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The molecular mechanism of Angelman syndrome (AS) has been studied in two large families with the finding that there is an imprinting mutation. In several patients in the past microdeletions upstream of the SNRPN (ital) gene have been seen, defining an imprinting center (IC) hypothesized to regulate the imprint switch process in the male and female germlines. In the families an AS imprinting mutation was segregated. One of the families was described in an earlier genetic linkage of AS to 15q11-q13. The original linkage is for the 15q11-q13 IC. Affected patients in the AS families have either a 5.5- or a 15-kb microdeletion, one of which narrowed the shortest region of deletion overlap to 1.15 kb in all the cases. The small region defines a component of the IC involved in AS, the paternal-to-maternal switch element. Genetic counseling issues for AS and Prader-Willi syndrome are brought out by the research.

[Ge.sub.x][As.sub.y][Se.sub.1-x-y] glasses are prepared with mean coordination (MCNs) and the elastic moduli of the glasses are estimated from the shear and compressional wave velocities. Two elastic transition thresholds are observed simultaneously and the elastic moduli of two groups of samples with the same MCN but different compositions have shown that the chemical compositions have an impact on the elastic properties.

We have prepared GexAsySe1-x-y glasses with mean coordination numbers (MCNs) from 2.2 to 2.86. Tg was found to generally increase with increasing MCN while the glass density showed a maximum at MCN≈2.45 and a minimum at MCN≈2.65. The elastic moduli of the glasses were estimated from the shear and compressional wave velocities measured by ultrasonic pulse interferometry. For the first time we simultaneously observed two elastic transition thresholds, the first at MCN≈2.45 and the second at MCN≈2.65, which appear closely correlated with changes in the glass microstructure. The elastic moduli of two groups of samples with the same MCN=2.4 and 2.64 but different compositions suggest that the chemical compositions also have an influence on the elastic properties. [ABSTRACT FROM AUTHOR]

While short-read sequencing currently dominates genetic research and diagnostics, it frequently falls short of capturing certain structural variants (SVs), which are often implicated in the etiology of neurodevelopmental disorders (NDDs). Optical genome mapping (OGM) is an innovative technique capable of capturing SVs that are undetectable or challenging-to-detect via short-read methods. This study aimed to investigate NDDs using OGM, specifically focusing on cases that remained unsolved after standard exome sequencing. OGM was performed in 47 families using ultra-high molecular weight DNA. Single-molecule maps were assembled de novo, followed by SV and copy number variant calling. We identified 7 variants of interest, of which 5 (10.6%) were classified as likely pathogenic or pathogenic, located in BCL11A, OPHN1, PHF8, SON, and NFIA. We also identified an inversion disrupting NAALADL2, a gene which previously was found to harbor complex rearrangements in two NDD cases. Variants in known NDD genes or candidate variants of interest missed by exome sequencing mainly consisted of larger insertions (> 1kbp), inversions, and deletions/duplications of a low number of exons (1-4 exons). In conclusion, in addition to improving molecular diagnosis in NDDs, this technique may also reveal novel NDD genes which may harbor complex SVs often missed by standard sequencing techniques., (© 2024. The Author(s).)

We studied a patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and sensorineural hearing loss. Instead of pathogenic variants in the mitochondrial maintenance genes, we identified previously unpublished variant in DHX16 gene, a de novo heterozygous c.1360C>T (p. Arg454Trp). Variants in DHX16 encoding for DEAH-box RNA helicase have previously been reported only in five patients with a phenotype called as neuromuscular oculoauditory syndrome including developmental delay, neuromuscular symptoms, and ocular or auditory defects with or without seizures. We performed functional studies on patient-derived fibroblasts and skeletal muscle revealing, that the DHX16 expression was decreased. Clinical features together with functional data suggest, that our patient's disease is associated with a novel pathogenic DHX16 variant, and mtDNA depletion could be a secondary manifestation of the disease., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Hormonal and reproductive factors affect the risk for cardiovascular events (CVE) in the general population. Although the risk of CVE is increased in rheumatoid arthritis (RA), the knowledge about the impact of hormonal factors for CVE in RA is sparse. Female postmenopausal patients ≤80 years with early RA were consecutively included in this observational study ( n = 803) between 1 January 1996 until 31 December 2017. Questionnaires regarding hormonal factors were distributed from the index date. Data regarding CVE were obtained from the Swedish National Health Register and Cause of Death Register. Associations between CVE and hormonal factors were analyzed using Cox proportional hazard regression. Of the postmenopausal women, 64 women had a CVE after RA onset. The time period from menopause to RA onset was significantly longer for CVE cases with higher proportion of postmenopausal women. In Cox proportional hazard regression models, years from last childbirth and multiparity were associated with higher CVE risk. Adjustments for traditional risk factors did not affect the results except for hypertension. RA onset after menopause and a longer duration from menopause until onset increased the CVE risk. Multiparity was associated with higher CVE risk whilst oral contraceptives decreased the risk. These results can contribute to identification of high-risk patients for CVE beyond traditional risk factors.

