Journal of Translational Genetics and Genomics

Fabry disease is a rare genetic disorder classified as a lysosomal storage disease. It is an X-linked disease, caused by the mutation of the GLA gene, leading to the deficit or absence of function of the enzyme α-galactosidase A. It is a multi-organ and progressive disease characterized by systemic involvement primarily affecting the cardiac, renal and neurological systems. Current treatment options include established therapies such as two enzyme replacement therapies (agalsidase α, agalsidase β), one chaperone treatment (migalastat), and a recently approved enzyme replacement therapy targeting pegunigalsidase α. New drugs are being developed, including substrate reduction therapy, mRNA therapy, and genetic therapy. These emerging treatments have the potential to address the limitations of current therapies and ensure more effective and personalized treatment. This review explores and analyzes the diverse therapeutic strategies available for treating this complex and intriguing disease.

Breast cancer (BC) remains the most common cause of death in women worldwide, but advances in science have allowed earlier diagnosis and more comprehensive treatment. This review highlights the impact of extensive molecular genetic testing in assessing the risk of BC susceptibility, as well as possible responses to chemotherapy and radiotherapy. Studies in the literature show that several Single Nucleotide Polymorphisms (SNPs) of genes involved in molecular pathways may become predictors of the risk of developing BC. For example, SNPs in genes such as RAD51 and XRCC3 , already known to be linked with high BC susceptibility, were also correlated with a different response to radiotherapy and related adverse effects. In addition, the SNP ESR1 PvuII (rs2234693), on the ESR1 gene, has been associated with a poor prognosis in advanced BC, but can be a good predictor of the therapeutic effect of hormonal treatment. Therefore, SNPs can be considered as possible new biomarkers for BC risk and prognosis. In this view, it is important to evaluate Polygenic Risk Score, an essential component for accurate BC risk prediction, which may potentially improve screening and prevention strategies. Bioinformatics tools are available to calculate polygenic risk by assessing the presence of SNPs and patients’ family and personal history. This represents an important step forward in the era of personalized medicine for BC.

Chronic inflammation and its role in driving cellular plasticity have recently been documented as a significant risk factor for prostate cancer. The progression of prostate cancer has been linked to stages of inflammation-driven changes, ranging from simple atrophy to prostatic intraepithelial neoplasia and eventually to low- and high-grade neoplastic forms. Long-term oxidative stress and the genetic damage caused by chronic inflammation are among the well-characterized risk factors in the development of prostate cancer. Both uncontrollable and controllable factors contribute to this transition process. Non-modifiable risk factors for prostate cancer include age, race, ethnicity, family history of obesity, and certain genetic predispositions. Modifiable risk factors, such as a sedentary lifestyle, poor diet, obesogenic habits, and microbial dysbiosis, may further elevate the risk of neoplastic transformation. Additionally, environmental pollutants, like chlordecone and nitrates, can interact with biological factors, potentially influencing cellular plasticity. These factors collectively contribute to an increased risk of prostate cancer and may facilitate neoplastic progression. Certain molecular markers have also been implicated in promoting chronic inflammation, enhancing cellular proliferation, and inhibiting apoptosis, thereby aiding in this transition. This review provides a comprehensive summary of the known modifiable and non-modifiable risk factors that contribute to the neoplastic transition in the prostate and elevate the risk of prostate cancer.

Fabry disease, a rare X-linked lysosomal storage disorder, is marked by a deficiency in the activity of the enzyme α-galactosidase A. This deficiency results in the accumulation of globotriaosylceramide (Gb3) within various tissues and organs, which leads to life-threatening complications and poor prognosis. Clinical manifestations are multisystemic, heterogeneous, and progressive. Early diagnosis and treatment are of great importance. Fabry nephropathy lesions are characterized by a cell vacuolization of glomeruli, tubules, interstitium, and arteries and by ultrastructural myelin bodies. Kidney injury can occur in various structures, with the podocytes being the first to be impacted due to their low regeneration and extensive exposure to Gb3. The accumulation of Gb3 causes injury to podocytes, which are essential components of glomerular cells, responsible for maintaining the integrity of the glomerular filtration barrier. Enzyme replacement therapy, dynamic monitoring of podocyte injury, and research on the repair and regeneration mechanism of podocyte injury will contribute to the overall treatment of kidney damage in Fabry disease and improve the renal prognosis.

