aim of the study. To describe the clinical and phenotypic features of a patient with a previously undescribed Xq12q13.2 duplication detected in the neonatal period.Materials and methods. The child was examined within the framework of a regional pilot project on selective exome screening of newborn children. DNA was isolated from a biological sample of venous blood of the newborn, and whole exome sequencing and chromosomal microarray analysis were performed. Signed informed voluntary consent for the publication of the examination data and a photograph of the child were obtained from the legal representatives of the proband.Results. Data in favor of the presence of a previously undescribed Xq12q13.2 duplication, confirmed by the reference method were obtained in a patient included in the project in accordance with the clinical criteria for the formation of a risk group according to the data of the conducted whole exome sequencing. Discussion. Xq12q13.2 duplication was detected in the proband from the present clinical observation with non-specific clinical manifestations in the neonatal period. Similar duplications have been described in the literature in three patients with congenital malformations, epilepsy and psychomotor retardation. Early diagnosis of such a copy number variation disorder before the appearance of severe clinical signs of the disease will allow determining the prognosis and tactics of observation and treatment of the patient.Conclusion. The described case of Xq12q13.2 duplication in a patient demonstrates the importance of timely genetic analysis to optimize medical genetic counseling, reduce diagnostic search and improve prognosis for patients.

Abstract Background Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous syndrome with variable phenotypes. Recent updates of TSC diagnostic criteria reaffirmed the defined genetic diagnostic criterion as the finding of a pathogenic DNA alteration in either TSC1 or TSC2 genes. It also slightly modified definite clinical diagnostic criteria. TSC-associated skin lesions in infancy are important clinical signs to select individuals with possible TSC for a closer clinical follow-up and genetic testing. Objective To raise awareness of the updated TSC diagnosis criteria; to assess the frequency of skin lesions in TSC patients as well as the first dermatological presentation; and to associate the findings with either TSC1 or TSC2 mutations. Methods Observational cross-sectional study. Clinical and genetic data were retrospectively collected from 37 TSC patients from a Brazilian University Hospital. Patients with skin signs were examined and prospectively assessed for 12 months. Results The earliest cutaneous lesions were hypomelanotic macules, which together with angiofibromas were the most frequent dermatological lesions. The total pathogenic DNA alteration ratio between TSC2 and TSC1 genes was 8:1. The frequency of a TSC2 pathogenic variant was 10-fold greater in the presence of ungual fibromas. Study limitations Small sample and a limited number of patients with TSC1 pathogenic variants. Conclusion Clinicians should be knowledgeable about TSC updated diagnostic criteria. Patients need to be followed up by a multidisciplinary team and treated accordingly. Early detection of cutaneous lesions is important for TSC diagnosis. A significant association between TSC2 gene pathogenic alterations and ungual fibromas is described.

Abstract Hailey-Hailey disease is a rare genodermatosis described in 1939, with an autosomal dominant inheritance pattern, characterized by compromised adhesion between epidermal keratinocytes. It has an estimated prevalence of 1/50,000, with no gender or race predilection. It results from a heterozygous mutation in the ATP2C1 gene, which encodes the transmembrane protein hSPA1C, present in all tissues, with preferential expression in keratinocytes. Mutations in the ATP2C1 gene cause changes in the synthesis of junctional proteins, leading to acantholysis. It usually begins in adulthood, with isolated cases at the extremes of life. It manifests as vesico-bullous lesions mainly in the flexural areas, which develop into erosions and crusts. Chronic lesions may form vegetative or verrucous plaques. Pruritus, a burning feeling and pain are common. It evolves with periods of remission and exacerbation, generally triggered by humidity, friction, heat, trauma and secondary infections. The diagnosis is based on clinical and histopathological criteria: marked suprabasal acantholysis, loosely joined keratinocytes, giving the appearance of a “dilapidated brick wall”, with a few dyskeratotic cells. The acantholysis affects the epidermis and spares the adnexal epithelia, which helps in the differential diagnosis with pemphigus vulgaris. Direct immunofluorescence is negative. The main differential diagnoses are Darier disease, pemphigus vegetans, intertrigo, contact dermatitis, and inverse psoriasis. There is no cure and the treatment is challenging, including measures to control heat, sweat and friction, topical medications (corticosteroids, calcineurin inhibitors, antibiotics), systemic medications (antibiotics, corticosteroids, immunosuppressants, retinoids and immunobiologicals) and procedures such as botulinum toxin, laser and surgery. There is a lack of controlled clinical trials to support the choice of the best treatment.

