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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28049, Madrid, Spain;Faculty of Experimental Sciences, Francisco de Vitoria University, Pozuelo de Alarcón, 28223, Madrid, Spain.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
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2019 (English)In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 62, no 6, article id 103526Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2019. Vol. 62, no 6, article id 103526
Keywords [en]
Cohesin complex, Cohesin protein, Cohesinopathy, Cornelia de Lange syndrome type 4, RAD21 cohesin complex component
National Category
Genetics Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-379362DOI: 10.1016/j.ejmg.2018.08.007ISI: 000470115000001PubMedID: 30125677OAI: oai:DiVA.org:uu-379362DiVA, id: diva2:1296418
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-06-26Bibliographically approved
In thesis
1. Translational Research of Mendelian Disorders: Applications of Cutting-Edge Sequencing Techniques and Molecular Tools
Open this publication in new window or tab >>Translational Research of Mendelian Disorders: Applications of Cutting-Edge Sequencing Techniques and Molecular Tools
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1551
Keywords
translational research, Mendelian disorders, intellectual disability, sequencing technologies
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-379363 (URN)978-91-513-0595-0 (ISBN)
Public defence
2019-05-03, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Supervisors
Available from: 2019-04-10 Created: 2019-03-17 Last updated: 2019-05-07

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Gudmundsson, SannaAnnerén, GöranWilbe, MariaMelin, MalinBondeson, Marie-Louise

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Medicinsk genetik och genomikScience for Life Laboratory, SciLifeLabDepartment of Immunology, Genetics and Pathology
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