Choroid plexus hyperplasia leading to communicating hydrocephalus is a rare disorder with only 24 patients reported so far in the literature. Furthermore, genetic information is only available for ...six of these cases: In one patient the condition was associated with trisomy 9p, in one patient with trisomy 9 mosaicism and in three patients with tetrasomy 9p. Here, we describe four additional patients with choroid plexus hyperplasia leading to various levels of hydrocephalus, and gain of the entire chromosome 9p region: Three with trisomy 9p and one with tetrasomy 9p. The three patients with trisomy 9p were siblings. Normal karyotypes were identified in the lymphocytes of the parents. Likely one of the parents is a mosaic for a cell line with trisomy 9p in the gonads. We demonstrate the importance of correctly diagnosing choroid plexus hyperplasia as the cause of hydrocephalus in patients with chromosome 9p gain since ventriculoperitoneal shunting is likely to fail due to intolerable formation of ascites.
The cervical mucus plug is a large, complex structure within the cervical canal that is shed shortly before or during labor. We propose that the cervical mucus plug fulfills critical 'gate-keeper' ...functions based on its physical and immunologic properties, which help prevent ascending infection and preterm labor. The viscoelastic properties of the cervical mucus plug are determined by mucins (large glycoproteins), which can inhibit viral replication and exclude larger molecules and bacteria by preventing their diffusion through the plug. Furthermore, the innate and adaptive immunological properties of the cervical mucus plug are well suited for arresting bacterial infection by stimulating a robust inflammatory response. A possible association between an impaired gate-keeper function of the cervical mucus plug and preterm birth is discussed.
Non-invasive prenatal testing is increasingly available worldwide and stakeholder viewpoints are essential to guide implementation. Here we compare the preferences of women and health professionals ...from nine different countries towards attributes of non-invasive and invasive prenatal tests for Down syndrome. A discrete choice experiment was used to obtain participants' stated preference for prenatal tests that varied according to four attributes: accuracy, time of test, risk of miscarriage, and type of information. Pregnant women and health professionals were recruited from Canada, Denmark, Iceland, Israel, Italy, the Netherlands, Portugal, Singapore, and the United Kingdom. A total of 2666 women's and 1245 health professionals' questionnaires were included in the analysis. Differences in preferences were seen between women and health professionals within and between countries. Overall, women placed greater emphasis on test safety and comprehensive information than health professionals, who emphasised accuracy and early testing. Differences between women's and health professionals' preferences are marked between countries. Varied approaches to implementation and service delivery are therefore needed and individual countries should develop guidelines appropriate for their own social and screening contexts.
Introduction
In Denmark, non‐invasive prenatal testing (NIPT) has been used since 2013. We aimed to evaluate the early clinical use of NIPT in Danish public and private healthcare settings before ...NIPT became an integrated part of the national guidelines on prenatal screening and diagnosis in 2017.
Material and methods
NIPT data were collected between March 2013 and June 2017 from national public registries and private providers. Results from follow‐up samples (chorionic villi, amniotic fluid, postnatal blood or fetal tissue) were included from The Danish Cytogenetics Central Registry and indications and outcome from The Danish Fetal Medicine Database.
Results
A total of 3936 NIPT results were included in the study from public hospitals (n = 3463, 88.0%) and private clinics (n = 473, 12.0%). The total number of prenatal tests was 19 713 during the study period: 20% were NIPT analyses (n = 3936) and 80% invasive procedures (n = 15 777). Twenty‐five percent of NIPTs in the private clinics were performed before gestational week 11+0, whereas NIPT in public settings was used only after combined first trimester screening (P < .001). Regardless of indication, the national public sensitivity was 96.9% (95% CI 82.0%‐99.8%) for trisomy 21, 100% (95% CI 46.3%‐100%) for trisomy 18, 100% (95% CI 5.5%‐100%) for trisomy 13, and 87.0% (95% CI 74.5%‐92.4%) for any fetal chromosomal aberration. Forty‐seven true‐positive NIPT results included cases of common aneuplodies (trisomy 21, n = 31; trisomy 18, n = 5; and trisomy 13, n = 1), sex chromosomal aberrations (n = 7) and atypical chromosomal aberrations (n = 3). One false‐negative NIPT result occurred (trisomy 21). Of 47 cases, 21 (45%) cases with a true‐positive NIPT result resulted in live births by choice; 11 of these children had Down and 4 had Edwards syndrome.
