| 1. |
|
|
| 2. |
- Eriksson, Mats Anders, et al.
(författare)
-
Rare copy number variants are common in young children with autism spectrum disorder
- 2015
-
Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 104:6, s. 610-618
-
Tidskriftsartikel (refereegranskat)abstract
- AimSeveral studies have suggested that rare copy number variants (CNVs) are an important genetic contributor to autism spectrum disorders. The aims of the study were to use chromosomal microarray to investigate the presence of rare copy number variants in a population-based cohort of well-characterised young children with autism spectrum disorders and to relate the genetic results to neurodevelopmental profiles and medical conditions. MethodsWe performed chromosomal microarray on samples from 162 children who had been referred to the Stockholm Autism Centre for Young Children in Sweden after being diagnosed with autism spectrum disorder between 20 and 54months of age. ResultsPathogenic aberrations were detected in 8.6% of the children and variants of uncertain significance were present in another 8.6%. CNVs were more frequent in children with congenital malformations or dysmorphic features as well as in the subgroup with intellectual disability. ConclusionOur results support the use of chromosomal microarray methods for the first tier genetic analysis of autism spectrum disorder. However, it is likely in the near future that chromosomal microarray methods will probably be replaced by whole-exome and whole-genome sequencing technologies in clinical genetic testing.
|
|
| 3. |
- Georgsson, Susanne, et al.
(författare)
-
Knowledge and attitudes regarding non-invasive prenatal testing (NIPT) and preferences for risk information among high school students in Sweden
- 2017
-
Ingår i: Journal of Genetic Counseling. - New York : Human Sciences Press. - 1059-7700 .- 1573-3599. ; 26:3, s. 447-454
-
Tidskriftsartikel (refereegranskat)abstract
- Non-invasive prenatal testing (NIPT) was recently introduced for prenatal testing of genetic disorders. Cell-free fetal DNA is present in maternal blood during pregnancy and enables detection of fetal chromosome aberrations in a maternal blood sample. The public perspective to this new, simple method has not been illuminated. The views of young people (i.e. future parents) are important to develop suitable counseling strategies regarding prenatal testing. The aim was to explore Swedish high school students' attitudes, knowledge and preferences regarding NIPT. A questionnaire was completed by 305 students recruited from one high school in Stockholm, November and December 2014. Most students (80 %) considered prenatal testing as good. The majority (65 %) was positive or very positive towards NIPT and 62 % stated that they potentially would like to undergo the test if they or their partner was pregnant. The vast majority (94 %) requested further information about NIPT. Most students (61 %) preferred verbal information, whereas 20 % preferred information via the Internet. The majority of the high school students was positive towards prenatal testing and most was positive towards NIPT. Further, information was requested by the vast majority before making a decision about NIPT. Most of the students preferred verbal information and to a lesser extent information via the Internet. The attitudes, knowledge and preferences for risk information concerning NIPT in young adults are important, in order to increase knowledge on how to educate and inform future parents.
|
|
| 4. |
- Lindstrand, Anna, et al.
(författare)
-
From cytogenetics to cytogenomics : whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
- 2019
-
Ingår i: Genome Medicine. - : BMC. - 1756-994X .- 1756-994X. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundSince different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.MethodsWe analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n=68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n=156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.ResultsFirst, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850kb (min 500bp, max 155Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (>10kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data.Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.ConclusionThe overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
|
|
| 5. |
- Lindstrand, Anna, et al.
(författare)
-
Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability
- 2022
-
Ingår i: Genetics in Medicine. - : ELSEVIER SCIENCE INC. - 1098-3600 .- 1530-0366. ; 24:11, s. 2296-2307
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
|
|
| 6. |
- Sahlin, Ellika, et al.
(författare)
-
Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth
- 2019
-
Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- The incidence of stillbirth in Sweden has essentially remained constant since the 1980s, and despite thorough investigation, many cases remain unexplained. It has been suggested that a proportion of stillbirth cases is caused by heart disease, mainly channelopathies. The aim of this study was to analyze DNA from 290 stillbirth cases without chromosomal abnormalities for pathogenic single nucleotide variants (SNVs) in 70 genes associated with cardiac channelopathies and cardiomyopathies. The HaloPlex Target Enrichment System (Agilent Technologies) was utilized to prepare sequencing libraries which were sequenced on the Illumina NextSeq platform. We found that 12.1% of the 290 investigated stillbirth cases had one (n = 31) or two (n = 4) variants with evidence supporting pathogenicity, i.e. loss-of-function variants (nonsense, frameshift, splice site substitutions), evidence from functional studies, or previous identification of the variants in affected individuals. Regarding identified putative pathogenic variants in genes associated with channelopathies, the prevalence was significantly higher in the stillbirth cohort (n = 23, 7.93%) than the corresponding prevalence of the same variants in the non-Finnish European population of the Exome Aggregation Consortium (2.70%, pamp;lt;0.001) and SweGen, (2.30%, pamp;lt;0.001). Our results give further support to the hypothesis that cardiac channelopathies might contribute to stillbirth. Screening for pathogenic SNVs in genes associated with heart disease might be a valuable complement for stillbirth cases where todays conventional investigation does not reveal the underlying cause of fetal demise.