Abstract Background Ectodermal dysplasia (ED) is a rare genetic disorder that affects structures derived from the ectodermal germ layer. Results In this study, we analyzed the genetic profiles of 27 Korean patients with ED. Whole exome sequencing (WES) was performed on 23 patients, and targeted panel sequencing was conducted on the remaining 4 patients. Among the patients in the cohort, 74.1% (20/27) tested positive for ED. Of these positive cases, EDA and EDAR mutations were found in 80% (16/20). Notably, 23.1% (3/13) of EDA-positive cases exhibited copy number variations. Among the 23 patients who underwent WES, we conducted a virtual panel analysis of eight well-known genes, resulting in diagnoses for 56.5% (13/23) of the cases. Additionally, further analysis of approximately 5,000 OMIM genes identified four more cases, increasing the overall positivity rate by approximately 17%. These findings underscore the potential of WES for improving the diagnostic yield of ED. Remarkably, 94.1% of the patients manifesting the complete triad of ED symptoms (hair/skin/dental) displayed detectable EDA/EDAR mutations. In contrast, none of the 7 patients without these three symptoms exhibited EDA/EDAR mutations. Conclusions When conducting molecular diagnostics for ED, opting for targeted sequencing of EDA/EDAR mutations is advisable for cases with classical symptoms, while WES is deemed an effective strategy for cases in which these symptoms are absent.

This narrative review explores the potential, complexities, and consequences of using artificial intelligence (AI) to screen large government-held facial image databases for the early detection of rare genetic diseases. Government-held facial image databases, combined with the power of artificial intelligence, offer the potential to revolutionize the early diagnosis of rare genetic diseases. AI-powered phenotyping, as exemplified by the Face2Gene app, enables highly accurate genetic assessments from simple photographs. This and similar breakthrough technologies raise significant privacy and ethical concerns about potential government overreach augmented with the power of AI. This paper explores the concept, methods, and legal complexities of AI-based phenotyping within the EU. It highlights the transformative potential of such tools for public health while emphasizing the critical need to balance innovation with the protection of individual privacy and ethical boundaries. This comprehensive overview underscores the urgent need to develop robust safeguards around individual rights while responsibly utilizing AI’s potential for improved healthcare outcomes, including within a forensic context. Furthermore, the intersection of AI and sensitive genetic data necessitates proactive cybersecurity measures. Current and future developments must focus on securing AI models against attacks, ensuring data integrity, and safeguarding the privacy of individuals within this technological landscape.

Abstract The prevalence of consanguineous marriages (CMs) varies worldwide from one country to another. However, the Middle East stands out as a region with a notably high rate of CMs. CM is particularly widespread in Saudi Arabia, where the prevalence of autosomal recessive genetic diseases has increased. This study aims to identify the Saudi population’s awareness of genetic diseases and premarital screening tests (PMSTs). It also seeks to understand couples’ perceptions of genetic diseases before and after marriage and their attitudes towards PMSTs and genetic counselling (GC) in reducing the risk of CM. Through the administration of online questionnaires, this cross-sectional study surveyed 2,057 participants to assess their awareness of genetic diseases and their understanding of testing and preventive measures for inherited diseases. Descriptive analysis, nonparametric chi-square tests and logistic regressions were performed to assess the association of categorical responses. This study included 2,035 Saudi Arabian respondents. A significant correlation was found between positive family history and partner selection (p = 0.001), as well as between partnering within the same tribe (p = 0.000139), with a different tribe (p = 0.000138) and from another family (p = 0.000489). About 91.3% of participants expressed agreement regarding the need to enhance public awareness and knowledge concerning genetic disorders, while 87% agreed that increased government regulations are required to prevent the spread of genetic diseases in affected families. Despite increased awareness of genetic diseases and PMSTs, there appears to be a lack of understanding regarding the limitations of PMSTs. The persistently high rate of CM underscores the challenge of altering marriage customs. Further governmental efforts are required to promote awareness of alternative reproductive options, establish new regulations and expand screening programmes.