Conclusions
The total number of NIPT analyses was low compared with the number of invasive procedures in the implementation period. In contrast to the generally high termination rate after a positive result following invasive testing in Denmark, a high proportion of true‐positive NIPT results from the public setting resulted in live births. NIPT may be an important risk‐free alternative to invasive testing for a minority of women in the public setting who wish to use prenatal genetic testing for information only and not for reproductive decision‐making.
Objectives: A few adult and adolescent patients with even severe cholestatic liver disease remain unexplained after standard diagnostic work-up. We studied the value of genetic examination in such ...patients and developed a panel of eight genes with known cholestatic associations.
Materials and methods: Thirty-three patients with unexplained cholestasis despite a thorough clinical work-up were examined for sequence variations in the coding regions of the ABCB4, ABCB11, ABCC2, ABCG5, ATP8B1, JAG1, NOTCH2, and UGT1A1 genes and the promoter region of UGT1A1 by massive parallel sequencing of DNA extracted from whole blood. Hepatologists and clinical geneticists evaluated the causal potential of genetic variants.
Results: In 9/33 patients (27%), we identified genetic variants as a certain causal factor and in further 9/33 (27%) variants as a possible contributing factor. In most cases, a detailed family history was necessary to establish the importance of genetic variants. Genetic causes were identified in 6/13 women (46%) with intrahepatic cholestasis during pregnancy and persisting abnormal biochemistry after delivery.
Conclusions: Our study suggests that a small number of well-known genetic variants are involved in at least 27-54% of patients with unexplained cholestasis. An expanded panel will likely explain more cases. This motivates genetic testing of these patients. Genetic testing, however, cannot stand alone but should be combined with a clinical genetic work-up in collaboration between hepatologists and clinical geneticists.
Healthy women of reproductive age have a vaginal pH around 4.5, whereas little is known about pH in the upper genital tract. A shift in the vaginal microbiota may result in an elevated pH in the ...upper genital tract. This might contribute to decreased fertility and increased risk of preterm birth. Therefore, we aimed to measure pH in different compartments of the female genital tract in both nonpregnant and pregnant women, stratifying into a normal and abnormal vaginal microbiota.
In this descriptive study, we included 6 nonpregnant, 12 early-pregnant, and 8 term-pregnant women. A pH gradient was recorded with a flexible pH probe. An abnormal vaginal microbiota was diagnosed by a quantitative polymerase chain reaction technique for
;
;
; bacterial vaginosis-associated bacterium 1, 2, 3, and TM7; and
spp. among others.
In all participants we found the pH gradient in the lower reproductive canal to be most acidic in the lower vagina and most alkaline in the upper uterine cavity. Women with an abnormal vaginal microbiota had an increased pH in the lower vagina compared to the other groups.
There is a pronounced pH gradient within the female genital tract. This gradient is not disrupted in women with an abnormal vaginal microbiota.
Pathogenic variants in the MED12 gene located on the X‐chromosome have primarily been reported in males with Lujan‐Fryns syndrome, Ohdo syndrome and the Opits‐Kaveggia syndrome. However, earlier ...reports of female patients and female mice suggest that MED12 deficiency causes severe malformations. We report a novel example of a MED12 de novo nonsense variant in a female fetus with severe malformations identified by trio‐exome sequencing. This finding further expands the clinical spectrum of MED12‐related disorders, which is vital for prenatal diagnosis and genetic counselling of couples.
Pathogenic variants in MED12 located on the X‐chromosome are linked to intellectual disability and dysmorphism in males. We report a novel MED12 de novo nonsense variant in a female fetus with malformations, further expanding the clinical spectrum.
