ABSTRACTObjectiveTo demonstrate the application of the atypicality index as an adjunct to first‐t... more ABSTRACTObjectiveTo demonstrate the application of the atypicality index as an adjunct to first‐trimester risk assessment for major trisomies by the combined test.MethodsThis was a study of 123 998 Danish women with a singleton pregnancy who underwent routine first‐trimester screening, including risk assessment for major trisomies. An atypicality index, which is a measure of the degree to which a profile is atypical, was produced for measurements of fetal nuchal translucency thickness and maternal serum free β‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A. The incidence of adverse pregnancy outcome, including miscarriage, intrauterine death and termination of pregnancy, was tabulated according to the screening result and atypicality index.ResultsIn pregnancies with low risk and those with high risk for major trisomies according to the combined screening test, the incidence of adverse pregnancy outcome increased with increasing atypicality index. In pregnanci...
Array-comparative genomic hybridization (array-CGH) is a very sensitive method for identifying ch... more Array-comparative genomic hybridization (array-CGH) is a very sensitive method for identifying chromosomal imbalances and is now used on a clinical basis for prenatal diagnosis. This article reviews the advantages and disadvantages of the method, the ethical considerations and the current recommendations for prenatal use in Denmark according to a new national guideline from The Danish Society of Foetal Medicine and the Danish Society of Medical Genetics.
Background: The existing risk of procedure-related miscarriage following invasive sampling for pr... more Background: The existing risk of procedure-related miscarriage following invasive sampling for prenatal diagnosis is higher for twin pregnancies and some women are reluctant to test these typically difficultly obtained pregnancies invasively. Therefore, there is a need for noninvasive testing options that can test twin pregnancies at an early gestational age and ideally test the twins individually.Case presentation: A pregnant woman opted for cell-based NIPT at GA 10 + 5. As cell-based NIPT is not established for use in twins, the test was provided in a research setting only, when an ultrasound scan showed that she carried dichorionic twins.Materials and Methods: Fifty mL of peripheral blood was sampled, and circulating fetal cells were enriched and isolated. Individual cells were subject to whole-genome amplification and STR analysis. Three fetal cells were analyzed by chromosomal microarray (aCGH).Results: We identified 20 fetal cells all sharing the same genetic profile, which in...
Background: Copy number variations (CNVs) represent an important type of genetic variation that d... more Background: Copy number variations (CNVs) represent an important type of genetic variation that deeply impact phenotypic polymorphisms and human diseases. The advent of high-throughput sequencing technologies provides an opportunity to revolutionize the discovery of CNVs and to explore their relationship with diseases. However, most of the existing methods depend on sequencing depth and show instability with low sequence coverage. In this study, using low coverage whole-genome sequencing (LCS) we have developed an effective population-scale CNV calling (PSCC) method. Methodology/Principal Findings: In our novel method, two-step correction was used to remove biases caused by local GC content and complex genomic characteristics. We chose a binary segmentation method to locate CNV segments and designed combined statistics tests to ensure the stable performance of the false positive control. The simulation data showed that our PSCC method could achieve 99.7%/100 % and 98.6%/100 % sensit...
To explore the relationship between small fetal second‐trimester head circumference (HC) and preg... more To explore the relationship between small fetal second‐trimester head circumference (HC) and pregnancy outcome and identify a cutoff point for offering genetic testing.
Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the lik... more Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the likelihood of receiving a diagnosis when fetal structural anomalies are identified. However, some parents will receive uncertain results such as variants of uncertain significance and secondary findings. We aimed to develop a set of attributes and associated levels for a discrete-choice experiment (DCE) that will examine parents’ preferences for tests that may reveal uncertain test results. A two phase mixed-methods approach was used to develop attributes for the DCE. In Phase 1, a “long list” of candidate attributes were identified via two approaches: 1) a systematic review of the literature around parental experiences of uncertainty following prenatal testing; 2) 16 semi-structured interviews with parents who had experienced uncertainty during pregnancy and 25 health professionals who return uncertain prenatal results. In Phase 2, a quantitative scoring exercise with parents prioritised t...