The one‐carbon metabolism pathway is involved in critical human cellular functions such as cell proliferation, mitochondrial respiration, and epigenetic regulation. In the homocysteine‐methionine cycle S‐adenosyl‐methionine (SAM) and S‐adenosyl‐homocysteine (SAH) are synthetized, and their levels are finely regulated to ensure proper functioning of key enzymes which control cellular growth and differentiation. Here we review the main biological mechanisms involving SAM and SAH and the known related human diseases. It was recently demonstrated that SAM and SAH levels are altered in plasma of subjects with trisomy 21 (T21) but how this metabolic dysregulation influences the clinical manifestation of T21 phenotype has not been previously described. This review aims at providing an overview of the biological mechanisms which are altered in response to changes in the levels of SAM and SAH observed in DS. [ABSTRACT FROM AUTHOR]

Copyright of Arquivos Brasileiros de Oftalmologia is the property of Arquivos Brasileiros de Oftalmologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Croatian Veterinary Reports / Hrvatski Verinarski Vjesnik is the property of Croatian Veterinary Chamber and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cerebral cavernous malformation (CCM) has variable clinical symptoms, including potentially fatal hemorrhagic stroke. Treatment options are very limited, presenting a large unmet need. REC‐994 (also known as tempol), identified as a potential treatment through an unbiased drug discovery platform, is hypothesized to treat CCMs through a reduction in superoxide, a reactive oxygen species. We investigated the safety, tolerability, and pharmacokinetic profile of REC‐994 in healthy volunteers. Single‐ and multiple‐ascending dose (SAD and MAD, respectively) studies were conducted in adult volunteers (ages 18–55). SAD study participants received an oral dose of REC‐994 or placebo. MAD study participants were randomized 3:1 to oral doses of REC‐994 or matching placebo, once daily for 10 days. Thirty‐two healthy volunteers participated in the SAD study and 52 in the MAD study. Systemic exposure increased in proportion to REC‐994 dose after single doses of 50–800 mg and after 10 days of dosing over the 16‐fold dose range of 50–800 mg. Median Tmax and mean t1/2 were independent of dose in both studies, and the solution formulation was more rapidly absorbed. REC‐994 was well tolerated. Treatment‐emergent adverse effects across both studies were mild and transient and resolved by the end of the study. REC‐994 has a favorable safety profile and was well tolerated in single and multiple doses up to 800 mg with no dose‐limiting adverse effects identified. Data support conducting a phase 2 clinical trial in patients with symptomatic CCM. [ABSTRACT FROM AUTHOR]

In this pilot study, we aimed to evaluate the feasibility of whole genome sequencing (WGS) as a first‐tier diagnostic test for infants hospitalized in neonatal intensive care units in the Brazilian healthcare system. The cohort presented here results from a joint collaboration between private and public hospitals in Brazil considering the initiative of a clinical laboratory to provide timely diagnosis for critically ill infants. We performed trio (proband and parents) WGS in 21 infants suspected of a genetic disease with an urgent need for diagnosis to guide medical care. Overall, the primary indication for genetic testing was dysmorphic syndromes (n = 14, 67%) followed by inborn errors of metabolism (n = 6, 29%) and skeletal dysplasias (n = 1, 5%). The diagnostic yield in our cohort was 57% (12/21) based on cases that received a definitive or likely definitive diagnostic result from WGS analysis. A total of 16 pathogenic/likely pathogenic variants and 10 variants of unknown significance were detected, and in most cases inherited from an unaffected parent. In addition, the reported variants were of different types, but mainly missense (58%) and associated with autosomal diseases (19/26); only three were associated with X‐linked diseases, detected in hemizygosity in the proband an inherited from an unaffected mother. Notably, we identified 10 novel variants, absent from public genomic databases, in our cohort. Considering the entire diagnostic process, the average turnaround time from enrollment to medical report in our study was 53 days. Our findings demonstrate the remarkable utility of WGS as a diagnostic tool, elevating the potential of transformative impact since it outperforms conventional genetic tests. Here, we address the main challenges associated with implementing WGS in the medical care system in Brazil, as well as discuss the potential benefits and limitations of WGS as a diagnostic tool in the neonatal care setting. [ABSTRACT FROM AUTHOR]

Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial disorder primarily resulting from m.3243A>G mutation. The clinical characteristics of MIDD exhibit significant heterogeneity. Our study aims to delineate these characteristics and determine the potential correlation with m.3243A>G heteroplasmy levels. This retrospective, descriptive study encompassed patients with confirmed m.3243A>G mutation and diabetes mellitus at Seoul National University Hospital. Our cohort comprises 40 patients with MIDD, with a mean age at study enrollment of 33.3±12.9 years and an average % of heteroplasmy of 30.0%± 14.6% in the peripheral blood. The most prevalent comorbidity was hearing loss (90%), followed by albuminuria (61%), seizure (38%), and stroke (33%). We observed a significant negative correlation between % of heteroplasmy and age at diabetes diagnosis. These clinical features can aid in the suspicion of MIDD and further consideration of genetic testing for m.3243A>G mutation. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited condition characterized by the growth of multiple bilateral cysts in the kidneys. We describe the case of a 35-year-old male with combined ADPKD and type 1 diabetes mellitus with a strong family history of both. At the age of 32, he developed end-stage kidney disease for which he underwent preemptive simultaneous pancreatic and kidney transplant, which in turn led to multiple perioperative complications. Evaluation of familial clustering of genetic disease is critical in genetic epidemiology and precision medicine as it enables estimation of lifetime disease risk and early assessment as well as detection of the disease among one's siblings. [ABSTRACT FROM AUTHOR]

During meat inspections in pigs, dystrophinopathies are among the muscle lesions targeted for disposal. In this study, the authors examined the lesions and the distribution of dystrophin expression in 25 pigs with dystrophinopathy. In addition, complementary deoxyribonucleic acid (cDNA) sequencing and western blotting were performed in 6 of the 25 cases, all of which were characterized by degeneration, necrosis, and fat replacement of muscle fibers. Comparing the results of immunohistochemistry with anti-dystrophin antibodies that recognized at different sites in the protein, the authors noted that the loss of dystrophin expression was most pronounced in the C-terminus-recognizing antibody (19/25 cases). The authors detected 5 missense mutations and 3 types of shortened transcripts generated by the skipping of exons in the cDNA, which were associated with the pathogenesis. One missense mutation had been reported previously, whereas the remaining mutations identified had not been previously documented in pigs. In the cases with shortened transcripts, normal-sized transcripts were detected together with the defective transcripts, suggesting that these mutations were caused by splicing abnormalities. In addition, they were in-frame mutations, all of which have similar pathogeneses of Becker muscular dystrophy in humans. These cases were 6 months of age and exhibited macroscopic discoloration, fatty replacement, and muscle degeneration, suggesting that the effect of these mutations on skeletal muscle was significant. [ABSTRACT FROM AUTHOR]

