Chromosome 15q11-q13 Duplication Syndrome: A Review of the Literature and 14 New Cases.

The 15q11.2q13 chromosomal region is particularly susceptible to chromosomal rearrangements due to low-copy repeats (LCRs) located inside this area. Specific breakpoints (BP1-BP5) that lead to deletions and duplications of variable size have been identified. Additionally, this specific region contains several imprinted genes, giving rise to complex syndromes (Prader-Willi, Angelman and 15q11-q13 duplication syndromes). 15q11.2-q13 duplication syndrome has been associated with neurodevelopmental disorders (hypotonia, developmental delay, speech delay and seizures) and ASD but is characterized by variable expressivity and reduced penetrance, features that make genetic counseling a complex procedure especially in prenatal cases. In the present study, a total of 14 pre- and postnatal cases were diagnosed as 15q11.2q13 duplication carriers using Affymetrix CytoScan 750 K array-CGH, and our analysis combined these with 120 cases existing in the literature. The inheritance pattern of the cases of this study is unknown, but as a review of the literature revealed, 62.96% of the affected carriers inherited the duplicated area from their mother. The combined results of this analysis (the present study and the literature) show that in the majority of the cases, the phenotype is a compound phenotype, with clinical characteristics that include ASD, intellectual disability, developmental delay and an absence of speech. The aim of this paper is to deliver new possibilities to genetic counseling that can be provided in prenatal and postnatal cases as the phenotype of 15q11.2q13 microduplication carriers cannot be fully predicted; so, clinical diagnoses should be a combination of molecular findings and clinical manifestations that are present.

The motivations and methods behind sharing a pediatric Prader-Willi syndrome diagnosis.

Prader-Willi syndrome (PWS) is a genetic condition caused by a lack of paternally-expressed imprinted genes at chromosome 15q11.2-q13 and characterized by hyperphagia, behavioral challenges, and variable intellectual disability. Once a PWS diagnosis is established, sharing diagnosis information with an affected child can be challenging due to its early age of onset and diverse phenotype. This mixed-methods study aimed to evaluate how parents and guardians have shared a PWS diagnosis with their child and examine the motivating and influencing factors behind their disclosure. Parents and guardians of children with PWS aged at least 5 years completed a survey, and a select group completed an interview. A total of 51 surveys and 15 interviews were completed, with the majority of participants (n = 46; 90%) having shared at least some diagnosis information with their child. Parents and guardians were more likely to disclose if they self-reported a higher level of knowledge about PWS (p = 0.004) and if their child is currently older (p = 0.02) and/or has at least one sibling (p = 0.046). Interview analysis revealed 15 themes and 10 subthemes that illustrated parents' motivations, methods, and experiences with disclosure. This research provides information for others considering disclosure of PWS or another rare diagnosis with their child.

Epigenomic newborn screening for conditions with intellectual disability and autistic features in Australian newborns.

This study describes a protocol to assess a novel workflow called Epi-Genomic Newborn Screening (EpiGNs) on 100,000 infants from the state of Victoria, Australia. The workflow uses a first-tier screening approach called methylation-specific quantitative melt analysis (MS-QMA), followed by second and third tier testing including targeted methylation and copy number variation analyzes with droplet digital PCR, EpiTYPER system and low-coverage whole genome sequencing. EpiGNs utilizes only two 3.2 mm newborn blood spot punches to screen for genetic conditions, including fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, Dup15q syndrome and sex chromosome aneuploidies. The program aims to: identify clinically actionable methylation screening thresholds for the first-tier screen and estimate prevalence for the conditions screened.

[Box: see text].

[Prenatal diagnosis of a fetus with 15q11q13 complex duplication syndrome and a literature review].

