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Papers by Charlotte Brasch-andersen
European journal of human genetics, Apr 3, 2024
Genome Medicine, Nov 8, 2023
PubMed, Nov 18, 2019
This is a case report of a 56-year-old woman with a history of postmenopausal bleeding, who prese... more This is a case report of a 56-year-old woman with a history of postmenopausal bleeding, who presented with an endometrioid adenocarcinoma and a co-existing non-gestational choriocarcinoma. We performed robotic assisted hysterectomy, bilateral oophorectomy and pelvic lymphadectomy, and histopathologic examination revealed a malignant tumour showing an endometrioid adenocarcinoma grade 2 with a minor component of choriocarcinoma incorporated into the adenocarcinoma. We compared data from exome sequencing of DNA from tumour and blood to show, that the choriocarcinoma component was most likely non-gestational.
Research Square (Research Square), Dec 22, 2022
Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellec... more Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1 +/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished cases). A Cux1 +/− mouse model was used to analyze CUX1 expression in the brain and evaluate susceptibility to epilepsy. We describe 34 patients with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development, and intellectual disability. In Cux1 +/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1 +/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was also reduced, although in early postnatal animals signi cantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some patients, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. Furthermore, the balance of CUX1 isoform expression in the brain during development appears to be important for this favorable clinical course.
Authorea (Authorea), Mar 30, 2022
Background: Surfactant Protein D (SP-D) is a pattern recognition molecule belonging to the family... more Background: Surfactant Protein D (SP-D) is a pattern recognition molecule belonging to the family of collectins expressed in multiple human organ systems, including the lungs. Previous studies have shown that SP-D levels in bronchoalveolar lavage samples decrease and serum levels increase in patients suffering from asthma, possibly due to a combination of induced SP-D synthesis and decreased air-blood barrier integrity. The aims of this study were to investigate whether serum levels of SP-D and common variants in the SP-D gene were associated with asthma in adolescents and young adults. Methods: Prospective observational study including 449 adolescents and young adults (age 11-27 years) previously diagnosed with asthma during a 2-year period from 2003 to 2005 (0-16 years). At follow-up from 2016 to 2017, 314 healthy controls with no history of asthma were recruited. Serum SP-D was analyzed on samples obtained at baseline as well as samples obtained at followup. SP-D genotyping was performed for rs721917, rs2243639, and rs3088308. Results: No differences were found in mean levels of sSP-D and SFTPD genotype among subjects with current asthma, no current asthma, and controls. Serum SP-D and SFTPD genotype were not associated with any clinical parameters of asthma. Furthermore, baseline sSP-D was not associated with asthma at follow-up.
Genetics in Medicine Open
EMJ Reproductive Health
The field of reproductive health is progressing rapidly from traditional non-molecular technologi... more The field of reproductive health is progressing rapidly from traditional non-molecular technologies based on visual microscope-based techniques to the latest molecular technologies, that are more accurate, objective, and efficient, and some of which are less invasive. Genome-wide technologies have been applied at different stages of the reproductive health lifecycle, such as preimplantation genetic testing, prenatal and postnatal testing, and preconception carrier screening. Next-generation sequencing is currently the platform of choice when it comes to preimplantation genetic testing, and analysis using cell-free DNA offers a potential non-invasive alternative to current methods. Molecular tests of endometrial receptivity identify the optimum timing for embryo implantation, thereby improving in vitro fertilisation (IVF) success rates for patients with recurrent implantation failure of endometrial origin. In the prenatal and postnatal settings, new technologies, such as microarrays ...
European Journal of Human Genetics, Jul 1, 2019
European Journal of Human Genetics, Dec 1, 2020
Prenatal Diagnosis
ObjectiveThis study aimed to assess the diagnostic yield of prenatal genetic testing using trio w... more ObjectiveThis study aimed to assess the diagnostic yield of prenatal genetic testing using trio whole exome sequencing (WES) and trio whole genome sequencing (WGS) in pregnancies with fetal anomalies by comparing the results with conventional chromosomal microarray (CMA) analysis.MethodsA total of 40 pregnancies with fetal anomalies or increased nuchal translucency (NT ≥ 5 mm) were included between the 12th and 21st week of gestation. Trio WES/WGS and CMA were performed in all cases.ResultsThe trio WES/WGS analysis increased the diagnostic yield by 25% in cases with negative CMA results. Furthermore, all six chromosomal aberrations identified by CMA were independently detected by WES/WGS analysis. In total, 16 out of 40 cases obtained a genetic sequence variant, copy number variant, or aneuploidy explaining the phenotype, resulting in an overall WES/WGS diagnostic yield of 40%. WES analysis provided a more reliable identification of mosaic sequence variants than WGS because of its h...