We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 famil... more We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy more common in females and autism more comm...
After playing handball, a 13-year-old girl developed a comatose condition during 7-10 days with h... more After playing handball, a 13-year-old girl developed a comatose condition during 7-10 days with hemiparesis and aphasia. From age three to nine she was treated for partial epilepsy. She never had symptoms of migraine. Her father had childhood epilepsy and at the age of 40 and 44 he experienced two attacks with prolonged coma, fever, seizures, hemiparesis and aphasia. His mother had symptoms of severe hemiplegic migraine. Father and daughter were genetically tested and an earlier described mutation in ATP1A2 gene was found. These cases illustrate the phenotypic variability in familial hemiplegic migraine type 2.
Few studies have assessed longitudinal changes in circulating cytokine levels during normal pregn... more Few studies have assessed longitudinal changes in circulating cytokine levels during normal pregnancy. We have examined the natural history of maternal plasma cytokines from early- to mid-pregnancy in a large, longitudinal cohort. Multiplex flow cytometry was used to measure interleukin (IL)-2, IL-6, IL-12, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) in early- (median [IQR]: 8.5 weeks [7.1, 10.0]) and mid-pregnancy (25.0 [24.1, 26.1]) from 1274 Danish women delivering singleton term infants. GM-CSF decreased from early- to mid-pregnancy (median percent change [95% CI]: -51.3% [-59.1%, -41.8%]), while increases were observed in IL-6 (24.3% [4.6%, 43.9%]), IL-12 (21.3% [8.9%, 35.7%]) and IFN-gamma (131.7% [100.2%, 171.6%]); IL-2 (-2.8% [-11.5%, 0.0%]) and TNF-alpha (0% [-5.9%, 25.6%]) remained stable. Positive correlations were found between all cytokines, both in early- and mid-pregnancy (all p<0.001). Early- and mid-pregnancy levels were rank-correlated for IL-2, IL-12, TNF-alpha and GM-CSF, but not IL-6 and IFN-gamma; these correlations were generally weaker than correlations between different cytokines at a single time point in pregnancy. Women with a pre-pregnancy BMI <18.5 had reduced levels of IFN-gamma and GM-CSF compared to women in other BMI categories, while women aged >or=35 years had elevated IL-2, IL-6, TNF-alpha and IFN-gamma. Early-pregnancy levels of TNF-alpha were higher in women with a prior preterm delivery. Cytokine levels were not associated with gravidity. In conclusion, cytokines were detected in plasma during early- and mid-pregnancy, with IL-6, IL-12, IFN-gamma and GM-CSF concentrations varying over pregnancy. Concentrations may depend on BMI, maternal age and prior preterm delivery.
Mice disrupted for the interleukin (IL)-18 gene appear more disposed to preterm delivery (PTD) in... more Mice disrupted for the interleukin (IL)-18 gene appear more disposed to preterm delivery (PTD) induced by inflammation. A synergy between IL-18 and IL-12 has been suggested. The objective of this study was to investigate a possible relation between human maternal serum levels of IL-18, IL-12 and spontaneous PTD. A cohort of 93 consecutive women with symptoms of threatening PTD on admission was enrolled at the delivery ward, Aarhus University Hospital, Denmark. Serum IL-18 and IL-12 measured using Luminex xMAP technology. Endpoint: PTD before 34 weeks gestation. Pregnant women admitted with symptoms of threatening PTD and delivering before 34 weeks of gestation had significantly lower levels of IL-18 compared to women delivering at or after 34 weeks of gestation (medians: 14.5 versus 26.6 pg/ml; p=0.035). IL-12 levels were not different in women delivering before or after 34 weeks of gestation. Patients having low IL-18 (below the 25-percentile) and high IL-12 (above the 75-percentile) had a twofold increase in risk of delivering before 34 weeks of gestation (RR 2.1 [1.7-2.6]). Results from this study indicate, that low serum IL-18 level could be associated with PTD in women with symptoms of PTD. A possible interaction between IL-18 and IL-12 was found, as the risk of delivering before 34 weeks is increased with the combination of low IL-18 and high IL-12, but further studies are warranted to investigate these interleukins and their possible role in PTD.