OBJECTIVE: To explore the clinical features and genetic etiology of a fetus with 15q11q13 complex duplication syndrome. METHODS: A fetus diagnosed with 15q11q13 duplication syndrome at Ningbo Women and Children's Hospital on April 19, 2023 was selected as the study subject. Clinical data was collected, and the fetus was subjected to invasive prenatal diagnosis including G-banded karyotyping and chromosomal microarray analysis (CMA). Following the discovery of chromosomal duplication, trio-whole exome sequencing was carried out to exclude single base variants and confirm the parental original of the duplication. Optical genome mapping was also performed to delineate the structural arrangement of the duplication. Relevant literature was searched in the PubMed, Wanfang Medical Network and CNKI databases using "15q11q13", "duplication", "hexasomy" and "Six fold repetition" as the key words from January 1, 2000 to August 1, 2023 for a review of previously reported 15q11q13 hexasomy cases. This study was approved by the Ningbo Women & Children's Hospital (Ethics No. EC2020-048). RESULTS: The fetus was found to have a mosaicism karyotype of 48,X?,+mar,+idic(15)(q13)[33]/47,X?,+idic(15)(q13)[17]. CMA and trio-WES have all shown a six-fold duplication in the PWS/AS critical region (PWACR) at 15q11.2q13.2 and quadruple duplication of 15q13.2q13.3 region, which have derived from its mother and formed supernumerary marker chromosomes (SMCs). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the 15q11.2q13.2 sixfold duplication was classified as pathogenic, whilst the 15q13.2q13.3 quadruple duplication was classified as variant of uncertain significance. Literature search has identified 11 cases of 15q11q13 duplication involving hexasomy of the PWACR, with all cases showing mental retardation, language delay and hypotonia, and most of them also had motor retardation, epilepsy and mild facial dysmorphism. CONCLUSION: Hexasomy for the PWACR combined with tetrasomy of 15q13.2q13.3 probably underlay the left hand polydactyly, polyhydramnios and intrauterine growth retardation in this fetus.

Multiscale spatio-temporal dynamics of UBE3A gene in brain physiology and neurodevelopmental disorders.

The UBE3A gene, located in the chromosomal region 15q11-13, is subject to neuron-specific genomic imprinting and it plays a critical role in brain development. Genetic defects of UBE3A cause severe neurodevelopmental disorders, namely the Angelman syndrome (AS) and the 15q11.2-q13.3 duplication syndrome (Dup15q). In the last two decades, the development of in vitro and in vivo models of AS and Dup15q were fundamental to improve the understanding of UBE3A function in the brain. However, the pathogenic mechanisms of these diseases remain elusive and effective treatments are lacking. Recent evidence suggests that UBE3A functions are both spatially and temporally specific, varying across subcellular compartments, brain regions, and neuronal circuits. In the present review, we summarize current knowledge on the role of UBE3A in neuronal pathophysiology under this spatio-temporal perspective. Additionally, we propose key research questions that will be instrumental to better understand the pathogenic mechanisms underpinning AS and Dup15q disorders and provide the rationale to develop novel therapies.

CNVDeep: deep association of copy number variants with neurocognitive disorders.

BACKGROUND: Copy number variants (CNVs) have become increasingly instrumental in understanding the etiology of all diseases and phenotypes, including Neurocognitive Disorders (NDs). Among the well-established regions associated with ND are small parts of chromosome 16 deletions (16p11.2) and chromosome 15 duplications (15q3). Various methods have been developed to identify associations between CNVs and diseases of interest. The majority of methods are based on statistical inference techniques. However, due to the multi-dimensional nature of the features of the CNVs, these methods are still immature. The other aspect is that regions discovered by different methods are large, while the causative regions may be much smaller. RESULTS: In this study, we propose a regularized deep learning model to select causal regions for the target disease. With the help of the proximal [20] gradient descent algorithm, the model utilizes the group LASSO concept and embraces a deep learning model in a sparsity framework. We perform the CNV analysis for 74,811 individuals with three types of brain disorders, autism spectrum disorder (ASD), schizophrenia (SCZ), and developmental delay (DD), and also perform cumulative analysis to discover the regions that are common among the NDs. The brain expression of genes associated with diseases has increased by an average of 20 percent, and genes with homologs in mice that cause nervous system phenotypes have increased by 18 percent (on average). The DECIPHER data source also seeks other phenotypes connected to the detected regions alongside gene ontology analysis. The target diseases are correlated with some unexplored regions, such as deletions on 1q21.1 and 1q21.2 (for ASD), deletions on 20q12 (for SCZ), and duplications on 8p23.3 (for DD). Furthermore, our method is compared with other machine learning algorithms. CONCLUSIONS: Our model effectively identifies regions associated with phenotypic traits using regularized deep learning. Rather than attempting to analyze the whole genome, CNVDeep allows us to focus only on the causative regions of disease.