ASXL1 (additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression. De novo protein-truncating mutations in ASXL1 cause Bohring-Opitz syndrome (BOS; OMIM #605039), a rare neurodevelopmental condition characterized by severe intellectual disabilities, distinctive facial features, hypertrichosis, increased risk of Wilms tumor, and variable congenital anomalies, including heart defects and severe skeletal defects giving rise to a typical BOS posture. These BOS-causing ASXL1 variants are also high-prevalence somatic driver mutations in acute myeloid leukemia. We used primary cells from individuals with BOS (n = 18) and controls (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations using comprehensive multiomics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral blood and skin fibroblasts. Our data show that regardless of cell type, ASXL1 mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome. The data showed a broad activation of canonical Wnt signaling at the transcriptional and protein levels and upregulation of VANGL2, which encodes a planar cell polarity pathway protein that acts through noncanonical Wnt signaling to direct tissue patterning and cell migration. This multiomics approach identifies the core impact of ASXL1 mutations and therapeutic targets for BOS and myeloid leukemias.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA1 gene, which encodes the enzyme glucocerebrosidase. This enzyme is crucial for breaking down glucocerebrosides, and its deficiency leads to their accumulation in the monocyte-macrophage system, forming Gaucher cells. These cells build up in the bone marrow, spleen, and liver, causing various clinical manifestations. GD is classified into three types based on clinical features and progression: GD1 (non-neuronopathic), GD2 (acute neuronopathic), and GD3 (subacute neuronopathic). GD1, the most common form, usually presents with splenomegaly, hepatomegaly, anemia, thrombocytopenia, and skeletal symptoms and has a relatively mild course. GD2 is marked by severe neurological involvement, with a poor prognosis and a maximum survival of three years. GD3 features a mix of visceral, hematological, neurological, and skeletal symptoms, with a variable prognosis depending on the subtype. Epidemiologically, GD is rare in the general population but more common among Ashkenazi Jews, who have a higher carrier frequency and prevalence. The genetic basis of GD is well-documented, with several mutations associated with different disease severities and outcomes. Diagnostic procedures include a comprehensive medical history, imaging studies, and biochemical and genetic tests to confirm reduced glucocerebrosidase activity and identify GBA1 mutations. Current treatments focus on enzyme replacement therapy (ERT) and substrate reduction therapy (SRT), with supportive care for specific symptoms. ERT is the primary treatment for all children with GD1 and GD3 and for adults who meet certain criteria, while SRT is an alternative for milder forms of GD1. Despite advances in treatment, managing GD remains complex, requiring a multidisciplinary approach to address the diverse clinical manifestations and improve patient outcomes.

Despite the decreasing number of cases, cataract is still the leading cause of visual impairment and blindness worldwide. The search for the causes of this disease, its risk factors and the relationship with systemic diseases is the subject of many studies and attracts the attention of scientists around the world. One of the most common cause of cataract and probably the most frequently reported in the literature, is aging. Other commonly described causes of cataracts are external factors and acquired diseases. Although genetic diseases are not the most common disorders associated with the occurrence and development of cataract, this review takes a broader look at this particular aspect, describing the relationship between cataracts and a group of genetic diseases. The links between cataracts and genetic diseases have been investigated. This review focuses on the diseases most frequently reported in the literature to be associated with cataracts, such as Down syndrome, myotonic dystrophy, neurofibromatosis type 2, Marfan syndrome, Wilson disease and Alport syndrome. The associations of cataracts with various genetic diseases, confirmed in previously published studies, were described. Despite the fact that it is difficult to distinguish individual factors influencing the development of cataract, the analyzed literature examples allowed to demonstrate that cataract in the course of the genetic disorders discussed in this review is not accidental.

BackgroundGenetic diseases exhibit significant clinical and genetic diversity, leading to a complex and challenging diagnostic process. Exploiting novel approaches is imperative for the molecular diagnosis of genetic diseases. In this study, we utilized whole-exome sequencing (WES) to facilitate early diagnosis in patients suspected of genetic disorders.MethodsThis retrospective analysis included 144 patients diagnosed by singleton-WES Trio-WES between January 2021 and December 2023. We investigated the relevance of diagnosis rates with age, clinical presentation, and sample type.ResultsAmong the 144 patients, 61 were diagnosed, yielding an overall diagnostic rate of 42.36%, with Trio-WES demonstrating a significantly higher diagnostic rate of 51.43% (36/70) compared to singleton-WES at 33.78% (25/74) (p

TANGO2 deficiency disorder is an autosomal recessive disease caused by biallelic pathogenic variants in the TANGO2 gene. First described in 2016, the disorder is characterized by acute metabolic crises, neurological dysfunctions, developmental delays, and intellectual disabilities. Laboratory findings indicate a mitochondrial fatty acid oxidation defect, with metabolic crises often triggered by stressors such as illness or fasting. The TANGO2 protein, implicated in lipid metabolism, membrane trafficking, and cellular homeostasis, is critical for maintaining lipid droplets, regulating phospholipid levels, and facilitating protein and lipid transport between cellular compartments. Symptoms of TANGO2 deficiency are diverse, including psychomotor delays, intellectual impairments, seizures, ataxia, and episodic neurological symptoms known as TANGO2 spells. Diagnosis involves genetic testing, with several pathogenic variants identified. During metabolic crises, patients may experience severe cardiac and metabolic disturbances. No curative treatment exists; management includes B-vitamin supplementation, antiepileptic drugs, and interventions for spasticity, dystonia, thyroid dysfunction, and arrhythmias. TANGO2 deficiency disorder can co-occur with DiGeorge syndrome, complicating diagnosis due to overlapping symptoms. Improved awareness and diagnostic strategies are crucial for effective management of this underrecognized condition.