This study aimed to analyze the associations between serum and cervicovaginal inflammatory marker... more This study aimed to analyze the associations between serum and cervicovaginal inflammatory markers and recurrent spontaneous preterm birth in a cohort study of 62 pregnant women with > or =1 prior early spontaneous birth. Serum samples and cervicovaginal swabs from the women were obtained at enrollment in early second trimester (week 12-25). Cervical length was measured by ultrasound and dicotomized in to short (< or =25 mm) and long cervices (>25 mm). The study endpoints were spontaneous preterm birth before 35 weeks and secondarily<37 weeks. Multiple inflammatory markers in serum (IL-1beta, IL-2, IL-5, IL-6, IL-8, IL-12, IL-18, TNF-alpha, TGF-beta, sTNF-R1, GM-CSF and TREM-1) and cervicovaginal secretions (IL-18, sTNF-RI and sIL-6) were individually associated with spontaneous preterm birth. Short cervical length did not explain associations between inflammatory markers and spontaneous preterm birth. Serum and cervicovaginal inflammatory markers did not correlate. In a combined prediction model using both serum and vaginal inflammatory markers, serum TNF-alpha, cervicovaginal sIL-6Ralpha and cervical length predicted 69% of all recurrent spontaneous preterm birth at a 5% false-positive rate. In conclusion, cervical length, serum TNF-alpha and cervicovaginal sIL-6Ralpha provide a clinically useful prediction of recurrent preterm birth in early second-trimester in women with a prior spontaneous preterm birth.
ABSTRACTObjectiveTo demonstrate the application of the atypicality index as an adjunct to first‐t... more ABSTRACTObjectiveTo demonstrate the application of the atypicality index as an adjunct to first‐trimester risk assessment for major trisomies by the combined test.MethodsThis was a study of 123 998 Danish women with a singleton pregnancy who underwent routine first‐trimester screening, including risk assessment for major trisomies. An atypicality index, which is a measure of the degree to which a profile is atypical, was produced for measurements of fetal nuchal translucency thickness and maternal serum free β‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A. The incidence of adverse pregnancy outcome, including miscarriage, intrauterine death and termination of pregnancy, was tabulated according to the screening result and atypicality index.ResultsIn pregnancies with low risk and those with high risk for major trisomies according to the combined screening test, the incidence of adverse pregnancy outcome increased with increasing atypicality index. In pregnanci...
Array-comparative genomic hybridization (array-CGH) is a very sensitive method for identifying ch... more Array-comparative genomic hybridization (array-CGH) is a very sensitive method for identifying chromosomal imbalances and is now used on a clinical basis for prenatal diagnosis. This article reviews the advantages and disadvantages of the method, the ethical considerations and the current recommendations for prenatal use in Denmark according to a new national guideline from The Danish Society of Foetal Medicine and the Danish Society of Medical Genetics.
Background: The existing risk of procedure-related miscarriage following invasive sampling for pr... more Background: The existing risk of procedure-related miscarriage following invasive sampling for prenatal diagnosis is higher for twin pregnancies and some women are reluctant to test these typically difficultly obtained pregnancies invasively. Therefore, there is a need for noninvasive testing options that can test twin pregnancies at an early gestational age and ideally test the twins individually.Case presentation: A pregnant woman opted for cell-based NIPT at GA 10 + 5. As cell-based NIPT is not established for use in twins, the test was provided in a research setting only, when an ultrasound scan showed that she carried dichorionic twins.Materials and Methods: Fifty mL of peripheral blood was sampled, and circulating fetal cells were enriched and isolated. Individual cells were subject to whole-genome amplification and STR analysis. Three fetal cells were analyzed by chromosomal microarray (aCGH).Results: We identified 20 fetal cells all sharing the same genetic profile, which in...