Minimal phenotypes in transgenic mice with the human LOXL1/LOXL1-AS1 locus associated with exfoliation glaucoma.

Exfoliation syndrome is a leading cause of secondary glaucoma worldwide. Among the risk-factors for exfoliation syndrome and exfoliation glaucoma that have been investigated, a genetic association with 15q24.1 is among the most striking. The leading candidates for the causal gene at this locus are LOXL1 and/or LOXL1-AS1, but studies have not yet coalesced in establishing, or ruling out, either candidate. Here, we contribute to studies of the 15q24.1 locus by making a partially humanized mouse model in which 166 kb of human genomic DNA from the 15q24.1 locus was introduced into the mouse genome via BAC transgenesis (B6-Tg(RP11-71M11)Andm). Transgenic expression of human genes in the BAC was only detectable for LOXL1-AS1. One cohort of 34 mice (21 experimental hemizygotes and 13 non-carrier control littermates) was assessed by slit-lamp exams and SD-OCT imaging at early (1-2 months) and mid (4-5 months) time points; fundus exams were performed at 5 months of age. A second smaller cohort (3 hemizygotes) were aged extensively (>12 months) to screen for overt abnormalities. Across all genotypes and ages, 136 slit-lamp exams, 128 SD-OCT exams, and 42 fundus exams detected no overt indices of exfoliation syndrome. Quantitatively, small, but statistically significant, age-related declines in ganglion cell complex thickness and total retinal thickness were detected in the hemizygotes at 4 months of age. Overall, this study demonstrates complexity in gene regulation from the 15q24.1 locus and suggests that LOXL1-AS1 is unlikely to be a monogenic cause of exfoliation syndrome but may contribute to glaucomatous retinal damage.

Identification of copy-number variants in patients with overgrowth disorders.

Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders whose main characteristic is that the weight, height or the head circumference are above the 97th centile or 2-3 standard deviations above the mean for age, gender, and ethnic group. Several copy-number variants (CNVs) have been associated with the development of OGS, such as the 5q35 microdeletion or the duplication of the 15q26.1-qter, among many others. In this study, we have applied 850K SNP-arrays to 112 patients and relatives with OGS from the Spanish OverGrowth Registry Initiative. We have identified CNVs associated with the disorder in nine individuals (8%). Subsequently, whole genome sequencing (WGS) analysis was performed in these nine samples in order to better understand these genomic imbalances. All the CNVs were detected by both techniques, settling that WGS is a useful tool for CNV detection. We have found six patients with genomic abnormalities associated with previously well-established disorders and three patients with CNVs of unknown significance, which may be related to OGS, based on scientific literature. In this report, we describe these findings and comment on genes associated with OGS that are located within the CNV regions.

A complex t(15;22;17)(q22;q11.2;q21) variant of APL.

The present study described an extremely rare case of acute promyelocytic leukemia (APL) characterized by a complex three­way (15;22;17)(q22;q11.2;q21) translocation. Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia with distinctive clinical and therapeutic characteristics. Besides being characterized by the t(15;17)(q22;q12) translocation, this subtype is also notable for its response to all-trans-retinoic acid (ATRA) treatment. APL is highly responsive to a combination of ATRA and chemotherapeutic agents, achieving over 90 % complete remission rates and over 80 % long-term remission rates. In this case, a 79-year-old male patient presented with complaints of weakness, fatigue, and petechial rash, with no other significant medical history except for diabetes mellitus and hypertension. Conventional cytogenetic methods, dual-color dual-fusion, and dual-color break-apart fluorescent in situ hybridization techniques together identified the t(15;22;17) translocation. RT-PCR analysis was performed for expression of PML/RARA fusion transcripts. The patient, diagnosed with APL, exhibited a complete response to all-trans retinoic acid (ATRA) and idarubicin treatment. In this paper, we present the second documented case of t(15;22;17) and explore the remarkable remission observed following treatment with All-Trans Retinoic Acid (ATRA).