The American Journal of Human Genetics
Human Genetics and Genomics Advances, 2022
Summary Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellec... more Summary Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function.
Body: BACKGOUND AND AIM BHR might be associated to the oxidative defense. We hypothesize that gen... more Body: BACKGOUND AND AIM BHR might be associated to the oxidative defense. We hypothesize that genotypes coding for normal antioxidative enzyme activity (AEA) influence the occurrence of BHR. METHODS In a cross sectional study 7,271 subjects aged 20-44 year (73% response rate) were recruited using an asthma screening questionnaire. All subjects with asthma (n = 460) and a 20% random sample (n= 728) were clinically investigated, including a bronchial provocation test, skin prick test (SPT) with 13 aeroallergens, and a blood sample. A bronchial provocation test was available for 956 subjects, and BHR was defined as at least 20% drop in baseline FEV 1. Variants in the following genes were genotyped: Glutathione peroxidase, GPX1 (Pro198Leu, rs1050450), manganese superoxide dismutase, SOD2 (Ala16Val, rs4880) and 3 glutathione S-transferases; GSTP1 (Ile105Val, rs1695), GSTT1 (gene copy nr) and GSTM1 (gene copy nr). RESULTS The frequency of BHR was 12.8% in the random sample and 42.6% in the asthma sample. Log. reg. models showed a neg. association between being BHR and having at least 4 genotypes coding for normal AEA compared to no normal genotype, OR 0.24 (0.06-0.94) adj. for smoking, FEV 1 , sex, atopy, height 2 and SPT-size of HDM. The result were similar after further adjustments for BMI, county and sample (random/case), OR 0.25 (0.06-1.06). ORs for BHR were decreased for 1-3 genotypes with normal AEA compared to no normal genotype, but not significantly so and no clear dose-response relations were seen. CONCLUSION This study suggests, that a combined effect of several genotypes coding for normal AEA might be a protective factor for BHR among young adults.
European journal of human genetics, Apr 3, 2024
Genome Medicine, Nov 8, 2023
PubMed, Nov 18, 2019
This is a case report of a 56-year-old woman with a history of postmenopausal bleeding, who prese... more This is a case report of a 56-year-old woman with a history of postmenopausal bleeding, who presented with an endometrioid adenocarcinoma and a co-existing non-gestational choriocarcinoma. We performed robotic assisted hysterectomy, bilateral oophorectomy and pelvic lymphadectomy, and histopathologic examination revealed a malignant tumour showing an endometrioid adenocarcinoma grade 2 with a minor component of choriocarcinoma incorporated into the adenocarcinoma. We compared data from exome sequencing of DNA from tumour and blood to show, that the choriocarcinoma component was most likely non-gestational.
Research Square (Research Square), Dec 22, 2022
Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellec... more Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1 +/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished cases). A Cux1 +/− mouse model was used to analyze CUX1 expression in the brain and evaluate susceptibility to epilepsy. We describe 34 patients with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development, and intellectual disability. In Cux1 +/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1 +/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was also reduced, although in early postnatal animals signi cantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some patients, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. Furthermore, the balance of CUX1 isoform expression in the brain during development appears to be important for this favorable clinical course.
Authorea (Authorea), Mar 30, 2022
Background: Surfactant Protein D (SP-D) is a pattern recognition molecule belonging to the family... more Background: Surfactant Protein D (SP-D) is a pattern recognition molecule belonging to the family of collectins expressed in multiple human organ systems, including the lungs. Previous studies have shown that SP-D levels in bronchoalveolar lavage samples decrease and serum levels increase in patients suffering from asthma, possibly due to a combination of induced SP-D synthesis and decreased air-blood barrier integrity. The aims of this study were to investigate whether serum levels of SP-D and common variants in the SP-D gene were associated with asthma in adolescents and young adults. Methods: Prospective observational study including 449 adolescents and young adults (age 11-27 years) previously diagnosed with asthma during a 2-year period from 2003 to 2005 (0-16 years). At follow-up from 2016 to 2017, 314 healthy controls with no history of asthma were recruited. Serum SP-D was analyzed on samples obtained at baseline as well as samples obtained at followup. SP-D genotyping was performed for rs721917, rs2243639, and rs3088308. Results: No differences were found in mean levels of sSP-D and SFTPD genotype among subjects with current asthma, no current asthma, and controls. Serum SP-D and SFTPD genotype were not associated with any clinical parameters of asthma. Furthermore, baseline sSP-D was not associated with asthma at follow-up.