Background: Copy number variations (CNVs) represent an important type of genetic variation that d... more Background: Copy number variations (CNVs) represent an important type of genetic variation that deeply impact phenotypic polymorphisms and human diseases. The advent of high-throughput sequencing technologies provides an opportunity to revolutionize the discovery of CNVs and to explore their relationship with diseases. However, most of the existing methods depend on sequencing depth and show instability with low sequence coverage. In this study, using low coverage whole-genome sequencing (LCS) we have developed an effective population-scale CNV calling (PSCC) method. Methodology/Principal Findings: In our novel method, two-step correction was used to remove biases caused by local GC content and complex genomic characteristics. We chose a binary segmentation method to locate CNV segments and designed combined statistics tests to ensure the stable performance of the false positive control. The simulation data showed that our PSCC method could achieve 99.7%/100 % and 98.6%/100 % sensit...
To explore the relationship between small fetal second‐trimester head circumference (HC) and preg... more To explore the relationship between small fetal second‐trimester head circumference (HC) and pregnancy outcome and identify a cutoff point for offering genetic testing.
Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the lik... more Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the likelihood of receiving a diagnosis when fetal structural anomalies are identified. However, some parents will receive uncertain results such as variants of uncertain significance and secondary findings. We aimed to develop a set of attributes and associated levels for a discrete-choice experiment (DCE) that will examine parents’ preferences for tests that may reveal uncertain test results. A two phase mixed-methods approach was used to develop attributes for the DCE. In Phase 1, a “long list” of candidate attributes were identified via two approaches: 1) a systematic review of the literature around parental experiences of uncertainty following prenatal testing; 2) 16 semi-structured interviews with parents who had experienced uncertainty during pregnancy and 25 health professionals who return uncertain prenatal results. In Phase 2, a quantitative scoring exercise with parents prioritised t...
We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 famil... more We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy more common in females and autism more comm...
After playing handball, a 13-year-old girl developed a comatose condition during 7-10 days with h... more After playing handball, a 13-year-old girl developed a comatose condition during 7-10 days with hemiparesis and aphasia. From age three to nine she was treated for partial epilepsy. She never had symptoms of migraine. Her father had childhood epilepsy and at the age of 40 and 44 he experienced two attacks with prolonged coma, fever, seizures, hemiparesis and aphasia. His mother had symptoms of severe hemiplegic migraine. Father and daughter were genetically tested and an earlier described mutation in ATP1A2 gene was found. These cases illustrate the phenotypic variability in familial hemiplegic migraine type 2.
Few studies have assessed longitudinal changes in circulating cytokine levels during normal pregn... more Few studies have assessed longitudinal changes in circulating cytokine levels during normal pregnancy. We have examined the natural history of maternal plasma cytokines from early- to mid-pregnancy in a large, longitudinal cohort. Multiplex flow cytometry was used to measure interleukin (IL)-2, IL-6, IL-12, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) in early- (median [IQR]: 8.5 weeks [7.1, 10.0]) and mid-pregnancy (25.0 [24.1, 26.1]) from 1274 Danish women delivering singleton term infants. GM-CSF decreased from early- to mid-pregnancy (median percent change [95% CI]: -51.3% [-59.1%, -41.8%]), while increases were observed in IL-6 (24.3% [4.6%, 43.9%]), IL-12 (21.3% [8.9%, 35.7%]) and IFN-gamma (131.7% [100.2%, 171.6%]); IL-2 (-2.8% [-11.5%, 0.0%]) and TNF-alpha (0% [-5.9%, 25.6%]) remained stable. Positive correlations were found between all cytokines, both in early- and mid-pregnancy (all p<0.001). Early- and mid-pregnancy levels were rank-correlated for IL-2, IL-12, TNF-alpha and GM-CSF, but not IL-6 and IFN-gamma; these correlations were generally weaker than correlations between different cytokines at a single time point in pregnancy. Women with a pre-pregnancy BMI <18.5 had reduced levels of IFN-gamma and GM-CSF compared to women in other BMI categories, while women aged >or=35 years had elevated IL-2, IL-6, TNF-alpha and IFN-gamma. Early-pregnancy levels of TNF-alpha were higher in women with a prior preterm delivery. Cytokine levels were not associated with gravidity. In conclusion, cytokines were detected in plasma during early- and mid-pregnancy, with IL-6, IL-12, IFN-gamma and GM-CSF concentrations varying over pregnancy. Concentrations may depend on BMI, maternal age and prior preterm delivery.
