Impact of Deletion on Angelman Syndrome Phenotype Variability: Phenotype-Genotype Correlation in 97 Patients with Motor Developmental Delay.

Angelman syndrome (AS) is a rare neurodevelopmental disorder due to genetic defects involving chromosome 15, known by intellectual disability, cognitive and behavioral disorders, ataxia, delayed motor development, and seizures. This study highlights the clinical spectrum and molecular research to establish the genotype-phenotype correlation in the pediatric Moroccan population. Methylation-specific-polymerase chain reaction (MS-PCR) is a primordial technique not only to identify the genetic mechanism of AS but also to characterize the different molecular classes induced in the appearance of the clinical symptoms. Patients with positive methylation profile were additionally studied by fluorescent in situ hybridization. Sequencing analysis of the UBE3A gene was performed for patients with negative MS-PCR. We used Fisher's test to assess differences in the distribution of features frequencies among the deletional and the nondeletional group. Statistical analysis was performed using R project. We identified from 97 patients diagnosed with AS, 14 (2.06%) had a classical AS phenotype, while 70 (84.5%) patients displayed a subset of consistent and frequent criteria. Development delay was shown severe in 63% and moderate in 37%. Nineteen out of 97 of them had MS-PCR positive in which 17 (89.47%) had 15q11-q13 deletion. Deletion patients presented a higher incidence of epileptic seizures ( p = 0.04), ataxia ( p = 0.0008), and abnormal electroencephalogram (EEG) profile ( p = 0.003). We further found out a frameshift deletion located at exon 9 of the UBE3A gene discovered in a 5 years old patient. We report in this study the genotype-phenotype correlation using different molecular testing. Correlation analysis did not reveal any statistical differences in phenotypic dissimilarity between deletion and nondeletion groups for most clinical features, except the correlation was highly significant in the abnormal EEG. According to our findings, we recommend offering MS-PCR analysis to all patients with severe intellectual disability, developmental delay, speech impairment, happy demeanor, and hypopigmentation.

Rally 'round the flag effects are not for all: Trajectories of institutional trust among populist and non-populist voters.

Using the Consequences of COVID-19 (COCO) dataset (quota sample of the adult Italian population, surveyed seven times by email), we analysed the trend of trust in political (political parties, parliament and local administrations), super partes (president of the Republic, judiciary and police) and international (the European Union and the United Nations) institutions from June 2019 to October 2022. Three latent growth curve models showed that trust in political institutions increased between June 2019 and April 2020 and subsequently decreased below the pre-pandemic level. Trust in super partes institutions decreased slightly between June 2019 and April 2020, decreased from April 2020 to April 2022 and increased in the subsequent months. Trust in international institutions declined between June 2019 and April 2020 and then returned to pre-pandemic levels. Three piecewise decompositions showed different trends in trust for non-populist voters, populist voters and non-voters. Strengths, weaknesses and possible developments of the study are discussed.

High OXPHOS efficiency in RA-FUdr-differentiated SH-SY5Y cells: involvement of cAMP signalling and respiratory supercomplexes.

Neurons are highly dependent on mitochondria to meet their bioenergetic needs and understanding the metabolic changes during the differentiation process is crucial in the neurodegeneration context. Several in vitro approaches have been developed to study neuronal differentiation and bioenergetic changes. The human SH-SY5Y cell line is a widely used cellular model and several differentiation protocols have been developed to induce a neuron-like phenotype including retinoic acid (RA) treatment. In this work we obtained a homogeneous functional population of neuron-like cells by a two-step differentiation protocol in which SH-SY5Y cells were treated with RA plus the mitotic inhibitor 2-deoxy-5-fluorouridine (FUdr). RA-FUdr treatment induced a neuronal phenotype characterized by increased expression of neuronal markers and electrical properties specific to excitable cells. In addition, the RA-FUdr differentiated cells showed an enrichment of long chain and unsaturated fatty acids (FA) in the acyl chain composition of cardiolipin (CL) and the bioenergetic analysis evidences a high coupled and maximal respiration associated with high mitochondrial ATP levels. Our results suggest that the observed high oxidative phosphorylation (OXPHOS) capacity may be related to the activation of the cyclic adenosine monophosphate (cAMP) pathway and the assembly of respiratory supercomplexes (SCs), highlighting the change in mitochondrial phenotype during neuronal differentiation.