Genetics in Medicine Open
EMJ Reproductive Health
The field of reproductive health is progressing rapidly from traditional non-molecular technologi... more The field of reproductive health is progressing rapidly from traditional non-molecular technologies based on visual microscope-based techniques to the latest molecular technologies, that are more accurate, objective, and efficient, and some of which are less invasive. Genome-wide technologies have been applied at different stages of the reproductive health lifecycle, such as preimplantation genetic testing, prenatal and postnatal testing, and preconception carrier screening. Next-generation sequencing is currently the platform of choice when it comes to preimplantation genetic testing, and analysis using cell-free DNA offers a potential non-invasive alternative to current methods. Molecular tests of endometrial receptivity identify the optimum timing for embryo implantation, thereby improving in vitro fertilisation (IVF) success rates for patients with recurrent implantation failure of endometrial origin. In the prenatal and postnatal settings, new technologies, such as microarrays ...
European Journal of Human Genetics, Jul 1, 2019
European Journal of Human Genetics, Dec 1, 2020
Prenatal Diagnosis
ObjectiveThis study aimed to assess the diagnostic yield of prenatal genetic testing using trio w... more ObjectiveThis study aimed to assess the diagnostic yield of prenatal genetic testing using trio whole exome sequencing (WES) and trio whole genome sequencing (WGS) in pregnancies with fetal anomalies by comparing the results with conventional chromosomal microarray (CMA) analysis.MethodsA total of 40 pregnancies with fetal anomalies or increased nuchal translucency (NT ≥ 5 mm) were included between the 12th and 21st week of gestation. Trio WES/WGS and CMA were performed in all cases.ResultsThe trio WES/WGS analysis increased the diagnostic yield by 25% in cases with negative CMA results. Furthermore, all six chromosomal aberrations identified by CMA were independently detected by WES/WGS analysis. In total, 16 out of 40 cases obtained a genetic sequence variant, copy number variant, or aneuploidy explaining the phenotype, resulting in an overall WES/WGS diagnostic yield of 40%. WES analysis provided a more reliable identification of mosaic sequence variants than WGS because of its h...
The American Journal of Human Genetics
Human Genetics and Genomics Advances, 2022
Summary Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellec... more Summary Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function.
Body: BACKGOUND AND AIM BHR might be associated to the oxidative defense. We hypothesize that gen... more Body: BACKGOUND AND AIM BHR might be associated to the oxidative defense. We hypothesize that genotypes coding for normal antioxidative enzyme activity (AEA) influence the occurrence of BHR. METHODS In a cross sectional study 7,271 subjects aged 20-44 year (73% response rate) were recruited using an asthma screening questionnaire. All subjects with asthma (n = 460) and a 20% random sample (n= 728) were clinically investigated, including a bronchial provocation test, skin prick test (SPT) with 13 aeroallergens, and a blood sample. A bronchial provocation test was available for 956 subjects, and BHR was defined as at least 20% drop in baseline FEV 1. Variants in the following genes were genotyped: Glutathione peroxidase, GPX1 (Pro198Leu, rs1050450), manganese superoxide dismutase, SOD2 (Ala16Val, rs4880) and 3 glutathione S-transferases; GSTP1 (Ile105Val, rs1695), GSTT1 (gene copy nr) and GSTM1 (gene copy nr). RESULTS The frequency of BHR was 12.8% in the random sample and 42.6% in the asthma sample. Log. reg. models showed a neg. association between being BHR and having at least 4 genotypes coding for normal AEA compared to no normal genotype, OR 0.24 (0.06-0.94) adj. for smoking, FEV 1 , sex, atopy, height 2 and SPT-size of HDM. The result were similar after further adjustments for BMI, county and sample (random/case), OR 0.25 (0.06-1.06). ORs for BHR were decreased for 1-3 genotypes with normal AEA compared to no normal genotype, but not significantly so and no clear dose-response relations were seen. CONCLUSION This study suggests, that a combined effect of several genotypes coding for normal AEA might be a protective factor for BHR among young adults.