|
|
| 7. |
- Sahlin, Ellika
(författare)
-
New molecular tools for prenatal diagnosis
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prenatal diagnosis enables identification of severe disease in the fetus, and allows for planning and management of future pregnancies if an underlying genetic mechanism is identified. The studies included in this thesis have taken advantage of the dramatic progress in medical genetics, in order to develop and evaluate new procedures to diagnose genetic disorders in fetal life. A correct diagnosis is important not only for the management and counseling of the patient or couple, but may also have an impact on the extended family, as there may be undetected carriers. The incidence of stillbirth in Sweden, i.e. fetal death occurring at gestational week ≥22, has essentially remained constant since the 1980’s, and despite thorough investigation, many cases remain unexplained. In Paper I, clinical chromosome analysis results from 481 stillbirth cases were compiled, and a subgroup of 90 cases were analyzed using chromosomal microarray (CMA) to study the potential benefits of the method. The conventional analysis detected chromosomal aberrations in 7.5% of the cases. CMA additionally identified two known syndromes, one disruption of a known disease gene, and 26 variants of unknown significance. Furthermore, CMA had a significantly higher success rate than cytogenetic analysis (100% vs. 80%, p<0.001). As CMA increased both the success rate and diagnosis rate, we concluded that it is a valuable tool in stillbirth investigation. In Paper II, DNA from 290 stillbirth cases was analyzed by massive parallel sequencing of 79 genes associated with heart disease. Sixty-two cases (21.4%) had putative pathogenic variants in genes associated with channelopathies (53%), cardiomyopathies (24%) or congenital heart defects (23%). Screening for pathogenic variants in genes associated with heart disease might be a valuable complement in cases where the conventional investigation does not reveal the underlying cause of fetal demise. Fetal tissue calcifications are occasionally noted during autopsy or ultrasound, but their biological importance is largely unexplored. In Paper III, a case-control study including 151 calcification cases and 302 matched controls was performed, to identify factors associated with calcifications. Chromosomal abnormalities, detected by conventional chromosome analysis or quantitative fluorescence-polymerase chain reaction, were significantly more common in cases compared with controls; 50% vs. 20% (p<0.001). When comparing cases and controls with chromosomal abnormalities, the cases had a significantly higher prevalence of malformations (96% vs. 77%, p=0.002). We concluded that fetal tissue calcifications are associated with chromosomal abnormalities, especially in combination with malformations. Non-invasive prenatal testing (NIPT) for fetal aneuploidy, based on sequencing analysis of cell-free fetal DNA in maternal plasma, has recently been made possible. Current methods require DNA amplification prior to sequencing, which inevitably leads to a bias because some DNA fragments amplify more efficiently than others. In Paper IV, an amplification-free NIPT protocol was evaluated on 31 samples, of which 15 had confirmed aneuploidies. All aneuploidies were correctly classified, except in one case where cytogenetic testing had confirmed the presence of both trisomy 18 and XXY, but NIPT failed to identify the extra X chromosome. Further analyses revealed that the fetus was mosaic, which probably explains why the extra X chromosome was missed. We concluded that the amplification-free protocol can potentially be used for NIPT, as it could distinguish aberrant samples from healthy controls. Compared to other NIPT protocols, it can be used on smaller quantities of input DNA, reduces GC bias and increases genome coverage. In Paper V, we aimed to gain an increased understanding of pregnant women’s awareness, attitudes, and preferences concerning prenatal testing with emphasis on NIPT, before its introduction into Swedish healthcare. In total, 1,003 pregnant women were recruited to fill in a questionnaire at nine maternity clinics located in different areas of Stockholm. The overwhelming majority of the women (91%) considered examinations aiming to detect fetal abnormalities to be good. Regarding NIPT, 60% stated that they had heard about the method previously, yet 74% would like to use the test if available. The main factor affecting the women’s decision to undergo prenatal chromosomal screening was worry about the baby’s health (83%), followed by the desire to have as much information as possible about their fetuses (55%). The results from the studies have provided support for the value of various genetic analysis methods in the field of prenatal diagnosis, as well as insights to the prevalence of genetic aberrations in fetuses.
|
|
| 8. |
- Sahlin, Ellika, et al.
