| 1. |
- Angius, Andrea, et al.
(författare)
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Exome sequencing in Crisponi/cold-induced sweating syndrome-like individuals reveals unpredicted alternative diagnoses
- 2019
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Ingår i: Clinical Genetics. - : WILEY. - 0009-9163 .- 1399-0004. ; 95:5, s. 607-614
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Tidskriftsartikel (refereegranskat)abstract
- Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.
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| 2. |
- Frisk, Sofia, et al.
(författare)
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Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth
- 2019
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Ingår i: Clinical Genetics. - : WILEY. - 0009-9163 .- 1399-0004. ; 96:2, s. 118-125
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Tidskriftsartikel (refereegranskat)abstract
- PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles.
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| 3. |
- Gudmundsson, Sanna, et al.
(författare)
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A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 : Review of the literature
- 2019
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Ingår i: European Journal of Medical Genetics. - : Elsevier. - 1769-7212 .- 1878-0849. ; 62:6
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Tidskriftsartikel (refereegranskat)abstract
- Cornelia de Lange syndrome (CdLS) is a heterogeneous developmental disorder where 70% of clinically diagnosed patients harbor a variant in one of five CdLS associated cohesin proteins. Around 500 variants have been identified to cause CdLS, however only eight different alterations have been identified in the RAD21 gene, encoding the RAD21 cohesin complex component protein that constitute the link between SMC1A and SMC3 within the cohesin ring. We report a 15-month-old boy presenting with developmental delay, distinct CdLS-like facial features, gastrointestinal reflux in early infancy, testis retention, prominent digit pads and diaphragmatic hernia. Exome sequencing revealed a novel RAD21 variant, c.1774_1776del, p.(Gln592del), suggestive of CdLS type 4. Segregation analysis of the two healthy parents confirmed the variant as de novo and bioinformatic analysis predicted the variant as disease-causing. Assessment by in silico structural model predicted that the p.Gln592del variant results in a discontinued contact between RAD21-Lys591 and the SMC1A residues Glu1191 and Glu1192, causing changes in the RAD21-SMC1A interface. In conclusion, we report a patient that expands the clinical description of CdLS type 4 and presents with a novel RAD21 p.(Glu592del) variant that causes a disturbed RAD21-SMC1A interface according to in silco structural modeling.
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| 4. |
- Gudmundsson, Sanna, 1989-, et al.
(författare)
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TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1's molecular functions remain elusive. In this study, we present a five-generation family affected with X-linked intellectual disability that co-segregated with a TAF1 c. 3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while heterozygous females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial function of human TAF1 during embryogenesis can be inferred from the model, demonstrating that intact taf1 is essential for embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment for genes associated with neurodevelopmental processes. In conclusion, we propose that functional TAF1 is essential for embryonic development and specifically neurodevelopmental processes.
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| 5. |
- Johansson, Josefin, et al.
(författare)
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A novel quantitative targeted analysis of X-chromosome Inactivation (XCI) using Nanopore sequencing
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- X-chromosome inactivation (XCI) analyses often assist in diagnostics of X-linked traits, however accurate assessment remains challenging with current methods. We developed a novel strategy using amplification-free Cas9 enrichment and Oxford nanopore technologies sequencing called XCI-ONT, to investigate and rigorously quantify XCI in human androgen receptor gene (AR) and human X-linked retinitis pigmentosa 2 gene (RP2). XCI-ONT measures methylation over 116 CpGs in AR and 58 CpGs in RP2, and separate parental X-chromosomes without PCR bias. We show the usefulness of the XCI-ONT strategy over the PCR-based golden standard XCI technique that only investigates one or two CpGs per gene. The results highlight the limitations of using the golden standard technique when the XCI pattern is partially skewed and the advantages of XCI-ONT to rigorously quantify XCI. This study provides a universal XCI-method on DNA, which is highly valuable in clinical and research framework of X-linked traits.
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| 6. |
- Laan, Loora, et al.
(författare)
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DNA methylation changes in Down syndrome derived neural iPSCs uncover co-dysregulation of ZNF and HOX3 families of transcription factors
- 2020
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7083 .- 1868-7075. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). Analysis of Down syndrome brain specimens has shown global epigenetic and transcriptional changes but their interplay during early neurogenesis remains largely unknown. We differentiated induced pluripotent stem cells (iPSCs) established from two DS patients with complete T21 and matched euploid donors into two distinct neural stages corresponding to early- and mid-gestational ages.Results: Using the Illumina Infinium 450K array, we assessed the DNA methylation pattern of known CpG regions and promoters across the genome in trisomic neural iPSC derivatives, and we identified a total of 500 stably and differentially methylated CpGs that were annotated to CpG islands of 151 genes. The genes were enriched within the DNA binding category, uncovering 37 factors of importance for transcriptional regulation and chromatin structure. In particular, we observed regional epigenetic changes of the transcription factor genes ZNF69, ZNF700 and ZNF763 as well as the HOXA3, HOXB3 and HOXD3 genes. A similar clustering of differential methylation was found in the CpG islands of the HIST1 genes suggesting effects on chromatin remodeling.Conclusions: The study shows that early established differential methylation in neural iPSC derivatives with T21 are associated with a set of genes relevant for DS brain development, providing a novel framework for further studies on epigenetic changes and transcriptional dysregulation during T21 neurogenesis.
