-
MedRxiv : the Preprint Server For... Sep 2023Recurrent copy number variants (rCNVs) are associated with increased risk of neuropsychiatric disorders but their pathogenic population-level impact is unknown. We...
Recurrent copy number variants (rCNVs) are associated with increased risk of neuropsychiatric disorders but their pathogenic population-level impact is unknown. We provide population-based estimates of rCNV-associated risk of neuropsychiatric disorders for 34 rCNVs in the iPSYCH2015 case-cohort sample (n=120,247). Most observed significant increases in rCNV-associated risk for ADHD, autism or schizophrenia were moderate (HR:1.42-5.00), and risk estimates were highly correlated across these disorders, the most notable exception being high autism-associated risk with Prader-Willi/Angelman Syndrome duplications (HR=20.8). No rCNV was associated with significant increase in depression risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint. Comparison with published rCNV studies suggests that prevalence of some rCNVs is higher, and risk of psychiatric disorders lower, than previously estimated. In an era where genetics is increasingly being clinically applied, our results highlight the importance of population-based risk estimates for genetics-based predictions.
PubMed: 37886536
DOI: 10.1101/2023.09.04.23294975 -
BMC Psychology Feb 2024Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that is often comorbid with Autism Spectrum Disorder (ASD). Due to the close association between these...
BACKGROUND
Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that is often comorbid with Autism Spectrum Disorder (ASD). Due to the close association between these two conditions, and recognizing that Theory of Mind (ToM) is related to social behaviors in ASD, there is a growing interest in studying the reciprocity of social communication between these two groups.
METHOD
The primary objective of this study was to compare how children (n = 45) with PWS (n = 15), ASD (n = 15), and a control group (n = 15) respond to emotion recognition of facial expressions and empathy, which are both concepts related to ToM. The study utilized two tools named FEEL and Deusto-e-Motion 1.0. We also evaluated the Working Memory index of the WISC-IV scale, the Social Perception domain of the NEPSY-II battery, and the SCQ in both clinical groups.
RESULTS
Our findings suggest that individuals with PWS exhibit lower accuracy in recognizing facial expressions and empathy compared to the control group. Both clinical groups exhibited a delayed reaction time compared to the control group. Children with PWS display difficulties in recognizing emotions of disgust and surprise. In terms of cognitive empathy, children with PWS showed a greater inclination to respond to disgust as compared to children with ASD.
CONCLUSIONS
This study represents the initial stage in comprehending the emotional and empathetic abilities of children with PWS and ASD. The findings can provide valuable insights for developing future interventions.
Topics: Child; Humans; Autism Spectrum Disorder; Empathy; Prader-Willi Syndrome; Facial Recognition; Emotions; Facial Expression
PubMed: 38395942
DOI: 10.1186/s40359-024-01590-3 -
European Journal of Translational... Apr 2024Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by hypothalamic dysfunction, hypotonia, cognitive deficits, and hyperphagia, primarily resulting...
Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by hypothalamic dysfunction, hypotonia, cognitive deficits, and hyperphagia, primarily resulting from genetic abnormalities on chromosome 15. Among its varied manifestations, musculoskeletal issues, notably scoliosis, pose important challenges in management. This study aims to investigate differences in postural-motor development and spinal range of movement between preadolescents and adolescents with PWS, with and without scoliosis, while also exploring the potential impact of scoliosis on caregiving burden, an aspect yet to be thoroughly explored in existing literature. This observational study evaluated 13 individuals diagnosed with PWS, including 5 with scoliosis (PWS-Sc) and 7 without (PWS-NSc). Inclusion criteria comprised ages 8 to 18 years, confirmed PWS diagnosis through genetic testing, and scoliosis diagnosis. Anamnestic data, physical examinations, and surface measurements were collected, along with parental burden assessments using the Zarit Burden Interview (ZBI). Both groups displayed delays in achieving postural-motor milestones, with the PWS-Sc group exhibiting a more pronounced delay, although statistical significance was not achieved. The main curve magnitude in the PWS-Sc group averaged 31.5° Cobb, with 60% of cases presenting an S-shaped curve. Surface measurements of physiological curves did not differ significantly between groups, but the scoliosis-affected group exhibited lower lumbar extension values (p=0.04). The overall ZBI revealed higher scores in the PWS-Sc group, although statistical significance was not reached. However, significant differences were observed in single questions score evaluating aspects such as social life and caregiver uncertainty (p=0.04 and p=0.03, respectively). Despite the small sample size, delays in achieving postural-motor milestones, particularly in individuals with scoliosis, were observed. The differences recorded in lumbo-pelvic movement suggest that tailored interventions may be beneficial. The heightened caregiving burden in the scoliosis group underscores the need for targeted support. Early intervention and ongoing monitoring should be important for accurate diagnosis and appropriate care, potentially with psychological support for caregivers.
