| 1. |
- 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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| 2. |
- 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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| 3. |
- Gudmundsson, Sanna
(författare)
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Translational Research of Mendelian Disorders : Applications of Cutting-Edge Sequencing Techniques and Molecular Tools
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Up to 8% of all live-born children are affected with a congenital disorder. Some are Mendelian disorders of known etiology, but many are of undetermined genetic cause and mechanism, limiting diagnosis and treatment. This project aims to investigate the underlying causes of unresolved Mendelian disorders, and especially syndromes associated with intellectual disability, by using cutting-edge sequencing techniques and molecular tools in a translational setting that intends to directly benefit affected families.In Paper I, we report the first keratitis-ichthyosis-deafness syndrome patient presenting with reversion of disease phenotype, a phenomenon known as revertant mosaicism. Third-generation sequencing and a cell assay were used to pin-point the mechanism of the somatic variants giving rise to healthy looking skin in the patient. In Paper II, we describe a novel approach to investigate parental origin, gonadal mosaicism, and estimate recurrence risk of disease in two families. Third-generation sequencing was used for haplotype phasing and detection of low-frequency variants in paternal sperm. The recurrence risk in future offspring in the families affected with Noonan syndrome and Treacher Collins syndrome was determined to be 40% and <0.1% respectively. In Paper III, we describe a novel variant in a patient affected with Cornelia de Lange Syndrome, primarily associated with intellectual disability. The affected gene is linked to an extremely rare form of the syndrome, with limited cases described in the literature, usually associated with mild symptoms. Investigation of rare intellectual disability syndromes was continued in Paper IV, by clinical and genetic characterization of six affected males with a likely pathogenic variant in the TAF1 gene. By creating the first TAF1 orthologue knockout we revealed that taf1 is essential for life and that lack of functional taf1 during embryonic development in zebrafish primarily impacts expression of genes in pathways associated with neurodevelopment. By progressive translational research, using state-of-the-art methodology, this project has illuminated the implication of revertant and gonadal mosaicism in disease (Papers I-II), as well as two extremely rare intellectual disability syndromes (Papers III-IV). In total, five families affected with five different disorders have gained clinical and genetic diagnosis and/or further understanding of prognosis and recurrence risk. The study has led to improved understanding of disease etiology and basic developmental processes, enabling development of new therapies and improved care of future patients.
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