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Symptoms in the index patient common to Phelan-McDermid syndrome and mosaic monosomy for chromosome 22 as well as atypical symptoms
Source publication
Background
Ring chromosome instability may influence a patient’s phenotype and challenge its interpretation.
Results
Here, we report a 4-year-old girl with a compound phenotype. Cytogenetic analysis revealed her karyotype to be 46,XX,r(22). aCGH identified a 180 kb 22q13.32 duplication, a de novo 2.024 Mb subtelomeric 22q13.32-q13.33 deletion, whi...
Contexts in source publication
Context 1
... is a develop- mental disorder (OMIM 606232). The symptoms of the index proband commonly associated with PHMDS are listed in Table 2. ...
Context 2
... of the patients had r(22), which could somehow, during the early stages of the development before its elimination from the cell, compensate for the phenotype. The symptoms of our proband are similar to those described in patients with mosaicism for monosomy 22 and are listed in Table 2. In addition, the index patient exhibits some symptoms that have not been described in any patient with either of the anomalies discussed above. ...
Context 3
... the index patient, among 43 identified symptoms, 18 have previously been described in other patients with PHMDS and 15 in patients with mosaic monosomy 22, while 14 symptoms have never been observed in any of the mentioned cases (Table 2). These symptoms include skeletal abnormalities, facial dysmorphism, wide umbilical ring, and enuresis. ...
Similar publications
Small supernumerary marker chromosomes cannot be accurately identified by G-banding, and the related phenotypes vary greatly. It is essential to specify the origin, size, and gene content of marker chromosomes using molecular cytogenetic techniques. Herein, three fetuses with de novo marker chromosomes were initially identified by G-banding. Single...
Citations
... The above results suggest a link between the FAM19A5 gene and the Phelan-McDermid syndrome described in girl. 35 After the discovery of TAFA genes in 2004, interest in FAM19A5 (TAFA-5) functions has been most noticeable in neurology, neurological and psychiatric diseases. ...
Aim
One of the most critical functions of adipose tissue is the production of adipokines, ie, numerous active substances that regulate metabolism. One is the newly discovered FAM19A5, whose older name is TAFA-5.
Purpose
The study aimed to review the literature on the FAM19A5 protein.
Methods
The review was conducted in December 2023 using the PubMed (Medline) search engine. Sixty-four papers were included in the review.
Results
This protein exhibits the characteristics of an adipokine with positive features for maintaining homeostasis. The results showed that FAM19A5 was highly expressed in adipose tissue, with mild to moderate expression in the brain and ovary. FAM19A5 may also inhibit vascular smooth muscle cell proliferation and migration through the perivascular adipose tissue paracrine pathway. Serum levels of FAM19A5 were decreased in obese children compared with healthy controls. There are negative correlations between FAM19A5, body mass index, and fasting insulin. Serum FAM19A5 level is correlated with type 2 diabetes, waist circumference, waist-to-hip ratio, glutamic pyruvic transferase, fasting plasma glucose, HbA1c, and mean shoulder pulse wave velocity. FAM19A5 expression was reduced in mice with obesity. However, the data available needs to be clarified or contradictory.
Conclusion
Considering today’s knowledge about FAM19A5, we cannot consider this protein as a biomarker of the metabolic syndrome. According to current knowledge, FAM19A5 cannot be considered a marker of metabolic disorders because the results of studies conducted in this area are unclear.
... Its amino acid sequence remains highly conserved across vertebrate evolution, but conservation between FAM19A families is relatively low, indicating that FAM19A5 has a distinct and crucial function in the brain (2,3). Recent knockout and genome-wide association studies have revealed that FAM19A5 plays a particularly important role in synapse-related brain function, such as learning and memory, as well as in diseases including Alzheimer's disease (AD), attention deficit hyperactivity disorder, and autism (4)(5)(6). While neurexin serves as a major presynaptic receptor for other FAM19As and participates in a wide range of neurological processes (7), it is suggested that FAM19A5 may act as a ligand for different synaptic receptors. ...
