| 1. |
- Zander, Cecilia Soussi, et al.
(författare)
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Breast-cancer stromal cells with TP53 mutations
- 2008
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 358:15, s. 1635-1635
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 2. |
- Celse, Tristan, et al.
(författare)
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OTX2 duplications : a recurrent cause of oculo-auriculo-vertebral spectrum
- 2023
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Ingår i: Journal of Medical Genetics. - : BMJ Publishing Group Ltd. - 0022-2593 .- 1468-6244. ; 60:6, s. 620-626
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Tidskriftsartikel (refereegranskat)abstract
- Background Oculo-auriculo-vertebral spectrum (OAVS) is the second most common cause of head and neck malformations in children after orofacial clefts. OAVS is clinically heterogeneous and characterised by a broad range of clinical features including ear anomalies with or without hearing loss, hemifacial microsomia, orofacial clefts, ocular defects and vertebral abnormalities. Various genetic causes were associated with OAVS and copy number variations represent a recurrent cause of OAVS, but the responsible gene often remains elusive.Methods We described an international cohort of 17 patients, including 10 probands and 7 affected relatives, presenting with OAVS and carrying a 14q22.3 microduplication detected using chromosomal microarray analysis. For each patient, clinical data were collected using a detailed questionnaire addressed to the referring clinicians. We subsequently studied the effects of OTX2 overexpression in a zebrafish model.Results We defined a 272 kb minimal common region that only overlaps with the OTX2 gene. Head and face defects with a predominance of ear malformations were present in 100% of patients. The variability in expressivity was significant, ranging from simple chondromas to severe microtia, even between intrafamilial cases. Heterologous overexpression of OTX2 in zebrafish embryos showed significant effects on early development with alterations in craniofacial development.Conclusions Our results indicate that proper OTX2 dosage seems to be critical for the normal development of the first and second branchial arches. Overall, we demonstrated that OTX2 genomic duplications are a recurrent cause of OAVS marked by auricular malformations of variable severity.
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| 3. |
- Englund, Annika, et al.
(författare)
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Changes in mortality and causes of death in the Swedish Down syndrome population
- 2013
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Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 161A:4, s. 642-649
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Tidskriftsartikel (refereegranskat)abstract
- During the past few decades age at death for individuals with Down syndrome (DS) has increased dramatically. The birth frequency of infants with DS has long been constant in Sweden. Thus, the prevalence of DS in the population is increasing. The aim of the present study was to analyze mortality and causes of death in individuals with DS during the period 19692003. All individuals with DS that died between 1969 and 2003 in Sweden, and all individuals born with DS in Sweden between 1974 and 2003 were included. Data were obtained from the Swedish Medical Birth Register, the Swedish Birth Defects Register, and the National Cause of Death Register. Median age at death has increased by 1.8 years per year. The main cause of death was pneumonia. Death from congenital heart defects decreased. Death from atherosclerosis was rare but more frequent than reported previously. Dementia was not reported in any subjects with DS before 40 years of age, but was a main or contributing cause of death in 30% of the older subjects. Except for childhood leukemia, cancer as a cause of death was rare in all age groups. Mortality in DS, particularly infant mortality, has decreased markedly during the past decades. Median age at death is increasing and is now almost 60 years. Death from cancer is rare in DS, but death from dementia is common.
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| 4. |
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| 5. |
- Halvardson, Jonatan, et al.
(författare)
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Mutations in HECW2 are associated with intellectual disability and epilepsy
- 2016
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 53:10, s. 697-704
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions.METHODS: Exome sequencing was performed on 39 patient-parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders.RESULTS: In 39 patient-parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy.CONCLUSIONS: Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders.
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| 6. |
- Sobol, Maria, et al.