Aim: Barth syndrome (BTHS; OMIM 302060) is an ultra-rare, complex, multi-system X-linked disorder that arises from pathogenic mutations in the gene TAFAZZIN . BTHS is characterized by cardiomyopathy, skeletal myopathy, muscle weakness, and neutropenia. To better understand the natural history and lived experience of affected individuals, the Barth Syndrome Foundation maintains the patient-inputted Barth Syndrome Registry and Repository (BRR). Methods: Available cross-sectional and longitudinal participant data (n = 115) were analyzed to illustrate the diagnostic odyssey, manifestations, and healthcare utilization across a broad range of affected individual age groups. Results: Individuals who experienced cardiomyopathy or heart failure as the first manifestation had the shortest times to diagnosis compared to less appreciated manifestations (e.g., frequent infections, poor muscle tone, growth delay). The most frequently reported manifestations across all ages were due to cardiac disorders (80.7%), gastrointestinal (GI) disorders (68.7%), neutropenia or frequent infections (67.2%), and fatigue (60.9%), with 47.1% of participants scoring in the moderate-to-severe range of the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 8A survey. Participants saw, on average, 3.6 specialists in the previous year, with cardiologists (97.9%) and hematologists (58.2%) being the most commonly seen specialists. Conclusion: The data suggest that cardiac disorders are the most common manifestations of BTHS, but also reveal a high frequency of feeding and GI-related issues that previous reports have not captured. Physician-targeted education on the lesser-known symptoms and population-based screening for BTHS may aid in timely diagnosis and improved clinical management.

The review article “Transcription regulation by long non-coding RNAs: mechanisms and disease relevance” by Jorge Ferrer and Nadya Dimitrova, published in Nature Reviews Molecular Cell Biology , explores the complex roles of long non-coding RNAs (lncRNAs) in gene transcription regulation. The authors discuss various mechanisms by which lncRNAs influence transcription, including their functions as cis-regulatory elements, transcription stabilizers, and scaffolds for regulatory complexes. The review also highlights the potential of lncRNAs in disease contexts and their therapeutic applications. However, it is essential to consider the potential limitations in current lncRNA research.

Prostate cancer remains the most commonly diagnosed and the second leading cause of cancer-related deaths in men in the United States. The neoplastic transformation of prostate epithelia, concomitant with modulations in the stromal compartment, known as reactive stromal response, is critical for the growth, development, and progression of prostate cancer. Reactive stroma typifies an emergent response to disrupted tissue homeostasis commonly observed in wound repair and pathological conditions such as cancer. Despite the significance of reactive stroma in prostate cancer pathobiology, our understanding of the ontogeny, phenotypic and functional heterogeneity, and reactive stromal regulation of the immune microenvironment in prostate cancer remains limited. Traditionally characterized to have an immunologically "cold" tumor microenvironment, prostate cancer presents significant challenges for advancing immunotherapy compared to other solid tumors. This review explores the detrimental role of reactive stroma in prostate cancer, particularly its immunomodulatory function. Understanding the molecular characteristics and dynamic transcriptional program of the reactive stromal populations in tandem with tumor progression could offer insights into enhancing immunotherapy efficacy against prostate cancer.

editorial on a special issue on DMD

The field of RNA-based therapeutics is rapidly evolving and targeting non-coding RNAs (ncRNAs) associated with disease is becoming increasingly feasible. MicroRNAs (miRNAs) are a class of small ncRNAs (sncRNAs) and the first anti-miRNA drugs, e.g., Miravirsen and Cobomarsen, have successfully completed phase II clinical trials. Long ncRNAs (lncRNAs) are another class of ncRNAs that are commonly dysregulated in disease. Thus, they hold potential as putative therapeutic targets or agents. LncRNAs can function through a variety of mechanisms, including as guide, scaffold or decoy molecules, and understanding of these actions is critical to devising effective targeting strategies. LncRNA expression can be modulated with small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), CRISPR-Cas9, or small molecule inhibitors. These approaches have been employed to target a number of lncRNAs and tested in animal models of disease, including targeting ANRIL for non-small cell lung cancer and H19 for pancreatitis. However, there are currently no clinical trials registered in the ClinicalTrials.gov database that target lncRNAs as a therapeutic intervention. In order to translate lncRNA targeting into clinical use, several limitations must be overcome, such as potential toxicity and off-target effects. Overall, while significant progress has been made in the field, further development is required before the clinical application of the first therapeutics targeting lncRNAs. In this review, we discuss recent advances in our understanding of the mechanisms of action of lncRNAs that present avenues for clinical therapeutic targeting and consider off-target effects as a limiting factor in their application.