PubMed: 38651535
DOI: 10.4081/ejtm.2024.12533 -
Investigative Ophthalmology & Visual... Feb 2024To reveal the clinical significance, pathological involvement and molecular mechanism of imprinted in Prader-Willi syndrome (IPW) in RPE anomalies that contribute to AMD.
PURPOSE
To reveal the clinical significance, pathological involvement and molecular mechanism of imprinted in Prader-Willi syndrome (IPW) in RPE anomalies that contribute to AMD.
METHODS
IPW expression under pathological conditions were detected by microarrays and qPCR assays. In vitro cultured fetal RPE cells were used to study the pathogenicity induced by IPW overexpression and to analyze its upstream and downstream regulatory networks.
RESULTS
We showed that IPW is upregulated in the macular RPE-choroid tissue of dry AMD patients and in fetal RPE cells under oxidative stress, inflammation and dedifferentiation. IPW overexpression in fetal RPE cells induced aberrant apical-basal polarization as shown by dysregulated polarized markers, disrupted tight and adherens junctions, and inhibited phagocytosis. IPW upregulation was also associated with RPE oxidative damages, as demonstrated by intracellular accumulation of reactive oxygen species, reduced cell proliferation, and accelerated cell apoptosis. Mechanically, N6-methyladenosine level of the IPW transcript regulated its stability with YTHDC1 as the reader. IPW mediated RPE features by suppressing MEG3 expression to sequester its inhibition on the AKT serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) pathway. We also noticed that the mTOR inhibitor rapamycin suppresses the AKT/mTOR pathway to alleviate the IPW-induced RPE anomalies.
CONCLUSIONS
We revealed that IPW overexpression in RPE induces aberrant apical-basal polarization and oxidative damages, thus contributing to AMD progression. We also annotated the upstream and downstream regulatory networks of IPW in RPE. Our findings shed new light on the molecular mechanisms of RPE dysfunctions, and indicate that IPW blockers may be a promising option to treat RPE abnormalities in AMD.
Topics: Humans; Retinal Pigment Epithelium; Prader-Willi Syndrome; Proto-Oncogene Proteins c-akt; Up-Regulation; Macular Degeneration; Oxidative Stress; TOR Serine-Threonine Kinases; Adenine
PubMed: 38315495
DOI: 10.1167/iovs.65.2.10 -
BMC Pediatrics Jan 2024Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader-Willi syndrome (PWS) in improving short stature and metabolism, but the effect of...
Evaluating the effect of recombinant human growth hormone treatment on sleep-related breathing disorders in toddlers with Prader-Willi syndrome: a one-year retrospective cohort study.
BACKGROUND
Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader-Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS.
METHODS
A total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected.
RESULTS
The mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea-hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO), lowest SpO, duration when SpO is lower than 90%, or proportion of the patients with SpO lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs.
CONCLUSION
Treatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.
Topics: Humans; Child, Preschool; Infant; Human Growth Hormone; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Prader-Willi Syndrome; Retrospective Studies; Sleep
PubMed: 38200464
DOI: 10.1186/s12887-023-04513-0 -
Brain and Behavior Apr 2024The 15q11-q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic...
