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- Nilsson, D., et al.
(författare)
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From cytogenetics to cytogenomics : whole genome sequencing as a comprehensive genetic test in rare disease diagnostics
- 2019
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Ingår i: European Journal of Human Genetics. - : Springer Nature. - 1018-4813 .- 1476-5438. ; 27, s. 1666-1667
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Rare genetic diseases are caused by different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements. Recent data indicates that whole genome sequencing (WGS) may be used as a comprehensive test to identify multiple types of pathologic genetic aberrations in a single analysis.We present FindSV, a bioinformatic pipeline for detection of balanced (inversions and translocations) and unbalanced (deletions and duplications) structural variants (SVs). First, FindSV was tested on 106 validated deletions and duplications with a median size of 850 kb (min: 511 bp, max: 155 Mb). All variants were detected. Second, we demonstrated the clinical utility in 138 monogenic WGS panels. SV analysis yielded 11 diagnostic findings (8%). Remarkably, a complex structural rearrangement involving two clustered deletions disrupting SCN1A, SCN2A, and SCN3A was identified in a three months old girl with epileptic encephalopathy. Finally, 100 consecutive samples referred for clinical microarray were also analyzed by WGS. The WGS data was screened for large (>2 kbp) SVs genome wide, processed for visualization in our clinical routine arrayCGH workflow with the newly developed tool vcf2cytosure, and for exonic SVs and SNVs in a panel of 700 genes linked to intellectual disability. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. The diagnostic rate (29%) was doubled compared to clinical microarray (12%).In conclusion, using WGS we have detected a wide range of structural variation with high accuracy, confirming it a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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- Adamovic, T, et al.
(författare)
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Association of a tagging single nucleotide polymorphism in the androgen receptor gene region with susceptibility to severe hypospadias in a Caucasian population
- 2013
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Ingår i: Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation. - : S. Karger AG. - 1661-5433. ; 7:4, s. 173-179
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Tidskriftsartikel (refereegranskat)abstract
- Hypospadias is a congenital malformation and a milder form of 46,XY disorder of sexual development (DSD). In the present study, we investigated 13 haplotype tagging single nucleotide polymorphisms (SNPs) covering the steroid-5-alpha reductase <i>(SRD5A2)</i> and androgen receptor<i>(AR) </i>gene region, respectively, in a cohort consisting of 260 individuals with mild hypospadias and 77 with severe disease, in addition to 471 healthy male controls. The investigated genes are known to have an important role in the hormone-dependent stage of sexual development. Our study revealed one novel marker located in the <i>AR </i>gene region (rs5919436; g.67024320C>G) to be significantly associated with an increased risk of severe hypospadias (adjusted p value: 0.02; odds ratio: 2.98). In concordance with this finding, we detected an association of a haplotype tagged by the minor allele of rs5919436 (adjusted p value: 0.04). We further detected no association between the investigated disease and the haplotype tagging polymorphisms covering the <i>SRD5A2</i> gene, which is of importance considering the conflicting results reported previously. In conclusion, our data implicate that the AR rs5919436 (g.67024320C>G) polymorphism may act as a novel genetic marker for increased susceptibility to severe hypospadias in Caucasians.
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- Baptista, Marisa A. P., et al.
(författare)
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Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8(+) T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFN gamma-producing CD8(+) T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8(+) T cells at the expense of CD4(+) T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8(+) T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells.
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- Verberne, EA, et al.
(författare)
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DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:14
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Tidskriftsartikel (refereegranskat)abstract
- JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test.
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- Sahlin, E, et al.
(författare)
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Molecular and cytogenetic analysis in stillbirth: results from 481 consecutive cases
- 2014
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Ingår i: Fetal diagnosis and therapy. - : S. Karger AG. - 1421-9964 .- 1015-3837. ; 36:4, s. 326-332
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Introduction:</i></b> The underlying causes of stillbirth are heterogeneous and in many cases unexplained. Our aim was to conclude clinical results from karyotype and quantitative fluorescence-polymerase chain reaction (QF-PCR) analysis of all stillbirths occurring in Stockholm County between 2008 and 2012. By screening a subset of cases, we aimed to study the possible benefits of chromosomal microarray (CMA) in the analysis of the etiology of stillbirth. <b><i>Methods:</i></b> During 2008-2012, 481 stillbirths in Stockholm County were investigated according to a clinical protocol including karyotype or QF-PCR analysis. CMA screening was performed on a subset of 90 cases, corresponding to all stillbirths from 2010 without a genetic diagnosis. <b><i>Results:</i></b> Chromosomal aberrations were detected by karyotype or QF-PCR analysis in 7.5% of the stillbirths. CMA analysis additionally identified two known syndromes, one aberration disrupting a known disease gene, and 26 variants of unknown significance. Furthermore, CMA had a significantly higher success rate than karyotyping (100 vs. 80%, p < 0.001). <b><i>Discussion:</i></b> In the analysis of stillbirth, conventional karyotyping is prone to failure, and QF-PCR is a useful complement. We show that CMA has a higher success rate and aberration detection frequency than these methods, and conclude that CMA is a valuable tool for identification of chromosomal aberrations in stillbirth.
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- Vergult, S, et al.
(författare)
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Nasal speech in patients with 12q15 microdeletions
- 2012
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Ingår i: EUROPEAN JOURNAL OF HUMAN GENETICS. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 20:4, s. 367-367
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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