(författare)
-
Positive Attitudes towards Non-Invasive Prenatal Testing (NIPT) in a Swedish Cohort of 1,003 Pregnant Women
- 2016
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:5
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The clinical utilization of non-invasive prenatal testing (NIPT) for identification of fetal aneuploidies is expanding worldwide. The aim of this study was to gain an increased understanding of pregnant women's awareness, attitudes, preferences for risk information and decision-making concerning prenatal examinations with emphasis on NIPT, before its introduction into Swedish healthcare.METHOD: Pregnant women were recruited to fill in a questionnaire, including multiple-choice questions and Likert scales, at nine maternity clinics located in different areas of Stockholm, Sweden.RESULTS: In total, 1,003 women participated in the study (86% consent rate). The vast majority (90.7%) considered examinations aiming to detect fetal abnormalities to be good. Regarding NIPT, 59.8% stated that they had heard about the method previously, yet 74.0% would like to use the test if available. The main factor affecting the women's decision to undergo prenatal chromosomal screening was worry about the baby's health (82.5%), followed by the urge to have as much information as possible about the fetus (54.5%). Most women (79.9%) preferred to receive NIPT information orally.CONCLUSION: The overwhelming majority of a cohort of 1,003 pregnant women considered prenatal examinations good. Moreover, the majority had a positive attitude towards NIPT and would like to use the test if available.
|
|
| 9. |
- Wedenoja, Satu, et al.
(författare)
-
Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia
- 2020
-
Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 59
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Fetal immune tolerance is crucial for pregnancy success. We studied the link between preeclampsia, a severe pregnancy disorder with uncertain pathogenesis, and fetal human leukocyte antigen G (HLA-G) and other genes regulating maternal immune responses.Methods: We assessed sex ratios and regulatory HLA-G haplotypes in population cohorts and series of preeclampsia and stillbirth. We studied placental mRNA expression of 136 genes by sequencing and HLA-G and interferon alpha (IFNα) protein expression by immunohistochemistry.Findings: We found underrepresentation of males in preeclamptic births, especially those delivered preterm or small for gestational age. Balancing selection at HLA-G associated with the sex ratio, stillbirth, and preeclampsia. We observed downregulation of HLA-G, its receptors, and many other tolerogenic genes, and marked upregulation of IFNA1 in preeclamptic placentas.Interpretation: These findings indicate that an evolutionary trade-off between immune tolerance and protection against infections at the maternal-fetal interface promotes genetic diversity in fetal HLA-G, thereby affecting survival, preeclampsia, and sex ratio. We highlight IFNA1 as a potential mediator of preeclampsia and a target for therapeutic trials.
|
|
| 10. |
- Winberg, Johanna, et al.
(författare)
-
Mutation Screening and Array Comparative Genomic Hybridization Using a 180K Oligonucleotide Array in VACTERL Association
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1, s. e85313-
-
Tidskriftsartikel (refereegranskat)abstract
- In order to identify genetic causes of VACTERL association (V vertebral defects, A anorectal malformations, C cardiac defects, T tracheoesofageal fistula, E esophageal atresia, R renal anomalies, L limb deformities), we have collected DNA samples from 20 patients diagnosed with VACTERL or with a VACTERL-like phenotype as well as samples from 19 aborted fetal cases with VACTERL. To investigate the importance of gene dose alterations in the genetic etiology of VACTERL association we have performed a systematic analysis of this cohort using a 180K array comparative genomic hybridization (array-CGH) platform. In addition, to further clarify the significance of PCSK5, HOXD13 and CHD7 genes in the VACTERL phenotype, mutation screening has been performed. We identified pathogenic gene dose imbalances in two fetal cases; a hemizygous deletion of the FANCB gene and a (9;18)(p24;q12) unbalanced translocation. In addition, one pathogenic mutation in CHD7 was detected, while no apparent disease-causing mutations were found in HOXD13 or PCSK5. Our study shows that although large gene dose alterations do not seem to be a common cause in VACTERL association, array-CGH is still important in clinical diagnostics to identify disease cause in individual cases.
|
|