BACKGROUND
The 15q11-q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic phenomenon that causes differential gene expression based on the parent of origin. In most diploid organisms, gene expression typically involves an equal contribution from both maternal and paternal alleles, shaping the phenotype. Nevertheless, in mammals, including humans, mice, and marsupials, the functional equivalence of parental alleles is not universally maintained. Notably, during male and female gametogenesis, parental alleles may undergo differential marking or imprinting, thereby modifying gene expression without altering the underlying DNA sequence. Neurodevelopmental disorders, such as Prader-Willi syndrome (PWS) (resulting from the absence of paternally expressed genes in this region), Angelman syndrome (AS) (associated with the absence of the maternally expressed UBE3A gene), and 15q11-q13 duplication syndrome (resulting from the two common forms of duplications-either an extra isodicentric 15 chromosome or an interstitial 15 duplication), are the outcomes of genetic variations in this imprinting region.
METHODS
Conducted a genomic study to identify the frequency of pathogenic variants impacting the 15q11-q13 region in an ethnically homogenous population from Bangladesh. Screened all known disorders from the DECIPHER database and identified variant enrichment within this cohort. Using the Horizon analysis platform, performed enrichment analysis, requiring at least >60% overlap between a copy number variation and a disorder breakpoint. Deep clinical phenotyping was carried out through multiple examination sessions to evaluate a range of clinical symptoms.
RESULTS
This study included eight individuals with clinically suspected PWS/AS, all previously confirmed through chromosomal microarray analysis, which revealed chromosomal breakpoints within the 15q11-q13 region. Among this cohort, six cases (75%) exhibited variable lengths of deletions, whereas two cases (25%) showed duplications. These included one type 2 duplication, one larger atypical duplication, one shorter type 2 deletion, one larger type 1 deletion, and four cases with atypical deletions. Furthermore, thorough clinical assessments led to the diagnosis of four PWS patients, two AS patients, and two individuals with 15q11-q13 duplication syndrome.
CONCLUSION
Our deep phenotypic observations identified a spectrum of clinical features that overlap and are unique to PWS, AS, and Dup15q syndromes. Our findings establish genotype-phenotype correlation for patients impacted by variable structural variations within the 15q11-q13 region.
Topics: Humans; Female; Male; Animals; Mice; DNA Copy Number Variations; Alleles; Angelman Syndrome; Prader-Willi Syndrome; Bangladesh; Mammals
PubMed: 38616334
DOI: 10.1002/brb3.3437 -
Genetics in Medicine : Official Journal... Jan 2024Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the...
PURPOSE
Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States.
METHODS
We performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns. Total creatine kinase testing and next generation sequencing of an 86-neuromuscular gene panel that included DMD were offered to parents of newborns who screened positive. Bivariate and multivariable analyses were performed to assess effects of biological and demographic predictors on CK-MM levels in DBS.
RESULTS
We screened 13,354 newborns and identified 2 males with DMD. The provisional 1626 ng/mL cutoff was raised to 2032 ng/mL to improve specificity, and additional cutoffs (900 and 360 ng/mL) were implemented to improve sensitivity for older and low-birthweight newborns.
CONCLUSION
Population-scale screening for elevated CK-MM in DBS is a feasible approach to identify newborns with DMD. Inclusion of birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improve sensitivity and specificity of screening.
Topics: Male; Humans; Infant, Newborn; Muscular Dystrophy, Duchenne; Neonatal Screening; Birth Weight; North Carolina; Prospective Studies; Creatine Kinase
PubMed: 37864479
DOI: 10.1016/j.gim.2023.101009 -
Journal of Pediatric Genetics Dec 2023Prader-Willi syndrome (PWS) is a genetic disorder caused by the expression disruption of genes on the paternally inherited allele of chromosome 15q11.2-q13. Apart from...