With the rapid evolution of diagnostic tools, particularly next-generation sequencing, the identification of genetic diseases, predominantly those with pediatric-onset, has significantly advanced. However, this progress presents challenges that span from selecting appropriate tests to the final interpretation of results. This review examines various genetic testing methodologies, each with specific indications and characteristics, emphasizing the importance of selecting the appropriate genetic test in clinical practice, taking into account factors like detection range, cost, turnaround time, and specificity of the clinical diagnosis. Interpretation of variants has become more challenging, often requiring further validation and significant resource allocation. Laboratories primarily classify variants based on the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science guidelines, however, this process has limitations. This review underscores the critical role of clinicians in matching patient phenotypes with reported genes/variants and considering additional factors such as variable expressivity, disease pleiotropy, and incomplete penetrance. These considerations should be aligned with specific gene-disease characteristics and segregation results based on an extended pedigree. In conclusion, this review aims to enhance understanding of the complexities of clinical genetic testing, advocating for a multidisciplinary approach to ensure accurate diagnosis and effective management of rare genetic diseases.

Abstract Introduction Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy. Methods Participants with classic A-T (n = 77), mild A-T (n = 13), and unaffected controls (n = 15) were recruited from two outpatient clinics. PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features. Results People with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4 + T cells and CD8 + T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls. Conclusion Using a transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy.

Abstract Background TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood. Methods We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools. Results Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein–protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain. Conclusion TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.

Introduction: To determine the optimum prescription and dosage for an ankle-foot orthosis and footwear, clinicians and families need to agree on goals for intervention. To facilitate family-centered collaborative goal setting, a table of potential goals and its pictorial representation had been developed previously. These tools incorporated the International Classification of Functioning, Disability, and Health (ICF) and International Organization for Standardization (ISO) clinical objectives for orthoses and were structured in an approach understandable to families. This study aimed to obtain consensus on the content validity of the Table and Pictorial Tools. Methods: Seventeen experts from seven countries (orthotists, physical therapists, physicians, surgeons, and engineers) were invited. A modified Delphi technique was used to evaluate and refine the Table Tool (rounds 1 and 2) and Pictorial Tool (rounds 3 and 4). Participants rated their agreement with overall tool structure, content, and feasibility of use on a 4-point Likert scale, and provided open-ended feedback. Consensus was defined as a median score ≥3 (agree) with 75% of responses ≥3. Data were collected using REDCap. After each round, thematic analysis guided document revisions and anonymized feedback. Results: Ten experts from four countries completed the study. Round 1 (Table Tool): median ratings were all 3; consensus was achieved for 3/5 questions. Round 2: full consensus was achieved. Round 3 (Pictorial Tool): median ratings were ≥3 for 10/11 questions; consensus was achieved for 4/11 questions. Round 4: full consensus was achieved. Conclusions: The content validity for the Table and Pictorial Tools was established by modified Delphi consensus. These tools represent a comprehensive selection of goals across all ICF components. Clinical Relevance: These novel tools have the potential to facilitate collaborative goal setting between families and clinicians and aid clinical education. A goal-setting framework specific to orthotic management may improve outcomes within the context of family-centered care. [ABSTRACT FROM AUTHOR]