Low-grade parental gonosomal mosaicism in CHD2 siblings with Smith-Magenis-like syndrome.

Loss-of-function CHD2 (chromodomain helicase DNA-binding protein 2) mutations are associated with a spectrum of neurodevelopmental disorders often including early-onset generalized seizures, photosensitivity, and epileptic encephalopathies. Patients show psychomotor delay/intellectual disability (ID), autistic features, and behavior disorders, such as aggression and impulsivity. Most reported cases are sporadic with description of germline mosaicism only in two families. We detect the first case of parental gonosomal CHD2 mosaicism disclosed by two brothers showing mild ID, born to healthy parents. The eldest brother has a history of drug-controlled generalized tonic-clonic seizures and displays sleep disorder and aggressive behavior suggestive of Smith-Magenis syndrome (SMS). Analysis of brothers' DNAs by next-generation sequencing (NGS) custom gene panel for pediatric epilepsy and/or ID disclosed in both the same pathogenic CHD2 variant. Additional NGS experiment on genomic DNA from parents' peripheral blood and from buccal swab raised the suspicion of low-grade gonosomal mosaicism in the unaffected mother subsequently confirmed by digital polymerase chain reaction (dPCR). This report underlines as worthwhile CHD2 screening in individuals presenting ID/developmental delay, with/without epilepsy, and behavior and sleep disorders suggestive of SMS. Detecting a CHD2 variant should prime testing probands' parents by NGS coupled to dPCR on different tissues to exclude/confirm gonosomal mosaicism and define the recurrence risk.

Case report: Variability in clinical features as a potential pitfall for the diagnosis of Barth syndrome.

Background: Barth syndrome is a rare genetic disease characterized by cardiomyopathy, skeletal muscle weakness, neutropenia, growth retardation and organic aciduria. This variable phenotype is caused by pathogenic hemizygous variants of the TAFAZZIN gene on the X chromosome, which impair metabolism of the mitochondrial phospholipid cardiolipin. Although most patients are usually diagnosed in the first years of life, the extremely variable clinical picture and the wide range of clinical presentations may both delay diagnosis. This is the case reported here of a man affected with severe neutropenia, who was not diagnosed with Barth syndrome until adulthood. Case presentation: We describe herein a family case, specifically two Caucasian male cousins sharing the same mutation in the TAFAZZIN gene with a wide phenotypic variability: an infant who was early diagnosed with Barth syndrome due to heart failure, and his maternal cousin with milder and extremely different clinical features who has received the same diagnosis only at 33 years of age. Conclusions: Our report supports the underestimation of the prevalence of Barth syndrome, which should be always considered in the differential diagnosis of male patients with recurrent neutropenia with or without signs and symptoms of cardiomyopathy.

Case report: atypical Silver-Russell syndrome patient with hand dystonia: the valuable support of the consensus statement to the wide syndromic spectrum.

The amount of Insulin Growth Factor 2 (IGF2) controls the rate of embryonal and postnatal growth. The IGF2 and adjacent H19 are the imprinted genes of the telomeric cluster in the 11p15 chromosomal region regulated by differentially methylated regions (DMRs) or imprinting centers (ICs): H19/IGF2:IG-DMR (IC1). Dysregulation due to IC1 Loss-of-Methylation (LoM) or Gain-of-Methyaltion (GoM) causes Silver-Russell syndrome (SRS) or Beckwith-Wiedemann syndrome (BWS) disorders associated with growth retardation or overgrowth, respectively. Specific features define each of the two syndromes, but isolated asymmetry is a common cardinal feature, which is considered sufficient for a diagnosis in the BWS spectrum. Here, we report the case of a girl with right body asymmetry, which suggested BWS spectrum. Later, BWS/SRS molecular analysis identified IC1_LoM revealing the discrepant diagnosis of SRS. A clinical re-evaluation identified a relative macrocephaly and previously unidentified growth rate at lower limits of normal at birth, feeding difficulties, and asymmetry. Interestingly, and never previously described in IC1_LoM SRS patients, since the age of 16, she has developed hand-writer's cramps, depression, and bipolar disorder. Trio-WES identified a VPS16 heterozygous variant [NM_022575.4:c.2185C>G:p.Leu729Val] inherited from her healthy mother. VPS16 is involved in the endolysosomal system, and its dysregulation is linked to autosomal dominant dystonia with incomplete penetrance and variable expressivity. IGF2 involvement in the lysosomal pathway led us to speculate that the neurological phenotype of the proband might be triggered by the concurrent IGF2 deficit and VPS16 alteration.