Alzheimer’s disease (AD) is characterized by the progressive loss of synapses, leading to cognitive decline. Immunotherapies targeting amyloidosis or tauopathy have shown promise in AD treatment, but additional therapies are needed to inhibit continuous and excessive synaptic loss, which could improve clinical outcomes by modifying the course of the disease. Understanding the mechanisms of synaptic loss is essential for the development of new therapies. Here, we propose an antibody-based immunotherapy targeting FAM19A5, a secretory protein in the brain. We found that FAM19A5 binds to LRRC4B, a post-synaptic adhesion molecule, which disassembles synaptic connections, leading to synapse elimination. FAM19A5 levels increased in association with aging and the progression of tau accumulation. We inhibited FAM19A5 using NS101, an anti-FAM19A5 monoclonal antibody, in mouse models of AD. NS101 preserved synaptic connections despite the presence of amyloid or tau aggregates. Consequently, the number of mature synapses and their function were restored, resulting in improved cognitive performance. In study participants, NS101 was delivered to the human brain across the blood-brain barrier, bound to FAM19A5, and cleared into the peripheral circulation without any toxicity. These findings demonstrate that restoring synapses by inhibiting synaptic elimination can be an effective therapeutic strategy and provide a fundamental basis for modifying AD.
One-Sentence Summary
The antibody NS101 targeting FAM19A5 restores synapse number and function in Alzheimer’s disease, improving cognition.
... This is supported by ndings from Fam19a5 KO mice, which exhibited hyperactivity, depressive-like behaviors, and reduced spatial learning and memory, as well as a decrease in dendritic spine density, glutamate signaling, and neuronal activity (20). Genome-wide association studies have revealed the association of FAM19A5 with neurological disorders including AD, attention de cit hyperactivity disorder, and autism (21,22). Furthermore, a single-nucleus RNA-seq (snRNA-seq) in human AD brain samples showed that FAM19A5 transcript levels in neurons were higher in those with early AD pathology than in those without (23). ...
Disruption in the dynamic balance of the synapse build-and-removal process is a major cause of neurological diseases, although the mechanisms underlying how the brain fine-tunes and balances this process remain poorly understood. Here, we demonstrate that FAM19A5 binds to the postsynaptic adhesion molecule LRRC4B and suppresses interaction between LRRC4B and presynaptic PTPRF, suggesting a role of FAM19A5 in synapse assembly. Decoys with the FAM19A5 binding (FB) domain redirect FAM19A5, promoting synapse formation. The anti-FAM19A5 antibody NS101 disrupts the FAM19A5-LRRC4B complex, transferring FAM19A5 from the brain to the bloodstream, restoring synaptic integrity and improving cognitive function in Alzheimer's mouse models. Our findings suggest NS101 could be a therapeutic strategy for neurodegenerative diseases requiring regeneration of neurites and formation of new synapses.
... About 20% of the total PMS population shows deletions or duplications caused by unbalanced chromosomal translocations and in few rare cases the chromosomal imbalance is inherited from one parent with a balanced translocation [3,5]. In other cases a ring chromosome 22 (r22) has been reported, either isolated or as part of a more complex rearrangement [6,7]. ...
Phelan-McDermid syndrome (PMS) is a multi-system disorder characterized by significant variability in clinical presentation. The genetic etiology is also variable with differing sizes of deletions in the chromosome 22q13 region and types of genetic abnormalities (e.g., terminal or interstitial deletions, translocations, ring chromosomes, or SHANK3 variants). Position effects have been shown to affect gene expression and function and play a role in the clinical presentation of various genetic conditions. This study employed a topologically associating domain (TAD) analysis approach to investigate position effects of chromosomal rearrangements on selected candidate genes mapped to 22q13 in 81 individuals with PMS. Data collected were correlated with clinical information from these individuals and with expression and metabolic profiles of lymphoblastoid cells from selected cases. The data confirmed TAD predictions for genes encompassed in the deletions and the clinical and molecular data indicated clear differences among individuals with different 22q13 deletion sizes. The results of the study indicate a positive correlation between deletion size and phenotype severity in PMS and provide evidence of the contribution of other genes to the clinical variability in this developmental disorder by reduced gene expression and altered metabolomics.