Diagnosis of Two Unrelated Syndromes of Prader-Willi and Calpainopathy: Insight from Trio Whole Genome Analysis and Isodisomy Mapping.

PURPOSE: An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS). METHODS: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected. RESULTS: Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15, expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2-15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy. CONCLUSION: This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM#253600) in the same patient. This report highlights the utility of joint analysis and the need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotypes.

Integration of CTCF loops, methylome, and transcriptome in differentiating LUHMES as a model for imprinting dynamics of the 15q11-q13 locus in human neurons.

Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that terminates at PWAR1 in non-neurons. qRT-PCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11 834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.

Prenatal diagnosis of a 15q24.1 microdeletion in a fetus with cerebral and urogenital abnormalities.

15q24.1 microdeletion syndrome is a recently described condition often resulting from non-allelic homologous recombination (NAHR). Typical clinical features include pre and post-natal growth retardation, facial dysmorphism, developmental delay and intellectual disability. Nonspecific urogenital, skeletal, and digit abnormalities may be present, although other congenital malformations are less frequent. Consequently, only one case was reported prenatally, complicating the genotype-phenotype correlation and the genetic counseling. We identified prenatally a second case, presenting with cerebral abnormalities including hydrocephaly, macrocephaly, cerebellum hypoplasia, vermis hypoplasia, rhombencephalosynapsis, right kidney agenesis with left kidney duplication and micropenis. Genome-wide aCGH assay allowed a diagnosis at 26 weeks of amenorrhea revealing a 1.6 Mb interstitial deletion on the long arm of chromosome 15 at 15q24.1-q24.2 (arr[GRCh37] 15q24.1q24.2(74,399,112_76,019,966)x1). A deep review of the literature was undertaken to further delineate the prenatal clinical features and the candidate genes involved in the phenotype. Cerebral malformations are typically nonspecific, but microcephaly appears to be the most frequent in postnatal cases. Our case is the first reported with a frank cerebellar involvement.

Trisomy 21 with Maternally Inherited Balanced Translocation (15q;22q) in a Female Fetus: A Rare Case of Probable Interchromosomal Effect.

Chromosomal rearrangements can interfere with the disjunction and segregation of other chromosome pairs not involved in the rearrangements, promoting the occurrence of numerical abnormalities in resulting gametes and predisposition to trisomy in offspring. This phenomenon of interference is known as the interchromosomal effect (ICE). Here we report a prenatal case potentially generated by ICE. The first-trimester screening ultrasound of the pregnant woman was normal, but the NIPT indicated a high risk for three copies of chromosome 21, thus suspecting trisomy 21 (T21). After a comprehensive clinical evaluation and genetic counseling, the couple decided to undergo amniocentesis. The prenatal karyotype confirmed T21 but also showed a balanced translocation between the long arm of chromosome 15 (q22) and the long arm of chromosome 22. The parents' karyotypes also showed that the mother had the 15;22 translocation. We reviewed T21 screening methods, and we performed a literature review on ICE, a generally overlooked phenomenon. We observed that ours is the first report of a prenatal case potentially due to ICE derived from the mother. The recurrence risk of aneuploidy in the offspring of translocated individuals is likely slightly increased, but it is not possible to estimate to what extent. In addition to supporting observations, there are still open questions such as, how frequent is ICE? How much is the aneuploidy risk altered by ICE?

Elimination of the extra chromosome of Dup15q syndrome iPSCs for cellular and molecular investigation.