Aim: Barth syndrome (BTHS) is a rare X-linked genetic disease in which mitochondrial oxidative phosphorylation is impaired due to a mutation in the TAFAZZIN gene. The protein kinase C delta (PKCδ) signalosome exists as a high molecular weight complex in mitochondria and controls mitochondrial oxidative phosphorylation. Method: Here, we examined PKCδ levels in mitochondria of aged-matched control and BTHS patient B lymphoblasts and its association with a higher molecular weight complex in mitochondria. Result: Immunoblot analysis of blue-native polyacrylamide gel electrophoresis mitochondrial fractions revealed an increase in total PKCδ protein expression in BTHS lymphoblasts compared to controls. In contrast, PKCδ associated with a higher molecular weight complex was markedly reduced in BTHS patient B lymphoblasts compared to controls. Given the decrease in PKCδ associated with a higher molecular weight complex in mitochondria, we examined the uptake of creatine, a compound whose utilization is enhanced upon high energy demand. Creatine uptake was markedly elevated in BTHS lymphoblasts compared to controls. Conclusion: We hypothesize that reduced PKCδ within this higher molecular weight complex in mitochondria may contribute to the bioenergetic defects observed in BTHS lymphoblasts and that enhanced creatine uptake may serve as one of several compensatory mechanisms for the defective mitochondrial oxidative phosphorylation observed in these cells.

Atypical neurofibromas (aNF) are peripheral nerve sheath tumors (PNSTs) histologically defined by cytologic atypia, hypercellularity, loss of neurofibroma architecture, and/or increased mitotic activity. aNF often have a heterozygous loss of CDKN2A/B in addition to homozygous NF1 loss. On MRI, aNF frequently appear as distinct nodular lesions, grow faster than plexiform neurofibromas, and have increased avidity on fluorodeoxyglucose positron emission tomography. At least some aNF are considered to be at greater risk for transformation to highly aggressive malignant PNSTs. We have observed that some PNSTs demonstrate a discrepancy between histological, clinical, and genomic criteria, where a PNST without histologically concerning findings may have clinical and imaging features concerning aNF and CDKN2A/B loss. This case series highlights this discrepancy and suggests the inclusion of CDKN2A/B loss to define aNF, along with clinical and imaging findings, to determine the potential for malignant transformation, and to select appropriate clinical management.

Cardiovascular diseases (CVDs) remain one of the leading causes of morbidity and mortality worldwide, with genetics being a major risk factor. Genetic cardiovascular disease can occur either because of single variant (Mendelian) or polygenic influences and has been linked to inherited cardiovascular conditions (ICC) such as arrhythmias, cardiomyopathies, dyslipidemias, and aortopathies which are significant factors leading to sudden cardiac death in young adults. Timely screening, diagnosis, and management of ICC can not only provide life-saving treatment to a patient, but also identify at-risk family members. The field of pharmacogenomics (PGx) helped to understand the variable action of medications such as clopidogrel, aspirin, warfarin, and statin according to genotype. Newer technologies such as multi-omics can combine data from multiple sources such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome. These advancements can contribute to the development of polygenic prediction scores and precision medicine tailored to individual genotypes. Substantial strides have been made in genetic-based therapeutics, gene editing technologies, and drug delivery systems, which have significantly expanded treatment options for patients with acquired or inherited CVDs. Although variable, the country- and society-specific guidelines on genetic testing for ICC and PGx and treatment are being continuously updated to keep up with ongoing research in the field. Along with appropriate knowledge, other factors including cost and availability of genetic testing play a vital role in the usage by both physicians and patients. With the advent of newer genetic testing for CVDs, a key factor is the availability of genetic counselors (GCs) who are specifically trained in cardiovascular genomics. The current review provides a concise summary of the major influences of genetics in the diagnosis and treatment of CVDs.

Long non-coding RNAs (lncRNAs) are a class of RNA transcripts that are long (i.e., more than 200 nucleotides) and not translated into proteins. They have recently emerged as potential treatment targets for numerous disorders due to their involvement in multiple cellular functions such as gene regulation, epigenetic modulation, and chromatin organization. This review highlights the current state of lncRNA-based therapeutics, the potential of lncRNAs as drug targets for treating human diseases, the various strategies and types of RNA-based therapeutics, and the complications of developing lncRNA-based drugs. We conclude that lncRNA-based therapeutics represent a promising class of drugs that can potentially treat various human diseases and that further research is needed to fully realize their therapeutic potential.