Prader-Willi syndrome (PWS) is a genetic disorder caused by the expression disruption of genes on the paternally inherited allele of chromosome 15q11.2-q13. Apart from clinical diagnostic criteria, PWS is confirmed by genetic testing. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is one of the molecular techniques used to analyze this syndrome. This study aimed to evaluate the concordance of the test results of MS-MLPA with conventional techniques in the diagnosis of PWS in Thai patients. Forty leftover specimens from routine genetic testing (MS-PCR and FISH) were tested to obtain MS-MLPA results. By comparison, perfect concordance was shown between the result of MS-MLPA and those of conventional techniques. In conclusion, MS-MLPA is an accurate and cost-effective assay that can be used to confirm PWS diagnosis with explicit deletion of affected genes.
PubMed: 38162164
DOI: 10.1055/s-0041-1741008 -
International Journal of Molecular... Jul 2023N-acetylglucosamine kinase (NAGK) has been identified as an anchor protein that facilitates neurodevelopment with its non-canonical structural role. Similarly, small...
N-acetylglucosamine kinase (NAGK) has been identified as an anchor protein that facilitates neurodevelopment with its non-canonical structural role. Similarly, small nuclear ribonucleoprotein polypeptide N (SNRPN) regulates neurodevelopment and cognitive ability. In our previous study, we revealed the interaction between NAGK and SNRPN in the neuron. However, the precise role in neurodevelopment is elusive. In this study, we investigate the role of NAGK and SNRPN in the axodendritic development of neurons. NAGK and SNRPN interaction is significantly increased in neurons at the crucial stages of neurodevelopment. Furthermore, overexpression of the NAGK and SNRPN proteins increases axodendritic branching and neuronal complexity, whereas the knockdown inhibits neurodevelopment. We also observe the interaction of NAGK and SNRPN with the dynein light-chain roadblock type 1 (DYNLRB1) protein variably during neurodevelopment, revealing the microtubule-associated delivery of the complex. Interestingly, NAGK and SNRPN proteins rescued impaired axodendritic development in an SNRPN depletion model of Prader-Willi syndrome (PWS) patient-derived induced pluripotent stem cell neurons. Taken together, these findings are crucial in developing therapeutic approaches for neurodegenerative diseases.
Topics: Humans; Autoantigens; Chromosomes, Human, Pair 15; Cytoplasmic Dyneins; Dyneins; Microtubules; Neurons; Peptides; Prader-Willi Syndrome; Ribonucleoproteins, Small Nuclear; snRNP Core Proteins
PubMed: 37511433
DOI: 10.3390/ijms241411672 -
BioRxiv : the Preprint Server For... Oct 2023Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder characterized principally by initial symptoms of neonatal hypotonia and failure-to-thrive in infancy,...
Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder characterized principally by initial symptoms of neonatal hypotonia and failure-to-thrive in infancy, followed by hyperphagia and obesity. It is well established that PWS is caused by loss of paternal expression of the imprinted region on chromosome 15q11-q13. While most PWS cases exhibit megabase-scale deletions of the paternal chromosome 15q11-q13 allele, several PWS patients have been identified harboring a much smaller deletion encompassing primarily . This finding suggests is a direct driver of PWS phenotypes. The gene cluster is composed of 30 copies of individual C/D box small nucleolar RNAs (snoRNAs). Many C/D box snoRNAs have been shown to guide chemical modifications of other RNA molecules, often ribosomal RNA (rRNA). However, snoRNAs are termed 'orphans' because no verified targets have been identified and their sequences show no significant complementarity to rRNA. It is crucial to identify the targets and functions of snoRNAs because all reported PWS cases lack their expression. To address this, we engineered two different deletions modelling PWS in two distinct human embryonic stem cell (hESC) lines to control for effects of genetic background. Utilizing an inducible expression system enabled quick, reproducible differentiation of these lines into neurons. Systematic comparisons of neuronal gene expression across deletion types and genetic backgrounds revealed a novel list of 42 consistently dysregulated genes. Employing the recently described computational tool snoGloBe, we discovered these dysregulated genes are significantly enriched for predicted targeting versus multiple control analyses. Importantly, our results showed it is critical to use multiple isogenic cell line pairs, as this eliminated many spuriously differentially expressed genes. Our results indicate a novel gene regulatory network controlled by is likely perturbed in PWS patients.
PubMed: 37873184
DOI: 10.1101/2023.10.03.560773