Chromosome 15q11.2-13.1 duplication (Dup15q) syndrome is one of the most common autism spectrum disorders (ASDs) associated with copy number variants (CNVs). For the analysis of CNV-relevant pathological cellular phenotypes, a CNV-corrected isogenic cell line is useful for excluding the influence of genetic background. Here, we devised a strategy to remove the isodicentric chromosome 15 by inserting a puro-ΔTK selection cassette into the extra chromosome using the CRISPR-Cas9 system, followed by a subsequent two-step drug selection. A series of assays, including qPCR-based copy number analysis and karyotype analysis, confirmed the elimination of the extra chromosome. Furthermore, cerebral organoids were generated from the parental Dup15q iPSCs and their isogenic iPSCs. scRNA-seq analysis revealed the alteration of expression levels in ion-channel-related genes and synapse-related genes in glutamatergic and GABAergic neurons in Dup15q organoids, respectively. The established isogenic cell line is a valuable resource for unraveling cellular and molecular alterations associated with Dup15q syndrome.

Cell-type-specific effects of autism-associated 15q duplication syndrome in the human brain.

Recurrent copy-number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder. Duplication of 15q11-q13 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of autism more than 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex, we conducted single-nucleus RNA sequencing and multi-omic sequencing on dup15q-affected individuals (n = 6) as well as individuals with non-dup15q autism (n = 7) and neurotypical control individuals (n = 7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene-expression changes. As compared to other cell types, neuronal subtypes showed greater upregulation of gene expression across a critical region within the duplication. Genes that fell within the duplicated region and had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and autism had largely distinct signatures of chromatin accessibility but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding-factor motifs implicated in each condition implicated distinct biological mechanisms: neuronal JUN and FOS networks in autism vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain, and it finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects of copy-number variants more broadly in neurodevelopmental disorders.

Genetic components of microdeletion syndromes and their role in determining schizophrenia traits.

Schizophrenia is a neuropsychiatric disorder characterized by various symptoms such as hallucinations, delusions, and disordered thinking. The etiology of this disease is unknown; however, it has been linked to many microdeletion syndromes that are likely to contribute to the pathology of schizophrenia. In this review we have comprehensively analyzed the role of various microdeletion syndromes, like 3q29, 15q13.3, and 22q11.2, which are known to be involved with schizophrenia. A variety of factors lead to schizophrenia phenotypes, but copy number variants that disrupt gene regulation and impair brain function and cognition are one of the causes that have been identified. Multiple case studies have shown that loss of one or more genes in the microdeletion regions lead to brain activity defects. In this article, we present a coherent paradigm that connects copy number variations (CNVs) to numerous neurological and behavioral abnormalities associated with schizophrenia. It would be helpful in understanding the different aspects of the microdeletions and how they contribute in the pathophysiology of schizophrenia.

Sleep EEG signatures in mouse models of 15q11.2-13.1 duplication (Dup15q) syndrome.

BACKGROUND: Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABAAR) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABAARs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls. METHODS: We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student's t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05. RESULTS: Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation. CONCLUSIONS: Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations.

Genotype-phenotype characteristics of 57 patients with Prader-Willi syndrome: a single-center experience from Turkey.

OBJECTIVES: Prader-Willi syndrome (PWS) is a rare and complex genetic disorder caused by the loss of expression of the paternal copy of the imprinted genes on chromosome 15q11-q13. A variety of findings have been reported on the phenotypic differences between the genetic subtypes of PWS. This article compares the clinical findings of 57 PWS patients by genetic subtype and explores possible associations in this context. METHODS: Methylation­specific multiplex ligation-dependent probe amplification and single nucleotide polymorphism microarrays were used to diagnose deletion and uniparental disomy (UPD). For phenotype-genotype correlation, clinical data were collected and genetic subgroups were compared statistically, and P  < 0.05 was considered to indicate statistical significance. RESULTS: These 57 patients consisted of 15 type I deletions, 20 type II deletions, six atypic deletions, 11 heterodisomy UPD, four isodisomy UPD, and one translocation-type PWS. All patients had hypotonia, poor neonatal sucking, and feeding difficulties during infancy. Other PWS-related clinical findings, such as speech articulation problems (85.9%), sleep apnea (77.2%), normal birth length (71.9%), small hands/feet (71.9%), childhood polyphagia (57.9%), clinodactyly (56.1%), thick viscous saliva (54.4%), and behavioral problems (50.9%) were observed at varying rates with no statistical difference between genetic subtypes in general. CONCLUSION: This study highlights the phenotype-genotype associations on PWS from a cohort of Turkish pediatric patients as a single-center experience.