Prostate cancer stands as the most prevalent cancer globally, constituting 21% of all cancer diagnoses in male patients. Urgent optimization of prostate cancer care is essential, given that this disease claims 345,000 lives every year. These innovative approaches hold substantial promise for both researchers and patients, representing a beacon of hope in the inhibitory act against prostate cancer. Prostate cancer's gradual advancement deems it suitable for immune therapy, but trials in metastatic cases show limited effectiveness, likely due to compromised immunity. Hindered by defective cellular responses, an immune-suppressive microenvironment, emerging evidence and breakthroughs, such as CAR-T therapy, inspire cautious optimism for advanced prostate cancer immunotherapy. Tumors utilize tactics to escape immune recognition, promoting the proliferation of MDSCs, Treg cells, and TAMs. Immunotherapy targets prostate cancer by mostly expressed target proteins and overexpressed target proteins. Immune cells play a role in tumor development and metastasis in advanced prostate cancer. Modulating the tumor microenvironment presents therapeutic possibilities. Certain prostate cancer types exhibit potential responses to immune checkpoint inhibitors, yet obstacles remain, necessitating additional research for enhanced efficacy. Immunotherapy faces hurdles in prostate cancer - limited inflammation, scarce antigens, and a resistant microenvironment. Grasping resistance intricacies is pivotal. The identification of DNA's helical structure propelled global progress in disease treatment through gene therapy. Choosing gene therapy vectors is critical; viruses are potent but toxic, while nonviral options, though less toxic, encounter barriers affecting transfection. In the realm of prostate cancer treatment, immunotherapy and gene therapy are emerging as increasingly viable options.

Twin studies are cutting-edge design methodologies proper to behavioral genetics that aim to investigate how the interplay between genetic and environmental factors can concur to explain individual differences in psychopathology, temperamental traits, and behavior. This particular research design has been widely applied to the study of comorbidity between internalizing (INT) and externalizing (EXT) symptoms, especially in childhood and adolescence. Notably, the high co-occurrence of symptoms of both these diagnostic domains has led to the hypothesis that at their basis, there might be one single latent common susceptibility factor, namely p factor. Twin studies have contributed to marking a relevant turning point in this regard by highlighting the consistent genetic nature of this factor. In light of these premises, the present narrative review aims to outline the path for future twin studies in investigating the comorbidity between Cognitive Disengagement Syndrome (CDS) and INT-EXT disorders, examining the evidence supporting this need and its clinical implications. Since CDS has not been recognized as a stand-alone syndrome until very recently, research on this condition is still in its infancy and the etiological factors at the basis of its comorbidity with INT-EXT are still unclear. Being aware of the causal factors underneath the comorbidity between INT-EXT might pave the way for improving assessment diagnostic procedures as well as setting up preventive interventions for CDS.

A significant portion of patients who are afflicted with lysosomal storage diseases (LSDs) encounter neurological manifestations, including cognitive issues and developmental delay, seizures, psychiatric issues, and an overall neurodegenerative decline. In order to enhance the development of effective therapies for these symptoms, it is imperative that we allude to the neuropathophysiology that underlies these manifestations. These distinct neurological and developmental features are particularly evident in patients with Alpha-Mannosidosis (AM), a type of LSD. However, there is limited published information regarding the mechanisms and pathophysiology of these presentations in patients with this condition. Although the precise impact of lysosomal storage on the biogenesis and functioning of neuronal cells has not been clearly defined, recent studies have placed emphasis on the significance of synaptic defects influencing this dysfunction. These defects encompass changes in synaptic spines, proteins, and vesicles, as well as postsynaptic densities that potentially precipitate functional disruptions in synaptic transmission and neurodegeneration. Ultimately, this cascade is thought to result in extensive neuronal loss and, consequently, the onset of cognitive manifestations. Uncovering the effects on synaptic components in LSDs with neurological symptoms like AM will enable a better understanding of disease progression. It will also allow us to identify critical targets for therapeutic intervention and the determination of optimal time frames for targeted treatments, as well as the effects of these treatments on mitochondrial function. The available therapeutic modalities in AM are not a definitive cure for affected patients, but rather an attempt to reduce the symptomatic severity in their presentation, while aiming to regress/slow down disease progression. This review will aim to discuss and rationalize the current treatment approaches in place for AM patients in relation to their effects on the improvement of neurocognitive symptoms in affected AM individuals.