Keloid are a fibroproliferative disorder caused by abnormal healing of skin, specifically reticular dermis, when subjected to pathological or inflammatory scars demonstrating redness, elevation above the skin surface, extension beyond the original wound margins and resulting in an unappealing cosmetic appearance. The severity of keloids and risk of developing keloids scars are subjected to elevation by other contributing factors such as systemic diseases, general health conditions, genetic disorders, lifestyle and natural environment. In particular, recently, daily physical work interpreted into mechanical force as well as the interplay between mechanical factors such as stress, strain and stiffness have been reported to strongly modulate the cellular behaviour of keloid formation, affect their location and shape in keloids. Herein, we review the extensive literature on the effects of these factors on keloids and the contributing predisposing mechanisms. Early understanding of these participating factors and their effects in developing keloids may raise the patient awareness in preventing keloids incidence and controlling its severity. Moreover, further studies into their association with keloids as well as considering strategies to control such factors may help clinicians to prevent keloids and widen the therapeutic options. [ABSTRACT FROM AUTHOR]

The rapid evolution of gene editing technology has markedly improved the outlook for treating genetic diseases. Base editing, recognized as an exceptionally precise genetic modification tool, is emerging as a focus in the realm of genetic disease therapy. We provide a comprehensive overview of the fundamental principles and delivery methods of cytosine base editors (CBE), adenine base editors (ABE), and RNA base editors, with a particular focus on their applications and recent research advances in the treatment of genetic diseases. We have also explored the potential challenges faced by base editing technology in treatment, including aspects such as targeting specificity, safety, and efficacy, and have enumerated a series of possible solutions to propel the clinical translation of base editing technology. In conclusion, this article not only underscores the present state of base editing technology but also envisions its tremendous potential in the future, providing a novel perspective on the treatment of genetic diseases. It underscores the vast potential of base editing technology in the realm of genetic medicine, providing support for the progression of gene medicine and the development of innovative approaches to genetic disease therapy. [ABSTRACT FROM AUTHOR]

The clinical application of technological progress in the identification of DNA alterations has always led to improvements of diagnostic yields in genetic medicine. At chromosome side, from cytogenetic techniques evaluating number and gross structural defects to genomic microarrays detecting cryptic copy number variants, and at molecular level, from Sanger method studying the nucleotide sequence of single genes to the high-throughput next-generation sequencing (NGS) technologies, resolution and sensitivity progressively increased expanding considerably the range of detectable DNA anomalies and alongside of Mendelian disorders with known genetic causes. However, particular genomic regions (i.e., repetitive and GC-rich sequences) are inefficiently analyzed by standard genetic tests, still relying on laborious, time-consuming and lowsensitive approaches (i.e., southern-blot for repeat expansion or long-PCR for genes with highly homologous pseudogenes), accounting for at least part of the patients with undiagnosed genetic disorders. Third generation sequencing, generating long reads with improved mappability, is more suitable for the detection of structural alterations and defects in hardly accessible genomic regions. Although recently implemented and not yet clinically available, long read sequencing (LRS) technologies have already shown their potential in genetic medicine research that might greatly impact on diagnostic yield and reporting times, through their translation to clinical settings. The main investigated LRS application concerns the identification of structural variants and repeat expansions, probably because techniques for their detection have not evolved as rapidly as those dedicated to single nucleotide variants (SNV) identification: gold standard analyses are karyotyping and microarrays for balanced and unbalanced chromosome rearrangements, respectively, and southern blot and repeat-primed PCR for the amplification and sizing of expanded alleles, impaired by limited resolution and sensitivity that have not been significantly improved by the advent of NGS. Nevertheless, more recently, with the increased accuracy provided by the latest product releases, LRS has been tested also for SNV detection, especially in genes with highly homologous pseudogenes and for haplotype reconstruction to assess the parental origin of alleles with de novo pathogenic variants. We provide a review of relevant recent scientific papers exploring LRS potential in the diagnosis of genetic diseases and its potential future applications in routine genetic testing. [ABSTRACT FROM AUTHOR]

Topoisomerases regulate the topological state of cellular genomes to prevent impediments to vital cellular processes, including replication and transcription from suboptimal supercoiling of double-stranded DNA, and to untangle topological barriers generated as replication or recombination intermediates. The subfamily of type IA topoisomerases are the only topoisomerases that can alter the interlinking of both DNA and RNA. In this article, we provide a review of the mechanisms by which four highly conserved N-terminal protein domains fold into a toroidal structure, enabling cleavage and religation of a single strand of DNA or RNA. We also explore how these conserved domains can be combined with numerous non-conserved protein sequences located in the C-terminal domains to form a diverse range of type IA topoisomerases in Archaea, Bacteria, and Eukarya. There is at least one type IA topoisomerase present in nearly every free-living organism. The variation in C-terminal domain sequences and interacting partners such as helicases enable type IA topoisomerases to conduct important cellular functions that require the passage of nucleic acids through the break of a single-strand DNA or RNA that is held by the conserved N-terminal toroidal domains. In addition, this review will exam a range of human genetic disorders that have been linked to the malfunction of type IA topoisomerase. [ABSTRACT FROM AUTHOR]