... In addition, FAM19A5 plays an important role in the development of nervous system from an early stage [5]. A recent study has reported that a patient with a combination of chromosomal abnormalities including TUSC7 gene, FAM19A5 gene and 43 RefSeq genes microdeletions shows development delay, mood swings, hyperexcitability and sleep disturbance [6]. Our previous study has identified that sphingosine-1-phosphate receptor 2 (S1PR2) is a G proteincoupled receptor for FAM19A5 [7]. ...
FAM19A5/TAFA5 is a member of the family with sequence similarity 19 with unknown function in emotional and cognitive regulation. Here, we reported that FAM19A5 was highly expressed in the embryonic and postnatal mouse brain, especially in the hippocampus. Behaviorally, genetic deletion of Fam19a5 resulted in increased depressive-like behaviors and impaired hippocampus-dependent spatial memory. These behavioral alterations were associated with the decreased expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and N-methyl-D-aspartic acid receptors, as well as significantly reduced glutamate release and neuronal activity in the hippocampus. Subsequently, these changes led to the decreased density of dendritic spines. In recent years, the roles of chronic stress participating in the development of depression have become increasingly clear, but the mechanism remains to be elucidated. We found that the levels of FAM19A5 in plasma and hippocampus of chronic stress-treated mice were significantly decreased whereas overexpression of human FAM19A5 selectively in the hippocampus could attenuate chronic stress-induced depressive-like behaviors. Taken together, our results revealed for the first time that FAM19A5 plays a key role in the regulation of depression and spatial cognition in the hippocampus. Furthermore, our study provided a new mechanism for chronic stress-induced depression, and also provided a potential biomarker for the diagnosis and a new strategy for the treatment of depression.
... A Korean study shows FAM19A5 plays a vital role at an early stage of nervous system development, and its functions are critical to the generation of stem cells in the adult brain such as neural stem cells and oligodendrocyte precursor cells [22]. Not only in animal experiments, the correlation between FAM19A5 and neurodevelopment in clinical studies has also been found [30,31]. More recent research shows that selective overexpression of FAM19A5 in the mouse hippocampus can alleviate chronic stress-related spatial learning and memory impairment [32]. ...
Objective:
Family with sequence similarity 19 member A5 (FAM19A5), a novel chemokine-like peptide, is a secreted protein mainly expressed in the brain. FAM19A5 was recently found to be involved in a variety of neurological diseases; however, its correlation with vascular dementia (VaD) remains unclear. The aim of the study is to explore the association between serum FAM19A5 and cognitive impairment in subjects with VaD.
Method:
136 VaD subjects and 81 normal controls were recruited in the study. Their demographic and clinical baseline data were collected on admission. All subjects received Mini-Mental State Examination (MMSE) evaluation, which was used to test their cognitive functions. A sandwich enzyme-linked immunosorbent assay (ELISA) was applied to detect the serum levels of FAM19A5.
Results:
No significant differences were found between the two groups regarding the demographic and clinical baseline data (p > 0.05). The serum FAM19A5 levels were significantly higher compared to normal controls (p < 0.001). The Spearman correlation analysis indicated that serum FAM19A5 levels and MMSE scores have a significant negative correlation in VaD patients (r = -0.414, <0.001). Further multiple regression analysis indicated that serum FAM19A5 levels were independent risk predictors for cognitive functions in VaD (β = 0.419, p = 0.031).
Conclusion:
The serum FAM19A5 level of VaD patients is significantly increased, which may serve as a biomarker to predict cognitive function of VaD.
... database shows that 47 human diseases are associated with the FAM19A5 gene including Alzheimer's 11,12 , schizophrenia 13,14 , bipolar disorder 15 , pancreatic carcinoma 16 , and endometrial neoplasm 17 , among others 18 . Interestingly, the mosaic monosomy of chromosome 22, which includes disruption of the FAM19A5 gene, leads to skeletal abnormalities, low body weight, and neuropsychiatric conditions, including attention deficit hyperactivity disorder, aggression, and autistic symptoms 19 . Recently, the deletion of chromosome 22q13.32, ...