Prenatal testing for imprinting disorders: A laboratory perspective.

Imprinting Disorders (ImpDis) are a group of congenital syndromes associated with up to four different types of molecular disturbances affecting the monoallelic and parent-of-origin specific expression of genomically imprinted genes. Though each ImpDis is characterized by aberrations at a distinct genetic site and a specific set of postnatal clinical signs, there is a broad overlap between several of them. In particular, the prenatal features of ImpDis are non-specific. Therefore, the decision on the appropriate molecular testing strategy is difficult. A further molecular characteristic of ImpDis is (epi)genetic mosaicism, which makes prenatal testing for ImpDis challenging. Accordingly, sampling and diagnostic workup has to consider the methodological limitations. Furthermore, the prediction of the clinical outcome of a pregnancy can be difficult. False-negative results can occur, and therefore fetal imaging should be the diagnostic tool on which decisions on the management of the pregnancy should be based. In summary, the decision for molecular prenatal testing for ImpDis should be based on close exchanges between clinicians, geneticists, and the families before the initiation of the test. These discussions should weigh the chances and challenges of the prenatal test, with focus on the need of the family.

Leader-member exchange (LMX) quality and follower well-being: A daily diary study.

Guided by self-determination and social exchange theories, we examine how leader-member exchange (LMX) quality impacts follower well-being. Despite LMX relationships being dynamic in nature, the way relationship quality varies over time and its impact on well-being has not been examined in detail. To address this important issue, a daily diary study is reported of employees from a variety of organizations. One hundred and fifty-eight participants completed a daily diary in the morning and evening for five consecutive workdays (k = 603 observations). Measures included hedonic and eudaimonic well-being, and social and economic LMX exchanges. There was a significant variation of LMX quality over the diary days. Daily LMX quality predicted daily follower well-being (while controlling for morning well-being). Further, for those that interacted with their manager, social LMX exchanges but not economic LMX exchanges predicted daily well-being. Interaction characteristics (frequency, time, content) had a relatively small impact on daily well-being. As predicted, work engagement mediated the relation between daily LMX quality and social LMX exchanges (but not daily economic LMX exchanges) with well-being. The results show how LMX quality affects followers' well-being that varies daily, that is affected by leaders' behaviors. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Corrigendum: Pubertal timing in children with Silver Russell syndrome compared to those born small for gestational age.

[This corrects the article DOI: 10.3389/fendo.2022.975511.].

Performance Metrics of the Scoring System for the Diagnosis of the Beckwith-Wiedemann Spectrum (BWSp) and Its Correlation with Cancer Development.

Different scoring systems for the clinical diagnosis of the Beckwith-Wiedemann spectrum (BWSp) have been developed over time, the most recent being the international consensus score. Here we try to validate and provide data on the performance metrics of these scoring systems of the 2018 international consensus and the previous ones, relating them to BWSp features, molecular tests, and the probability of cancer development in a cohort of 831 patients. The consensus scoring system had the best performance (sensitivity 0.85 and specificity 0.43). In our cohort, the diagnostic yield of tests on blood-extracted DNA was low in patients with a low consensus score (~20% with a score = 2), and the score did not correlate with cancer development. We observed hepatoblastoma (HB) in 4.3% of patients with UPD(11)pat and Wilms tumor in 1.9% of patients with isolated lateralized overgrowth (ILO). We validated the efficacy of the currently used consensus score for BWSp clinical diagnosis. Based on our observation, a first-tier analysis of tissue-extracted DNA in patients with <4 points may be considered. We discourage the use of the consensus score value as an indicator of the probability of cancer development. Moreover, we suggest considering cancer screening for negative patients with ILO (risk ~2%) and HB screening for patients with UPD(11)pat (risk ~4%).

Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants.

Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, associated to mild and severe phenotype, respectively, and of an RTT male harboring the close to p.Arg255*, p.Gly252Argfs*7 variant. Truncated MeCP2 proteins were revealed by Western blot and immunofluorescence analysis. We compared the mutant versus control neurons at 42 days for morphological parameters and at 120 days for electrophysiology recordings, including girls' isogenic clones. A precocious reduced morphological complexity was evident in neurons with truncating variants, while in p.Arg133Cys neurons any significant differences were observed in comparison with the isogenic wild-type clones. Reduced nuclear size and branch number show up as the most robust biomarkers. Patch clamp recordings on mature neurons allowed the assessment of cell biophysical properties, V-gated currents, and spiking pattern in the mutant and control cells. Immature spiking, altered cell capacitance, and membrane resistance of RTT neurons, were particularly pronounced in the Arg255* and Gly252Argfs*7 mutants. The overall results indicate that the specific markers of in vitro cellular phenotype mirror the clinical severity and may be amenable to drug testing for translational purposes.

Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in tafazzin knockdown mice.

Barth Syndrome (BTHS), a genetic disease associated with early-onset cardioskeletal myopathy, is caused by loss-of-function mutations of the TAFAZZIN gene, which is responsible for remodeling the mitochondrial phospholipid cardiolipin (CL). Deregulation of CL biosynthesis and maturation in BTHS mitochondria result in a dramatically increased monolysocardiolipin (MLCL)/CL ratio associated with bioenergetic dysfunction. One of the most promising therapeutic approaches for BTHS includes the mitochondria-targeted tetrapeptide SS-31, which interacts with CL. Here, we used TAFAZZIN knockdown (TazKD) mice to investigate for the first time whether in vivo administration of SS-31 could affect phospholipid profiles and mitochondrial dysfunction. The CL fingerprinting of TazKD cardiac mitochondria obtained by MALDI-TOF/MS revealed the typical lipid changes associated with BTHS. TazKD mitochondria showed lower respiratory rates in state 3 and 4 together with a decreased in maximal respiratory rates. Treatment of TazKD mice with SS-31 improved mitochondrial respiratory capacity and promoted supercomplex organization, without affecting the MLCL/CL ratio. We hypothesize that SS-31 exerts its effect by influencing the function of the respiratory chain rather than affecting CL directly. In conclusion, our results indicate that SS-31 have beneficial effects on improving cardiac mitochondrial dysfunction in a BTHS animal model, suggesting the peptide as future pharmacologic agent for therapy.

First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders.

BACKGROUND: Imprinting disorders, which affect growth, development, metabolism and neoplasia risk, are caused by genetic or epigenetic changes to genes that are expressed from only one parental allele. Disease may result from changes in coding sequences, copy number changes, uniparental disomy or imprinting defects. Some imprinting disorders are clinically heterogeneous, some are associated with more than one imprinted locus, and some patients have alterations affecting multiple loci. Most imprinting disorders are diagnosed by stepwise analysis of gene dosage and methylation of single loci, but some laboratories assay a panel of loci associated with different imprinting disorders. We looked into the experience of several laboratories using single-locus and/or multi-locus diagnostic testing to explore how different testing strategies affect diagnostic outcomes and whether multi-locus testing has the potential to increase the diagnostic efficiency or reveal unforeseen diagnoses. RESULTS: We collected data from 11 laboratories in seven countries, involving 16,364 individuals and eight imprinting disorders. Among the 4721 individuals tested for the growth restriction disorder Silver-Russell syndrome, 731 had changes on chromosomes 7 and 11 classically associated with the disorder, but 115 had unexpected diagnoses that involved atypical molecular changes, imprinted loci on chromosomes other than 7 or 11 or multi-locus imprinting disorder. In a similar way, the molecular changes detected in Beckwith-Wiedemann syndrome and other imprinting disorders depended on the testing strategies employed by the different laboratories. CONCLUSIONS: Based on our findings, we discuss how multi-locus testing might optimise diagnosis for patients with classical and less familiar clinical imprinting disorders. Additionally, our compiled data reflect the daily life experiences of diagnostic laboratories, with a lower diagnostic yield than in clinically well-characterised cohorts, and illustrate the need for systematising clinical and molecular data.

