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OBJECTIVE: To compare mosaicisms in prenatal chorionic villus samples (CVSs) with corresponding postpartum placental samples.METHOD: We collected placentas from 15 consecutive cases of mosaicism detected in CVSs and obtained five standardized samples on each placenta after delivery. All pre- and postnatal placental samples were uncultured and analyzed by high-resolution chromosomal microarray.RESULTS: Ten cases of mosaicism for whole chromosome aneuploidy (mWC) and five cases with mosaicism for (sub)chromosomal copy number variations (mCNVs) were included. In 5/10 mWC cases and in 4/5 mCNV cases the prenatally detected aberration was confirmed in the postpartum placenta. Three postpartum placentas revealed various complex aberrations differing from the prenatal results: (1) mosaicisms for different deletions/duplications on 9p and 9q in all samples (prenatal: mosaic 5.3 Mb duplication on 9p24), (2) different regions with deletions/duplications/loss of heterozygosity on 1p in all samples (prenatal: mosaic 2.3 Mb 1p36 duplication), and (3) mosaicism for a duplication on 5q and a deletion on 6p in one out of five samples (prenatal: mosaic trisomy 7).CONCLUSION: CNVs constitute a complex subgroup in placental mosaicism. Counseling of these couples after chorionic villus sampling should not focus on the specific CNV involved, but on the nature of mosaicism and the option of amniocentesis and ultrasound.

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

Objective: To evaluate the risk of fetal involvement when trisomy 8 mosaicism (T8M) is detected in chorionic villus samples (CVS). Methods: A retrospective descriptive study of registered pregnancies in Denmark with T8M in CVS identified through a database search and a review of published cases of T8M found through a systematic literature search and inclusion of cross references. Pregnancies with T8M in CVS and no additional numerical chromosomal aberrations were included. Results: A total of 37 Danish cases and 60 published cases were included. T8M detected in a CVS was associated with fetal involvement in 18 out of 97 pregnancies (18.6% [95%CI: 11.4–27.7]). Eight out of 70 (11.4% [95%CI: 5.1–21.3]) interpreted prenatally to be confined placental mosaicism (CPM) were subsequently found to be true fetal mosaicisms (TFM). Conclusion: T8M detected in CVS poses a significant risk of fetal involvement, and examination of amniotic fluid (AF) and/or fetal tissue should be offered. However, a normal result of AF still has a considerable residual risk of fetal involvement. Genetic counselling at an early gestational age is essential, and follow-up ultrasonography should be performed to predict fetal involvement if possible.

Objective: Pathogenic variants in SCN 8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS ) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID ) or movement disorders without epilepsy have been reported. The vast majority of the published SCN 8A patients suffer from severe developmental and epileptic encephalopathy (DEE ). In this study, we aimed to provide further insight on the spectrum of milder SCN 8A‐related epilepsies. Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results: We found 36 probands who presented with an SCN 8A‐related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure‐free, two‐thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance: With this study, we explore the electroclinical features of an intermediate SCN 8A‐related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.

Objective: To evaluate the prevalence of mosaicism in chorionic villus sampling (CVS) samples after chromosomal microarray (CMA) and clinical outcome of pregnancies affected by confined placental mosaicism. Method: We retrieved all results from CMA, array-based comparative genomic hybridization, on CVS samples from January 2011 to November 2017 from Central and North Denmark Regions. Mosaic results from uncultured chorionic villi, cytotrophoblasts and mesenchymal cells, after CVS and follow-up on amniocytes, fetal tissue, or postnatal blood were studied and matched with clinical data from The Danish Fetal Medicine Database. Results: Prevalence of mosaicism was 93 out of 2,288 (4.1%) CVS samples of which 17 (18.3%) concerned submicroscopic copy number variations (CNVs)

International audience; The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts. Recently, causative variants in SPECC1L were reported in a pedigree reported in 1988 as atypical Opitz GBBB syndrome. Six families with SPECC1L variants have been reported thus far. We report here eight further pedigrees with SPECC1L variants, including a three-generation family, and a further individual of a previously published family. We discuss the nosology of Teebi and GBBB, and the syndromes related to SPECC1L variants. Although the phenotype of individuals with SPECC1L mutations shows overlap with Opitz syndrome in its craniofacial anomalies, the canonical laryngeal malformations and male genital anomalies are not observed. Instead, individuals with SPECCL1 variants have branchial fistulae, omphalocele, diaphragmatic hernias, and uterus didelphis. We also point to the clinical overlap of SPECC1L syndrome with mild Baraitser-Winter craniofrontofacial syndrome: they share similar dysmorphic features (wide, short nose with a large tip, cleft lip and palate, blepharoptosis, retrognathia, and craniosynostosis), although intellectual disability, neuronal migration defect, and muscular problems remain largely specific to Baraitser-Winter syndrome. In conclusion, we suggest that patients with pathogenic variants in SPECC1L should not be described as "dominant (or type 2) Opitz GBBB syndrome", and instead should be referred to as "SPECC1L syndrome" as both disorders show distinctive, non overlapping developmental anomalies beyond facial communalities.