Mice disrupted for the interleukin (IL)-18 gene appear more disposed to preterm delivery (PTD) in... more Mice disrupted for the interleukin (IL)-18 gene appear more disposed to preterm delivery (PTD) induced by inflammation. A synergy between IL-18 and IL-12 has been suggested. The objective of this study was to investigate a possible relation between human maternal serum levels of IL-18, IL-12 and spontaneous PTD. A cohort of 93 consecutive women with symptoms of threatening PTD on admission was enrolled at the delivery ward, Aarhus University Hospital, Denmark. Serum IL-18 and IL-12 measured using Luminex xMAP technology. Endpoint: PTD before 34 weeks gestation. Pregnant women admitted with symptoms of threatening PTD and delivering before 34 weeks of gestation had significantly lower levels of IL-18 compared to women delivering at or after 34 weeks of gestation (medians: 14.5 versus 26.6 pg/ml; p=0.035). IL-12 levels were not different in women delivering before or after 34 weeks of gestation. Patients having low IL-18 (below the 25-percentile) and high IL-12 (above the 75-percentile) had a twofold increase in risk of delivering before 34 weeks of gestation (RR 2.1 [1.7-2.6]). Results from this study indicate, that low serum IL-18 level could be associated with PTD in women with symptoms of PTD. A possible interaction between IL-18 and IL-12 was found, as the risk of delivering before 34 weeks is increased with the combination of low IL-18 and high IL-12, but further studies are warranted to investigate these interleukins and their possible role in PTD.
This study aimed to analyze the associations between serum and cervicovaginal inflammatory marker... more This study aimed to analyze the associations between serum and cervicovaginal inflammatory markers and recurrent spontaneous preterm birth in a cohort study of 62 pregnant women with > or =1 prior early spontaneous birth. Serum samples and cervicovaginal swabs from the women were obtained at enrollment in early second trimester (week 12-25). Cervical length was measured by ultrasound and dicotomized in to short (< or =25 mm) and long cervices (>25 mm). The study endpoints were spontaneous preterm birth before 35 weeks and secondarily<37 weeks. Multiple inflammatory markers in serum (IL-1beta, IL-2, IL-5, IL-6, IL-8, IL-12, IL-18, TNF-alpha, TGF-beta, sTNF-R1, GM-CSF and TREM-1) and cervicovaginal secretions (IL-18, sTNF-RI and sIL-6) were individually associated with spontaneous preterm birth. Short cervical length did not explain associations between inflammatory markers and spontaneous preterm birth. Serum and cervicovaginal inflammatory markers did not correlate. In a combined prediction model using both serum and vaginal inflammatory markers, serum TNF-alpha, cervicovaginal sIL-6Ralpha and cervical length predicted 69% of all recurrent spontaneous preterm birth at a 5% false-positive rate. In conclusion, cervical length, serum TNF-alpha and cervicovaginal sIL-6Ralpha provide a clinically useful prediction of recurrent preterm birth in early second-trimester in women with a prior spontaneous preterm birth.
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