(författare)
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Proximal Deletion 12q with a New Insight to Growth Retardation
- 2020
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Ingår i: Molecular Syndromology. - : S. Karger AG. - 1661-8769 .- 1661-8777. ; 11:3, s. 115-124
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Tidskriftsartikel (refereegranskat)abstract
- Proximal deletion of the long arm of chromosome 12 is a rare chromosomal abnormality described in about 20 patients. Known deletions span the region from 12q11 to 12q13 and include the genes YAF2, AMIGO2, and NELL2. These are suggested as candidate genes for the key phenotypic features such as growth and psychomotor retardation. Here, we present a case with a 3.1-Mb interstitial deletion at 12q12q13.11. The clinical observations of our patient overlap with the major common findings for published cases. The deletion detected in our patient does not involve the previously suggested candidate genes YAF2 and AMIGO2. We draw a correlation between proximal deletion 12q and ARID2 deficiency by comparing patients carrying gross deletions with a cohort of patients carrying small intragenic ARID2 deletions as well as patients with single nucleotide variants (SNVs) in ARID2. Growth retardation <-2 SD is present in cohorts with both gross and small deletions spanning ARID2. However, ARID2 SNVs do not correlate with severe growth retardation.
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| 7. |
- Thierry, Gaelle, et al.
(författare)
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Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures
- 2012
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Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 158A:7, s. 1633-1640
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Tidskriftsartikel (refereegranskat)abstract
- Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies. By oligoarray-based comparative genomic hybridization (aCGH) covering the 1q44 region at a high resolution, we obtained a critical deleted region containing two coding genesHNRNPU and FAM36Aand one non-coding geneNCRNA00201. All three genes were expressed in different normal human tissues, including in human brain, with highest expression levels in the cerebellum. Mutational screening of the HNRNPU and FAM36A genes in 191 patients with unexplained isolated ID did not reveal any deleterious mutations while the NCRNA00201 non-coding gene was not analyzed. Nine of the 11 patients did not present with microcephaly or corpus callosum abnormalities and carried a small deletion containing HNRNPU, FAM36A, and NCRNA00201 but not AKT3 and ZNF238, two centromeric genes. These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for ID and seizures.
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| 8. |
- Thuresson, Ann-Charlotte, et al.
(författare)
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Novel PNKP mutations associated with reduced DNA single-strand break repair and severe microcephaly, seizures, and developmental delay
- 2024
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Ingår i: Molecular Genetics & Genomic Medicine. - : John Wiley & Sons. - 2324-9269. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Microcephaly with early-onset seizures (MCSZ) is a neurodevelopmental disorder caused by pathogenic variants in the DNA strand break repair protein, polynucleotide kinase 3 '-phosphatase (PNKP).Methods: We have used whole genome sequencing and Sanger sequencing to identify disease-causing variants, followed by a minigene assay, Western blotting, alkaline comet assay, gamma H2AX, and ADP-ribose immunofluorescence.Results: Here, we describe a patient with compound heterozygous variants in PNKP, including a missense variant in the DNA phosphatase domain (T323M) and a novel splice acceptor site variant within the DNA kinase domain that we show leads to exon skipping. We show that primary fibroblasts derived from the patient exhibit greatly reduced levels of PNKP protein and reduced rates of DNA single-strand break repair, confirming that the mutated PNKP alleles are dysfunctional.Conclusion: The data presented show that the detected compound heterozygous variants result in reduced levels of PNKP protein, which affect the repair of both oxidative and TOP1-induced single-strand breaks, and most likely causes MCSZ in this patient.
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| 9. |
- Thuresson, Ann-Charlotte, et al.
(författare)
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Whole-gene duplication of SCN2A and SCN3A is associated with neonatal seizures and a normal intellectual development
- 2017
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 91:1, s. 106-110
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Tidskriftsartikel (refereegranskat)abstract
- Duplications at 2q24.3 encompassing the voltage-gated sodium channel gene cluster are associated with early onset epilepsy. All cases described in the literature have presented in addition with different degrees of intellectual disability, and have involved neighbouring genes in addition to the sodium channel gene cluster. Here we report eight new cases with overlapping duplications at 2q24 ranging from 0.05 Mb to 7.63 Mb in size. Taken together with the previously reported cases, our study suggests that having an extra copy of SCN2A has an effect on epilepsy pathogenesis, causing benign familial infantile seizures which eventually disappear at the age of one to two years.. However, the number of copies of SCN2A does not appear to have an effect on cognitive outcome.
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| 10. |
- Zander, Cecilia Soussi
(författare)
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Beckwith-Wiedemann Syndrome Revisited.
- 2015
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 36:9
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Tidskriftsartikel (refereegranskat)
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