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| 7. |
- Schuster, Jens, Assistant Professor, 1972-, et al.
(författare)
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Generation of two human iPSC lines (UUIGPi013-A and UUIPGi014-A) from cases with Down syndrome and full trisomy for chromosome 21 (T21)
- 2020
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Ingår i: Stem Cell Research. - AMSTERDAM, NETHERLANDS : Elsevier BV. - 1873-5061 .- 1876-7753. ; 49
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Tidskriftsartikel (refereegranskat)abstract
- Down syndrome (DS) is caused by trisomy for chromosome 21 (T21). We generated two induced pluripotent stem cell (iPSC) lines from skin fibroblasts of two males with DS using Sendai virus delivery of OCT4, SOX2, KLF4, and c-MYC. Characterization of the two iPSC lines, UUIGPi013-A and UUIPGi014-A, showed that they are genetically stable with a 47,XY,+21 karyotype. Both lines displayed expression of pluripotency markers and trilineage differentiation capacity. These two iPSC lines provide a useful resource for DS modeling and pharmacological interventions.
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| 8. |
- Sobol, Maria, et al.
(författare)
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Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions
- 2019
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Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 56:10, s. 7113-7127
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Tidskriftsartikel (refereegranskat)abstract
- Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at two stages of differentiation revealed strong temporal dynamics of dysregulated genes, proteins and pathways belonging to 11 major functional clusters. DNA replication, synaptic maturation and neuroactive clusters were disturbed at the early differentiation time point accompanied by a skewed transition from the neural progenitor cell stage and reduced cellular growth. With differentiation, growth factor and extracellular matrix, oxidative phosphorylation and glycolysis emerged as major perturbed clusters. Furthermore, we identified a marked dysregulation of a set of genes encoded by chromosome 21 including an early upregulation of the hub gene APP, supporting its role for disturbed neurogenesis, and the transcription factors OLIG1, OLIG2 and RUNX1, consistent with deficient myelination and neuronal differentiation. Taken together, our findings highlight novel sequential and differentiation-dependent dynamics of disturbed functions, pathways and elements in T21 neurogenesis, providing further insights into developmental abnormalities of the DS brain.
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| 9. |
- Wentzel, Christian, 1976-, et al.
(författare)
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Unbalanced de novo translocation in mother resulting in one child with a 6q13-q16 deletion and one child with a 6q13-q16 duplication
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Here we report on two sisters with reciprocal CNVs at 6q13-q16.1. Both the deletion and the duplication were inherited from the healthy mother carrying an insertion of 6q13-q16 to 15q11. The deleted region in one of the sisters has previously been described. However, to our knowledge this is the first report of a duplication at the region 6q13q16. In the report we submit a detailed phenotypical description of both patients as well as candidate genes for some of the various symptoms that the patients presented.
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| 10. |
- Wester Oxelgren, Ulrika, 1960-, et al.
(författare)
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An intervention targeting social, communication and daily activity skills in children and adolescents with Down syndrome and autism : a pilot study
- 2019
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Ingår i: Neuropsychiatric Disease and Treatment. - 1176-6328 .- 1178-2021. ; 15, s. 2049-2056
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate whether an intervention, targeting deficits in social communication, interaction and restricted activities in children and adolescents with Down syndrome and autism could lead to enhanced participation in family and school activities.Methods: The intervention included education for parents and school staff about autism, and workshops to identify social-communication and daily living activities that would be meaningful for the child to practice at home and at school. Thereafter, a three-month period of training for the child followed. Outcome measures comprised evaluation of goal achievement for each child, the Family Strain Index questionnaire and a visual scale pertaining to the parents' general opinion about the intervention.Results: On average, more than 90% of the goals were (to some extent or completely) achieved at home and at school. The mean scores of the Family Strain Index were almost identical at the follow-up to those before intervention. The evaluation supported that the use of strategies, intended to facilitate activities and communication, remained largely 18 months after start of the intervention.Conclusion: Despite the group involved in this study being composed of older children and adolescents, most of whom had severe and profound intellectual disability, the goal achievements and parents' views on the intervention were encouraging.
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