Aim: 47,XXY (KS) is the most frequently occurring sex chromosome aneuploidy (SCA) with an incidence rate of 1:500 to 1:650 live male births. 47,XXY is characterized by androgen insufficiency and hypogonadism, diminished phallus size, hypotonia, and increased stature. This investigation examines the relationship between Early Hormonal Treatment (EHT) and growth in boys with 47,XXY from birth to 5 years. Methods: A cohort of 134 males with 47,XXY was seen as part of a natural history study and anthropometric measurements were completed at each evaluation for height (HT), weight (WT), and head circumference (HC). Data was analyzed for these factors in the group receiving testosterone as EHT (T group) and a no treatment (No-T) control group. Results: Significant differences in HC were observed between the T group and No-T group for birth to 12 months. There was no other significant difference in HC for boys between the ages of 13 to 60 months. Only significant differences were observed in the birth to 12 months group for HT between the T group and No-T group. There were only significant differences in WT in the birth to 12-month age range between the T group and the No-T group, as well as in the 12-24-month age range. Conclusion: EHT is not associated with reducing or advancing growth in children with 47,XXY over 2 years old. After 24 months of age there is no discernible difference between boys with 47,XXY with EHT and without EHT.

Prostate cancer remains the most common malignancy among men in the United States. Advancements in androgen receptor signaling blockade have led to landmark approvals for its use in patients with locally advanced and metastatic disease. However, additional novel therapeutic strategies for both hormone-sensitive and castration-resistant diseases remain ongoing areas of study. Thus, we turn to the growth of immuno-oncology, which has led to improved treatment outcomes for a variety of hematologic and solid tumor malignancies. Prostate cancers have shown only modest results with immune checkpoint inhibition in published trials, and innovative strategies are now looking into enhancing cytotoxic T-cell activity against cancer cells. This review provides a thorough evaluation of tumor-associated antigens that are integrated into novel chimeric antigen receptor T-cell and bispecific T-cell engager therapies. Our review will evaluate the most recent advancements in immunotherapies, while also illustrating major obstacles and underlying limiting factors.

Aims: The revised 2022 World Health Organization classification recognizes myeloid neoplasms with associated germline predisposition as a defined subcategory, underscoring the clinical significance of likely pathogenic (LPV) and pathogenic (PV) germline variation in these diseases. To better understand the role of LPV/PV in blood or marrow transplants (BMT), a curative therapy for myeloid neoplasms, we measure their frequency and association with mortality in two cohorts of donor-recipient pairs. Methods: LPV/PV frequencies in 665 cancer-related genes were measured using exomechip genotyping data in 1990 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and their unrelated donors, registered with the Center for International Blood and Marrow Transplant Research. Cox proportional hazard models were used to test variant association with recipient mortality one-year post-transplant. Results: Thirteen autosomal dominant (AD) LPV/PV in eight genes were found in 2.8% of patients and 2.2% of donors; those linked to autosomal recessive conditions appeared in 11.1% of patients and 11% of donors. The most common AD LPV/PV mutations in recipients were found in DDX41 (n = 18). For donors, the most frequent AD PVs occurred in CHEK2 (n = 21) and Fanconi Anemia (FA) genes (n = 7). DDX41 and CHEK2 variation did not correlate with patient survival, but patients with donors with an LPV/PVs in an FA gene had lower survival (HR = 2.38, 95%CI: 1.06-5.31, P = 0.035) than patients whose donors did not have an FA LPV/PV. Conclusion: We identified LPVs/PVs in cancer genes in donors and recipients and are the first to show an association of donor FA PVs with mortality after BMT.

Young-onset type 2 diabetes (YOD), defined as diabetes diagnosis before age 40, has an aggressive clinical course with premature mortality, in part due to long disease duration and lack of evidence to guide diagnosis and management. Autoimmune type 1 diabetes, maturity-onset diabetes of the young (MODY), and latent autoimmune diabetes in adults (LADA) are subtypes of diabetes in young people, which, however, cannot fully explain their complex clinical course. Similarly, family members carrying the same rare genetic variant of monogenic diabetes can have different presentations and outcomes. Ancestral heterogeneity, ecological transition, inter-ethnic differences in genomic architecture, and variations in living environment, lifestyles, access to care, and timeliness of diagnosis and treatment can influence the age of diagnosis and exposure to these cardiometabolic-renal risk factors. Despite the wealth of literature on genetic associations with diabetes, the familial cosegregation of rare variants and their relevance to YOD remains uncertain. This perspective was motivated by decades of clinical observations and learnings from an ongoing randomized controlled trial that uses biogenetic markers to classify patients with YOD for improving outcomes. Apart from highlighting the need to use family-based studies to improve the precision of diagnosis, we discussed atypical causes for diabetic ketoacidosis and the importance of lifecourse and psychosocial-behavioral factors in patients with YOD. Apart from detailed clinical evaluation, we propose using plasma C peptide, homeostasis model of assessment (HOMA) indexes, autoantibodies, and polygenic risk scores to stratify risk, classify diabetes subtypes, and personalize treatment in YOD. To achieve these goals, we advocate changing the practice environment and team structure to enable physicians to use the insights they learn from patients and their family members to implement precision medicine and improve the outlook of these high-risk individuals.