Investigating the correlation between genotype and phenotype in Prader-Willi syndrome: a study of 45 cases from Brazil.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in PWS is crucial for improved genetic counseling and prognosis. In this study, we aimed to investigate the correlation between genotype and phenotype in 45 PWS patients who previously underwent methylation-sensitive high-resolution melting (MS-HRM) for diagnosis. RESULTS: We employed methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and Sanger sequencing, along with collecting phenotypic data from the patients for comparison. Among the 45 patients, 29 (64%) exhibited a deletion of 15q11-q13, while the remaining 16 (36%) had uniparental disomy. No statistically significant differences were found in the main signs and symptoms of PWS. However, three clinical features showed significant differences between the groups. Deletion patients had a higher prevalence of myopia than those with uniparental disomy, as well as obstructive sleep apnea and an unusual skill with puzzles. CONCLUSIONS: The diagnostic tests (MS-HRM, MS-MLPA, and Sanger sequencing) yielded positive results, supporting their applicability in PWS diagnosis. The study's findings indicate a general similarity in the genotype-phenotype correlation across genetic subtypes of PWS.

Human C15orf39 Inhibits Inflammatory Response via PRMT2 in Human Microglial HMC3 Cell Line.

Microglia-mediated inflammatory response is one key cause of many central nervous system diseases, like Alzheimer's disease. We hypothesized that a novel C15orf39 (MAPK1 substrate) plays a critical role in the microglial inflammatory response. To confirm this hypothesis, we used lipopolysaccharide (LPS)-and interferon-gamma (IFN-γ)-induced human microglia HMC3 cells as a representative indicator of the microglial in vitro inflammatory response. We found that C15orf39 was down-regulated when interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) expression increased in LPS/IFN-γ-stimulated HMC3 cells. Once C15orf39 was overexpressed, IL-6 and TNFα expression were reduced in LPS/IFN-γ-stimulated HMC3 cells. In contrast, C15orf39 knockdown promoted IL-6 and TNFα expression in LPS/IFN-γ-stimulated HMC3 cells. These results suggest that C15orf39 is a suppressive factor in the microglial inflammatory response. Mechanistically, C15orf39 interacts with the cytoplasmic protein arginine methyltransferase 2 (PRMT2). Thus, we termed C15orf39 a PRMT2 interaction protein (PRMT2 IP). Furthermore, the interaction of C15orf39 and PRMT2 suppressed the activation of NF-κB signaling via the PRMT2-IκBα signaling axis, which then led to a reduction in transcription of the inflammatory factors IL6 and TNF-α. Under inflammatory conditions, NF-κBp65 was found to be activated and to suppress C15orf39 promoter activation, after which it canceled the suppressive effect of the C15orf39-PRMT2-IκBα signaling axis on IL-6 and TNFα transcriptional expression. In conclusion, our findings demonstrate that in a steady condition, the interaction of C15orf39 and PRMT2 stabilizes IκBα to inhibit IL-6 and TNFα expression by suppressing NF-κB signaling, which reversely suppresses C15orf39 transcription to enhance IL-6 and TNFα expression in the microglial inflammatory condition. Our study provides a clue as to the role of C15orf39 in microglia-mediated inflammation, suggesting the potential therapeutic efficacy of C15orf39 in some central nervous system diseases.