FAM19A5 (also called TAFA5) is a novel secretory protein that is primarily expressed in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function. Furthermore, genome-wide association study (GWAS) and RNA-seq analyses revealed that the FAM19A5 was associated with a variety of diseases and tumorigenesis in peripheral tissues. We investigated FAM19A5 transcript and protein levels in the peripheral tissues, including adipose tissues from wild-type, FAM19A5 knock-out, and LacZ knock-in mice. In general, total FAM19A5 transcript levels in the central and peripheral nervous systems were higher than levels in any of the peripheral tissues including adipose tissues. Brain tissues expressed similar levels of the FAM19A5 transcript isoforms 1 and 2, whereas expression in the peripheral tissues predominantly expressed isoform 2. In the peripheral tissues, but not the brain, FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for analysis by Western blot. Additionally, we found that FAM19A5 protein did not interact with the S1PR2 receptor for G-protein-mediated signal transduction, β-arrestin recruitment, and ligand-mediated internalization. Instead, FAM19A5 was internalized into HEK293 cells in an extracellular matrix protein-dependent manner. Taken together, the present study determined basal levels of FAM19A5 transcripts and proteins in peripheral tissues, which provides compelling evidence to further investigate the function of FAM19A5 in peripheral tissues under pathological conditions, including metabolic diseases and/or tumorigenesis.
... Family with sequence similarity 19 [chemokine (CeC motif)like] member A5 (FAM19A5) encoded by TAFA genes (TAFA-1 to TAFA-5) is a secretory protein with cytokine-like properties [8] that is highly expressed in the brain and adipose tissues with very low expression in other peripheral organs [8e11]. In adipose tissues, FAM19A5 expression was reduced in rodent models of obesity with high-fat diet-induced obese and leptin receptor-deficient mice [10]. ...
... Since FAM19A5 expression was first reported in the brain [8], a limited number of studies have reported possible brain functions of FAM19A5 in pathophysiological and psychiatric conditions; genetic analyses show involvement of FAM19A5 in human Alzheimer's disease [17,18], a chromosomal mutation that disrupts the FAM19A5 gene is correlated with low body weight and neuropsychiatric problems such as aggression and autistic symptoms [19] and a mutation with multiple copies of FAM19A5 is associated with glioma in some patients [20]. A recent study described FAM19A5 expression in neurons, microglia and astrocytes using X-gal staining in FAM19A5-LacZ knock-in mice, finding that X-gal expression increased in cortical neurons following traumatic brain injury [21]. ...
The cytokine-like protein FAM19A5 is highly expressed in the brain, but little is known about its functions there. Here, we found that FAM19A5 was expressed in mouse hypothalamic cells expressing proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related peptide (AgRP), and in the microglia. Tumor necrosis factor-α (TNF-α), which induces inflammatory sickness responses, greatly increased hypothalamic expression of FAM19A5. Knockdown of FAM19A5 expression resulted in decreased TNF-α-induced anorexia, body weight loss and TNF-α-induced expression of inflammatory factors. In contrast, intracerebroventricular administration of FAM19A5 induced anorexia, body weight loss and hyperthermia, together with increased expression of inflammatory factors. FAM19A5 injection also induced increases in c-fos activation and POMC mRNA level in hypothalamic POMC neurons. Together, these results suggest that FAM19A5 plays an important role in hypothalamic inflammatory responses.
... Genome-wide association studies have demonstrated an association of FAM19A5 with late-onset Alzheimer disease in humans (Herold et al., 2016;Mez et al., 2017). Mosaic monosomy of chromosome 22-which includes disruption of the FAM19A5 gene-leads to skeletal abnormalities, low body weight, and neuropsychiatric problems, including attention deficit hyperactivity disorder (ADHD), aggression, or autistic symptoms (Kashevarova et al., 2018). Multiple gene copies of the FAM19A5 gene seems to be associated with glioma in some patients (Díaz De Ståhl et al., 2005), implying the role of FAM19A5 in tumorigenesis of the central nervous system (CNS). ...