Background: The increased comorbidity and mortality in rheumatoid arthritis (RA) patients are largely due to cardiovascular disease (CVD). Previously, we demonstrated increased frequencies of risk factors for CVD (elevated body mass index (BMI), elevated apoliprotein (Apo) B:ApoA1 ratio, and smoking) in pre-RA individuals compared with matched controls., Objectives: Assess the impact of traditional CV risk factors present before the onset of RA on the risk of CV events (CVE) after diagnosis in comparison with matched controls., Methods: A case-control study including 521 pre-symptomatic individuals and 1566 controls identified within the Health Surveys of the Medical Biobank was performed. CVD risk factors were hypertension, elevated ApoB:A1 ratio, BMI, diabetes, and smoking. Information on comorbidities was requested from the Swedish National Patient Register and Cause of Death Register., Results: Pre-RA individuals had a higher risk of future CVE compared with matched controls (HR [95% CI] 1.70 [1.31-2.21]), which remained after adjustments for risk factors for CVD (HR [95% CI] 1.73 [1.27-2.35]). Most risk factors were associated with CVE after diagnosis, and a combination resulted in a higher risk in RA compared with controls; two risk factors, HR [95% CI] 2.70 [1.19-6.13] vs. 1.26 [0.75-2.13]; and three to four risk factors, HR [95% CI] 6.32 [2.92-13.68] vs. 3.77 [2.34-6.00]., Conclusions: Risk factors for CVD present in pre-RA individuals were associated with future CVE, and even after adjustments for these risk factors and treatments after RA onset, pre-RA individuals had a higher risk of CVE compared with controls. These findings further highlight the importance of the early assessment of risk for CVD.

Background: Microduplications are a rare cause of disease in X-linked neurodevelopmental disorders but likely have been under reported due challenges in detection and interpretation., Methods: We performed exome sequencing and subsequent microarray analysis in two families with a neurodevelopmental disorder., Results: Here, we report on two families each with unique inherited microduplications at Xp21.2 and Xq13.1, respectively. In the first family, a 562.8-kb duplication at Xq13.1 covering DLG3, TEX11, SLC7A3, GDPD2, and part KIF4A was identified in a boy whose phenotype was characterized by delayed speech development, mild intellectual disability (ID), mild dysmorphic facial features, a heart defect, and neuropsychiatric symptoms. By interrogating all reported Xq13.1 duplications in individuals affected with a neurodevelopmental disorder, we provide evidence that this genomic region and particularly DLG3 might be sensitive to an increased dosage. In the second family with four affected males, we found a noncontinuous 223- and 204-kb duplication at Xp21.2, of which the first duplication covers exon 6 of IL1RAPL1. The phenotype of the male patients was characterized by delayed speech development, mild to moderate ID, strabismus, and neurobehavioral symptoms. The carrier daughter and her mother had learning difficulties. IL1RAPL1 shows nonrecurrent causal structural variation and is located at a common fragile site (FRAXC), prone to re-arrangement., Conclusion: In conclusion, we show that comprehensive clinical and genetic examination of microduplications on the X-chromosome can be helpful in undiagnosed cases of neurodevelopmental disease., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency., Objective: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1., Methods: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used., Results: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain., Conclusions: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Plastic packaging exemplifies recycling's potential; 95 percent of plastic's material use vanishes after a short first-use cycle. Yet over half of plastic packaging could be recycled effectively, economically, and in an environmentally sound manner, with individuals and households playing a focal role in raising recycling rates. This paper draws on the theory of planned behaviour (TPB) to identify and examine household plastic sorting and recycling factors in Finland's new recycling scheme. The results of a regression analysis generally support existing research, except paradoxically, the easier it was to obtain recycling information the less people recycled. TPB's attitude (environmental concerns) and perceived behavioural control factors (low behavioural costs, and dealing with waste) showed significant positive relationships with Finnish recycling behaviour; the subjective norm (social norms) had an insignificant relationship. Age, living quarters, the time spent recycling, the distance to collection points, and the willingness to improve also related significantly to diligent plastic waste sorting. In addition to re-examining the information type and delivery, the significant role of costs and facilitating conditions offer intervention possibilities to support households to recycle more plastic packaging., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)