Masculinity, Perceived Vulnerability to COVID-19, and Adoption of Protective Behaviors.

Epidemiological data show that men and women have similar probabilities of contracting COVID-19. However, men with COVID-19 tend to have more severe outcomes than women. We performed two studies to analyze the associations between gender, adherence to traditional masculinity ideology, perceived vulnerability to COVID-19, and the adoption of protective behaviors against COVID-19. In Study 1 (quota sample of the Italian adult population, N = 1,142), we found no differences between men and women in terms of the perceived probability of contracting COVID-19. However, compared to women, men perceived themselves to be less likely to suffer severe consequences if falling ill. In Study 2 (Italian community sample, N = 305), a moderated mediation model showed that adherence to traditional masculinity ideology moderated the association between being man and the perceived severity of the consequences of COVID-19, which, in turn, showed negative associations with three protective behaviors against COVID-19. The article ends with a discussion of the strengths and limitations of this research.

Pubertal timing in children with Silver Russell syndrome compared to those born small for gestational age.

Context: Data on pubertal timing in Silver Russell syndrome (SRS) are limited. Design and methods: Retrospective observational study including twenty-three SRS patients [11p15 loss of methylation, (11p15 LOM, n=10) and maternal uniparental disomy of chromosome 7 (mUPD7, n=13)] and 21 small for gestational age (SGA). Clinical (thelarche in females; testis volume ≥ 4 ml in males; pubarche), BMI SD trend from the age of 5 to 9 years to the time of puberty, biochemical parameters of puberty onset [Luteinizing hormone (LH), 17-ß-estradiol, testosterone], and bone age progression were evaluated. Results: Pubertal onset and pubarche occurred significantly earlier in children with SRS than in SGA (p 0.03 and p 0.001, respectively) and clinical signs of puberty onset occurred earlier in mUPD7 than in 11p15LOM group (p 0.003). Five SRS children experienced central precocious puberty and LH, 17-ß-estradiol, testosterone were detected earlier in SRS than in SGA (p 0.01; p 0.0001). Bone age delay in SRS children was followed by rapid advancement; the delta between bone age and chronological age in SRS group became significantly higher than in SGA group at the age of 9-11 years (p 0.007). 11p15LOM patients were underweight at the age of 5 years and showed a progressive normalization of BMI that was significantly higher than in mUPD7 (p 0.04) and SGA groups (p 0.03) at puberty onset. Conclusion: Timing of puberty is affected in SRS and occurred earlier in mUPD7 compared to 11p15LOM. The impact of early puberty on adult height and metabolic status deserves long-term evaluation.

Household crowding during the COVID-19 lockdown fosters anti-democracy even after 17 months: A 5-wave latent growth curve study.

In an earlier cross-sectional study, Roccato et al. (2021) showed that household crowding during the COVID-19 lockdown was positively related to support for anti-democratic political systems. However, little is known about the persistence of these effect over time. In this study, we examined its duration in a longitudinal study structured in five waves, the first in May-June 2019 (before the COVID-19 outbreak, N = 1504) and the others during the pandemic, in April 2020 (during the lockdown, N = 1199), October 2020 (N = 1156), April 2021 (N = 1148), and October 2021 (N = 1151). The increase in support for anti-democratic systems associated with household overcrowding in the initial phase of the lockdown (Wave 2) did not change over the subsequent 17 months. Moreover, the effect was stronger among those who had high (compared with low) trust in democratic political institutions before the pandemic. Strengths, limitations, and potential developments of the study are discussed.

Congenital hypothyroidism after newborn screening program reorganization in the Apulia region.