The C1QBP protein (complement component 1 Q subcomponent‐binding protein), encoded by the C1QBP gene, is a multifunctional protein predominantly localized in the mitochondrial matrix. Biallelic ...variants have previously been shown to give rise to combined respiratory‐chain deficiencies with variable phenotypic presentation, severity, and age at onset, from intrauterine with a mostly lethal course, to a late‐onset mild myopathy. We present two fetuses, one male and one female, of first‐cousin parents, with severe intrauterine growth retardation, oligo/anhydramnios, edema, and cardiomyopathy as the most prominent prenatal symptoms. Both fetuses showed no copy number variants by chromosome microarray analysis. Analysis of a fibroblast culture from one of the fetuses showed deficiency of respiratory chain complex IV, and using exome sequencing, we identified homozygosity for a novel variant in C1QBP in both fetuses. To our knowledge, only six patients with pathogenic variants in C1QBP have been reported previously and with this report, we add a novel pathogenic variant in C1QBP found in two related fetuses.
Is MED13L-related intellectual disability a recognizable syndrome? Tørring, Pernille Mathiesen; Larsen, Martin Jakob; Brasch-Andersen, Charlotte ...
European journal of medical genetics,
February 2019, 2019-Feb, 2019-02-00, 20190201, Volume:
62, Issue:
2
Journal Article
Peer reviewed
Open access
MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related ...intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients.
In the search for genetic aberrations in individuals with ID, two of the patients were identified by chromosomal microarray analysis, and five by exome sequencing. One of the individuals, suspected of MED13L-related intellectual disability, based on clinical features, was identified by Sanger sequencing.
All 8 individuals had de novo MED13L aberrations, including two intragenic microdeletions, two frameshift, three nonsense variants, and one missense variant. Phenotypically, they all had intellectual disability, speech and motor delay, and features of the mouth (open mouth appearance, macroglossia, and/or macrostomia). Two individuals were diagnosed with autism, and one had autistic features. One had complex congenital heart defect, and one had persistent foramen ovale. The literature was reviewed with respect to clinical and dysmorphic features, and genetic aberrations.
Even if most clinical features of MED13L-related intellectual disability are rather non-specific, the syndrome may be suspected in some individuals based on the association of developmental delay, speech impairment, bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance.
High concentrations of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been identified in the cervical mucus plug (CMP) at term of pregnancy. Their ...physiological and pathophysiological implications, however, remain to be elucidated, and CMPs from preterm labor have never been examined. This study was therefore conducted to describe the concentrations of MMP-2, TIMP-1, MMP-8 and MMP-9 in the CMP in relation to gestational age, IL-8 as an indicator of inflammation, compartment of the CMP, and preterm labor.
An aliquot of the distal plug compartment facing the vaginal microflora (CMP-dist) was collected from non-pregnant (n = 15), early pregnant (n = 15) and term pregnant women (n = 15). Whole CMPs shed during active vaginal term (n = 15) and preterm (n = 4) labor were also included. Protein concentrations were determined by enzyme-linked immunosorbent assay (ELISA).
MMP-2 was not detectable in the non-pregnant CMP-dists whereas high concentrations were found in early pregnancy followed by an 85% decline at term. High concentrations of TIMP-1 were found in both the non-pregnant and early pregnant CMP-dists with a 90% decline at term. Consequently, the molar TIMP/MMP ratio was 40 in the non-pregnant state and 0.2 at term. The MMP-2 and TIMP-1 concentrations were alike in the CMP-dists and the whole CMPs.MMP-8, MMP-9, and IL-8 were mainly found in the distal CMP compartment. MMP-8 and MMP-9 concentrations were several fold increased in this compartment during pregnancy compared to the non-pregnant state. In the preterm whole CMPs, MMP-8, MMP-9 and IL-8 were 2 to 5 fold increased compared to term whole CMPs.
These results suggest that CMP MMP-2 reflects the non-leukocyte dependent cervical remodeling that occurs in early pregnancy, whereas MMP-8 and MMP-9 are involved in the defense against ascending infections primarily located to the distal compartment of the CMP. The upregulation of MMP-8, MMP-9 and IL-8 in whole CMPs from preterm labor may indicate the involvement of an intrauterine infection.
PDF