... In summary, the FAM19A5 expression pattern revealed by X-gal staining during mouse embryogenesis and in the adult brain following TBI suggests FAM19A5 is a key regulator in both CNS development and the injury response of the brain. Understanding the function of FAM19A5 in the brain is of particular importance because recent clinical studies have revealed the genetic association of FAM19A5 with brain development-related symptoms, such as ADHD and autism (Kashevarova et al., 2018), and degenerative disease, such as Alzheimer disease (Herold et al., 2016;Mez et al., 2017). FAM19A5 is expressed in a variety of brain cell types but primarily in pyramidal neurons in the cortex and hippocampus and in OPCs in the corpus callosum, as well as in astrocytes and microglia. ...
FAM19A5 is a secretory protein that is predominantly expressed in the brain. Although the FAM19A5 gene has been found to be associated with neurological and/or psychiatric diseases, only limited information is available on its function in the brain. Using FAM19A5-LacZ knock-in mice, we determined the expression pattern of FAM19A5 in developing and adult brains and identified cell types that express FAM19A5 in naïve and traumatic brain injury (TBI)–induced brains. According to X-gal staining results, FAM19A5 is expressed in the ventricular zone and ganglionic eminence at a very early stage of brain development, suggesting its functions are related to the generation of neural stem cells and oligodendrocyte precursor cells (OPCs). In the later stages of developing embryos and in adult mice, FAM19A5 expression expanded broadly to particular regions of the brain, including layers 2/3 and 5 of the cortex, cornu amonis (CA) region of the hippocampus, and the corpus callosum. X-gal staining combined with immunostaining for a variety of cell-type markers revealed that FAM19A5 is expressed in many different cell types, including neurons, OPCs, astrocytes, and microglia; however, only some populations of these cell types produce FAM19A5. In a subpopulation of neuronal cells, TBI led to increased X-gal staining that extended to the nucleus, marked by slightly condensed content and increased heterochromatin formation along the nuclear border. Similarly, nuclear extension of X-gal staining occurred in a subpopulation of OPCs in the corpus callosum of the TBI-induced brain. Together, these results suggest that FAM19A5 plays a role in nervous system development from an early stage and increases its expression in response to pathological conditions in subsets of neurons and OPCs of the adult brain.
... Over 1500 children with idiopathic intellectual disability were examined as part of the European Union project "Improving Diagnoses of Mental Retardation in Children in Eastern Europe and Central Asia through Genetic Characterisation and Bioinformatics/Statistics" (CHERISH), and the RIMG identified several novel chromosomal microdeletions and microduplications [46][47][48][49]. All clinical and molecular protocols were introduced into the Genetics Clinic of the RIMG in Tomsk and are now available to patients. ...
We provide an overview of the recent achievements in psychiatric genetics research in the Russian Federation and present genotype-phenotype, population, epigenetic, cytogenetic, functional, ENIGMA, and pharmacogenetic studies, with an emphasis on genome-wide association studies. The genetic backgrounds of mental illnesses in the polyethnic and multicultural population of the Russian Federation are still understudied. Furthermore, genetic, genomic, and pharmacogenetic data from the Russian Federation are not adequately represented in the international scientific literature, are currently not available for meta-analyses and have never been compared with data from other populations. Most of these problems cannot be solved by individual centers working in isolation but warrant a truly collaborative effort that brings together all the major psychiatric genetic research centers in the Russian Federation in a national consortium. For this reason, we have established the Russian National Consortium for Psychiatric Genetics (RNCPG) with the aim to strengthen the power and rigor of psychiatric genetics research in the Russian Federation and enhance the international compatibility of this research.
The consortium is set up as an open organization that will facilitate collaborations on complex biomedical research projects in human mental health in the Russian Federation and abroad. These projects will include genotyping, sequencing, transcriptome and epigenome analysis, metabolomics, and a wide array of other state-of-the-art analyses. Here, we discuss the challenges we face and the approaches we will take to unlock the huge potential that the Russian Federation holds for the worldwide psychiatric genetics community.