BACKGROUND: Congenital hypothyroidism (CH) is the most frequent congenital endocrine disorder. The purpose of the present study was to evaluate the incidence and etiological classification of CH in Apulia in a three-year period according to the reorganization of the regional screening program in a single central laboratory, as well as to analyze the growth characteristics and the associated risk factors of the CH newborns diagnosed during the study period. METHODS: Data derived from the reorganization of the newborn screening program for CH in a single central laboratory that collects dried blood spot (DBS) from 27 Maternity Hospitals are analyzed over a three-year period. Birth weight and length, daily dose of L-T4 at specific key points (3, 6, 12 and 18 months, 2, 2.5 and 3 years) were also obtained from medical records of the CH newborns during the study period and calculated as standard deviation score (SDS). RESULTS: The screening program diagnosed 90 newborns with confirmed CH (incidence 1:990; recall rate: 3.6%). In detail, 75.6% newborns had an eutopic thyroid, and 24.4% had thyroid dysgenesis; 33 out of the 90 newborns (36.6%) had one or more risk factors. Among these, the multiple pregnancies are the most important because they tripled the risk of CH. At diagnosis, TSH levels were different between patients with dysgenesis and those with an eutopic thyroid (p = 0.005). Treatment was started at a mean of 18.5 ± 12.8 days of life. The mean starting dose of levothyroxine (L-T4) was 11.38 ± 2.46 µg/kg/day. CONCLUSIONS: The results of these study show an increase of CH cases in newborns with an eutopic thyroid compared to the traditional classification. The centralization of the screening program allows a closer cooperation between laboratory and clinical centers and facilitates the implementation of appropriate diagnostic evaluations and timely initiation of treatment, with positive effects on the management of the condition.

A unique Smith-Magenis patient with a de novo intragenic deletion on the maternally inherited overexpressed RAI1 allele.

RAI1 is a dosage-sensitive gene whose decreased or increased expression by recurrent and non-recurrent 17p11.2 deletions or duplications causes Smith-Magenis (SMS) or Potocki-Lupski syndromes (PTLS), respectively. Here we report on a 21-year-old female patient showing SMS phenotype who was found to carry a 3.4 kb de novo intragenic RAI1 deletion. Interestingly, a significant increase in RAI1 transcript levels was identified in the patient's, brother's and mother's peripheral blood cells. Allele-specific dosage analysis revealed that the patient's maternally inherited overexpressed RAI1 allele harbors the intragenic deletion, confirming the SMS diagnosis due to the presence of a single wild-type RAI1 functional allele. The mother and brother do not present any PTLS neurologic/behavioral clinical features. Extensive sequencing of RAI1 promoter and predicted regulatory regions showed no potential causative variants accounting for gene overexpression. However, the mother and both children share a novel private missense variant in RAI1 exon 3, currently classified as a VUS (uncertain significance), though predicted by two bioinformatic tools to disrupt the binding site of one specific transcription factor. The reported familial case, the second showing RAI1 overexpression in the absence of RAI1 duplication, may help to understand the regulation of RAI1 dosage sensitivity although its phenotypic effect remains to be determined.

Clinical and molecular characterization of patients affected by Beckwith-Wiedemann spectrum conceived through assisted reproduction techniques.

The prevalence of Beckwith-Wiedemann spectrum (BWSp) is tenfold increased in children conceived through assisted reproductive techniques (ART). More than 90% of ART-BWSp patients reported so far display imprinting center 2 loss-of-methylations (IC2-LoM), versus 50% of naturally conceived BWSp patients. We describe a cohort of 74 ART-BWSp patients comparing their features with a cohort of naturally conceived BWSp patients, with the ART-BWSp patients previously described in literature, and with the general population of children born from ART. We found that the distribution of UPD(11)pat was not significantly different in ART and naturally conceived patients. We observed 68.9% of IC2-LoM and 16.2% of mosaic UPD(11)pat in our ART cohort, that strongly differ from the figure reported in other cohorts so far. Since UPD(11)pat likely results from post-fertilization recombination events, our findings allows to hypothesize that more complex molecular mechanisms, besides methylation disturbances, may underlie BWSp increased risk in ART pregnancies. Moreover, comparing the clinical features of ART and non-ART BWSp patients, we found that ART-BWSp patients might have a milder phenotype. Finally, our data show a progressive increase in the prevalence of BWSp over time, paralleling that of ART usage in the last decades.