Introduction. Treacher Collins syndrome (TCS) is a rare genetic condition characterized by typical head and neck malformations occurring in 1:50,000 newborns. Permanent conductive or mixed hearing loss of various degrees is diagnosed in 50% of individuals with TCS. A prerequisite for speech and language development in children with permanent mixed hearing impairment is the application of one of the bone conduction hearing aids. Choosing an adequate hearing aid in this case depends primarily on the degree of hearing impairment and the type of ear malformation. Case report. We present a female patient with multiple genetic malformations due to TCS. The patient was, immediately after birth, referred for audiological evaluation because of considerable ear and face malformations. Using a hearing test battery, permanent mixed, predominantly conductive, bilateral hearing loss of severe degree was diagnosed. The use of bone conduction hearing aids (including the Vibrant® Soundbridge middle ear implant) in the patient did not give the expected results - sufficient amplification for adequate speech and language development. Only after cochlear implantation at the age of nine did the patient's hearing threshold stabilize and her communication and academic potential develop to full capacity. Conclusion. If a middle ear implant is not sufficient for adequate amplification, cochlear implantation should be considered as an appropriate solution for treating severe permanent mixed hearing impairment in patients with TCS. [ABSTRACT FROM AUTHOR]

Introduction. Autism spectrum disorders (ASD) represent pervasive developmental disorders of neurobiological origin, involving disruptions in communication and interaction, as well as restricted and repetitive interests and actions. According to the latest report published by the Centers for Disease Control and Prevention USA, 1 in 36 children is diagnosed with ASD. The aim of study is to estimate the prevalence of genetic disorders among children with ASD in order to enhance diagnosis and assistance for children with ASD. Materials and Methods. We employed an observational method of official studies, synthesizing and critically analyzing published articles (54 articles, 52 patients with ASD) from 2016-2024 on platforms such as PubMed, Medscape, NEJM, GeneCards, Lecturio, AMBOSS regarding ASD in children with genetic diseases. Results. The study included a group of 52 children with ASD examined during the medical genetics consultation at the Mother and Child Institute. Among them, 24 children had defects in genes or various genetic diseases associated with ASD, such as Rett syndrome, Fragile X syndrome, Angelman syndrome, tuberous sclerosis, Sotos syndrome, etc. Among the genetic mutations causing genetic disorders and ASD in children are genes responsible for transcription regulation (MECP2, MEF2C, FOXG1), cell growth (TSC1, TSC2, PTEN), synaptic channels (SCN2A), and synaptic structure (CASK, CDKL5, FMR1, SHANK3). Conclusions. ASD is encountered in children with genetic disorders. Awareness of genetic pathologies associated with ASD, will improve the assessment process for these children by specialists in genetics, neurology, and pediatrics working in pediatric medical institutions. Early clinical-genetic diagnosis of children with genetic diseases associated with ASD will enhance the psychoneurological development of these children. [ABSTRACT FROM AUTHOR]

Animal models are extensively used in all aspects of biomedical research, with substantial contributions to our understanding of diseases, the development of pharmaceuticals, and the exploration of gene functions. The field of genome modification in rabbits has progressed slowly. However, recent advancements, particularly in CRISPR/Cas9-related technologies, have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases, including cardiovascular disorders, immunodeficiencies, agingrelated ailments, neurological diseases, and ophthalmic pathologies. These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice. This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine, underscoring their impact and future potential in translational medicine. [ABSTRACT FROM AUTHOR]

Background: TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood. Methods: We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools. Results: Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein–protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain. Conclusion: TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood. [ABSTRACT FROM AUTHOR]