Less than one hundred cases of the acrofacial dysostosis, Nager syndrome, have been described. The cardinal features of Nager syndrome are micrognathia, midface retrusion and limb malformations, predominately of the radial ray of upper extremities. Within the past three years haploinsufficiency of SF3B4 has been confirmed as the major cause of Nager syndrome. Different loss-of-function point-mutations in SF3B4 have been found in approximately 2/3 of patients diagnosed with Nager syndrome. Whole gene deletions of SF3B4 have also been suggested to be the cause of Nager syndrome in SF3B4 point mutation negative patients. Only four prenatal cases displaying Nager-like features in the 2nd or 3rd trimester which have been genetically confirmed with SF3B4 point-mutation after birth have been described. We report a case of a 12-week-old fetus with micrognathia, malformed wrists, bilateral club foot and short long bones diagnosed prenatally by chromosomal microarray with a de novo 0.4 Mb deletion at chromosome 1q21.2 involving SF3B4. To our knowledge, this is the first report of Nager syndrome caused by a SF3B4 whole gene deletion. The case presented also shows that high-resolution chromosomal microarray in early pregnancy can confirm Nager syndrome caused by SF3B4-deletion prenatally.

Objective To assess the clinical value of using high-resolution chromosomal microarray (CMA) for the examination of genomic imbalances in prenatal uncultured chorionic villus samples from fetuses with increased nuchal translucency (NT) and a normal quantitative fluorescent polymerase chain reaction (QF-PCR) result, in a clinical setting in which more than 95% of pregnant women receive first-trimester combined screening. Methods From January 2013 to July 2014, we included 132 chorionic villus samples from consecutive ongoing pregnancies, with fetal NT ≥ 3.5 mm at 11–13 weeks' gestation, from obstetric units (publicly funded healthcare) in Central and North Denmark Regions. DNA was extracted directly from the samples and examined with QF-PCR (n = 132) and 180 kb oligonucleotide array-based comparative genomic hybridization (n = 94). Results In 38 cases, aneuploidies for chromosomes 18, 21 or X, or triploidy, were detected by QF-PCR. Among the 94 cases with a normal QF-PCR result, we detected pathogenic copy number variants (CNVs) by CMA in 12 fetuses (12.8% (95% CI, 7.5–21.0%)). In an additional three (3.2%) cases, CNVs with uncertain clinical significance were detected. Conclusion CMA is a valuable diagnostic technique in pregnancies with isolated fetal NT ≥ 3.5 mm. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.

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.European Journal of Human Genetics advance online publication, 18 November 2015; doi:10.1038/ejhg.2015.249.

Cell-free DNA testing (cfDNA testing) in maternal plasma has recently been implemented in Danish healthcare. Prior to that we wanted to evaluate the preferences among pregnant women, partners and health professionals regarding cfDNA testing compared with invasive prenatal diagnostics.Responders were recruited at public hospitals in the Central and North Denmark Regions. Stated preferences for prenatal testing were obtained through an online questionnaire incorporating a discrete choice experiment. Test choices differed according to attributes such as risk of miscarriage (none or small) and genetic information provided by the test; simple (Down syndrome only) or comprehensive (chromosomal abnormalities beyond Down syndrome).No risk of miscarriage was the key attribute affecting the preferences of women (n = 315) and partners (n = 102). However, women with experiences of invasive testing placed more emphasis on comprehensive genetic information and less on risk of miscarriage compared with other women. Likewise, foetal medicine experts, obstetricians and sonographers (n = 57) had a greater preference for comprehensive genetic information than midwives who were not directly involved in counselling for prenatal testing (n = 48).As safety seems to affect the majority of pregnant couples' choice behaviour, thorough pre-test counselling by trained health professionals is of paramount importance.Aarhus University and The Foundation of 17-12-1981.This study was registered with the Danish Data Protection Agency (1-16-02-586-13/ 2007-58-0010).