With a population prevalence of 1%, schizophrenia is widespread, yet the aetiology of this psychiatric disorder remains elusive. There is an evident genetic component of schizophrenia, with heritability estimates lying at 60%-80%. While genome-wide association studies have identified 120 gene loci associated with schizophrenia risk, these involved common variants that confer only small effects on individual risk (median odds ratio < 1.2). The recent emergence of whole exome sequencing (WES) technologies has facilitated the identification of rare sequence variants, including some protein-truncating variants that have significant effects on risk. Three key large-scale WES studies have demonstrated that rare sequence variants in the genes SETD1A, CACNA1G, CUL1, GRIA3, GRIN2A, HERC1, RB1CC1, SP4, TRIO, XPO7, and AKAP11 confer substantial risk for schizophrenia. These genes are highly expressed in central nervous system neurons and their products participate in diverse molecular functions including synaptic transmission, transcriptional regulation, and ubiquitin ligation. The understanding of these functional roles illuminates putative molecular mechanisms which may lead to schizophrenia-like phenotypes. It will also be possible to develop model systems in which the effects of impaired function of these genes can be further explored. Genetic studies of rare variants to date suggest that glutamatergic system dysregulation, chromatin modification, and the ubiquitin-proteasome system play key roles in schizophrenia aetiology.

Autism spectrum disorder (ASD) is a behaviorally defined syndrome affected by multiple genetic and environmental factors. A wide variety of risk factors for ASD have been identified and many of these affect immune functions. This may not be surprising, since the immune system and the nervous system share common signaling mechanisms and affect each other as a part of the neuroimmune network. The ever-expanding scope of inborn errors of immunity (IEIs) has revealed multiple pathogenic gene variants that manifest overlapping clinical features of common neuropsychiatric diseases, including ASD. These IEIs often cause dysregulated immune activation and resultant chronic inflammation affecting multiple organs. Some IEIs also cause changes in morphogenesis and plasticity of the central nervous system. Such patients often present with a puzzling array of clinical features and some of them may be diagnosed with ASD or other neuropsychiatric conditions. The progress of our understanding of disease mechanisms for IEIs at the molecular levels has led to gene-specific treatment measures in some diseases. In addition, some ASD patients are found to have laboratory findings of neuroinflammation that resemble those seen in IEI patients. This may pave the way for applying specific treatment measures used for IEI patients in such ASD patients. This review focuses on describing IEIs that have overlapping features of ASD. Emphasis is also on IEIs that can be treated by targeting identified disease mechanisms. Such information may be helpful for clinicians who are considering genetic/metabolic workup in ASD patients.

Moebius Syndrome (MBS) is a rare neurodevelopmental disorder characterised by facial paralysis and ocular motility defects. Its origins trace back to the 19th century, with its clinical delineation attributed to German neurologist Paul Möbius. The syndrome presents with a spectrum of variable systemic clinical features, necessitating a multidisciplinary approach to diagnosis and management. The prevalence of MBS has been estimated to range between 1 in 50,000 to 1 in 500,000 individuals, with a universal distribution across ethnicities and genders. The aetiology of MBS is poorly understood but is likely multifactorial, with developmental, genetic, and environmental factors playing roles. Recent research has identified potential genetic contributors, REV3L and PLXND1, but further work is needed to elucidate the genetic landscape of this rare neurodevelopmental disorder. Here we describe the current understanding of the clinical features, aetiology, genetic landscape, and management of MBS, emphasising the importance of early diagnosis and a holistic approach to patient care. We also propose a set of criteria aimed at standardising MBS reporting to enhance information sharing and bolster MBS research initiatives. Collaborative research efforts in the future hold the potential to offer transformative insights and improved outcomes for affected individuals and their families.