Older mothers and increased impact of prenatal screening: stable livebirth prevalence of trisomy 21 in the Netherlands for the period 2000-2013.

In the Netherlands, there is no registry system regarding the livebirth prevalence of trisomy 21 (T21). In 2007, a national screening programme was introduced for all pregnant women, which may have changed the livebirth prevalence of T21. The aim of this study is to analyse trends in factors that influence livebirth prevalence of T21 and to estimate the livebirth prevalence of T21 for the period of 2000-2013. National data sets were used on the following: (1) livebirths according to maternal age and (2) prenatal testing and termination of pregnancy (ToP) following diagnosis of T21. These data are combined in a model that uses maternal age-specific risk on T21 and correction factors for natural foetal loss to assess livebirth prevalence of T21. The proportion of mothers aged ≥ 36 years has increased from 12.2% in 2000 to 16.6% in 2009, to gradually decrease afterwards to 15.2% in 2013. The number of invasive tests performed adjusted for total livebirths decreased (5.9% in 2000 vs. 3.2% in 2013) with 0.18% a year (95% CI: -0.21 to -0.15; p < 0.001). Following invasive testing, a higher proportion of foetuses was diagnosed with T21 (1.6% in 2000 vs. 4.8% in 2013) with a significant increase of 0.22% a year (95% CI: 0.18-0.26; p < 0.001). The proportion of ToP subsequent to T21 diagnosis was on average 85.7%, with no clear time trend. This resulted in a stable T21 livebirth prevalence of 13.6 per 10,000 livebirths (regression coefficient -0.025 (95% CI: -0.126 to 0.77; p = 0.60).

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

Mutations in the mitochondrial arginyl tRNA synthetase (RARS2) gene are associated with Pontocerebellar Hypoplasia type 6 (PCH6). Here we report two patients, compound heterozygous for RARS2 mutations, presenting with early onset epileptic encephalopathy and (progressive) atrophy of both supra- and infratentorial structures. Early pontocerebellar hypoplasia was virtually absent and respiratory chain (RC) defects could not be detected in muscle biopsies. Both patients carried a novel missense mutation c.1544A>G (p.(Asp515Gly)) in combination with either a splice site (c.297+2T>G) or a frameshift (c.452_454insC) mutation. The splice site mutation induced skipping of exon 4.These two patients expand the phenotypical spectrum associated with RARS2 mutations beyond the first report of PCH6 by Edvardson and colleagues. We propose to classify RARS2-associated phenotypes as an early onset mitochondrial encephalopathy, since this is more in agreement with both clinical presentation and underlying genetic cause.

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands.

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

Population-Attributable Risk of Risk Factors for Recurrent Wheezing in Moderate Preterm Infants During the First Year of Life.

BACKGROUND: Recurrent wheezing in young infants has a high prevalence, influences quality of life, and generates substantial health care costs. We previously showed that respiratory syncytial virus infection is an important mechanism of recurrent wheezing in moderate preterm infants. We aimed to provide population-attributable risks (PAR) of risk factors for recurrent wheezing during the first year of life in otherwise healthy moderate preterm infants. METHODS: RISK is a multicentre prospective birth cohort study of 4424 moderate preterm infants born at 32-35 weeks gestation. We estimated PAR of risk factors for recurrent wheezing, which was defined as three or more parent-reported wheezing episodes during the first year of life. RESULTS: We evaluated 3952 (89%) children at 1 year of age, of whom 705 infants (18%) developed recurrent wheezing. Fourteen variables were independently associated with recurrent wheezing. Hospitalisation for respiratory syncytial virus bronchiolitis had a strong relationship with recurrent wheezing (RR 2.6; 95% confidence interval, CI, 2.2, 3.1), but a relative modest PAR (8%; 95% CI 6, 11%) which can be explained by a low prevalence (13%). Day-care attendance showed a strong relationship with recurrent wheezing (RR 1.9; 95% CI 1.7, 2.2) and the highest PAR (32%; 95% CI 23, 37%) due to a high prevalence (67%). The combined adjusted PAR for the 14 risk factors associated with recurrent wheezing was 49% (95% CI 46, 52%). CONCLUSIONS: In moderate preterm infants, day-care attendance has the largest PAR for recurrent wheezing. Trial evidence is needed to determine the potential benefit of delayed day-care attendance in this population.

Maternal Plasma DNA and RNA Sequencing for Prenatal Testing.

Cell-free DNA (cfDNA) testing has recently become indispensable in diagnostic testing and screening. In the prenatal setting, this type of testing is often called noninvasive prenatal testing (NIPT). With a number of techniques, using either next-generation sequencing or single nucleotide polymorphism-based approaches, fetal cfDNA in maternal plasma can be analyzed to screen for rhesus D genotype, common chromosomal aneuploidies, and increasingly for testing other conditions, including monogenic disorders. With regard to screening for common aneuploidies, challenges arise when implementing NIPT in current prenatal settings. Depending on the method used (targeted or nontargeted), chromosomal anomalies other than trisomy 21, 18, or 13 can be detected, either of fetal or maternal origin, also referred to as unsolicited or incidental findings. For various biological reasons, there is a small chance of having either a false-positive or false-negative NIPT result, or no result, also referred to as a "no-call." Both pre- and posttest counseling for NIPT should include discussing potential discrepancies. Since NIPT remains a screening test, a positive NIPT result should be confirmed by invasive diagnostic testing (either by chorionic villus biopsy or by amniocentesis). As the scope of NIPT is widening, professional guidelines need to discuss the ethics of what to offer and how to offer. In this review, we discuss the current biochemical, clinical, and ethical challenges of cfDNA testing in the prenatal setting and its future perspectives including novel applications that target RNA instead of DNA.

Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature.

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc.

Changing to NIPT as a first-tier screening test and future perspectives: opinions of health professionals.

OBJECTIVE: The aim of this study was to investigate health professionals' opinions toward offering noninvasive prenatal testing (NIPT) as first-tier screening test regardless of pregnant women's risk, and toward a potential broader range of disorders. METHODS: A questionnaire completed by obstetric health professionals (n = 240) after an in-service NIPT training in the West and North of the Netherlands. RESULTS: The majority (72%) of respondents favored replacing first-trimester combined test (FCT) by NIPT, although 43% preferred to maintain nuchal translucency measurement. Many respondents believed that replacing FCT by NIPT would only have advantages (57%), would lead to more pregnant women opting for prenatal testing (69%), and would simplify counseling (47%). Differences in attitudes toward counseling between health professionals were observed. When considering NIPT to screen for broader range of disorders, the majority (92%) thought that this should include disorders characterized by neonatal death, whereas 52% of the respondents favored testing for fetomaternal risk factors. Overall, 46% thought screening should be offered as a fixed list of disorders. CONCLUSION: Most health professionals favor NIPT instead of FCT but prefer to maintain nuchal translucency measurement. If NIPT becomes available as a first-tier screening test, attention remains necessary to ensure that pregnant women make well-informed decisions in line with the aim of prenatal screening.

[Maternal uniparental disomy 14; differential diagnosis with Prader-Willi syndrome]. / Maternale uniparentale disomie 14. In de differentiaaldiagnose bij Prader-Willi-syndroom.

BACKGROUND: Maternal uniparental disomy 14 is a rare genetic disorder in which both chromosomes 14 are maternally inherited. The disorder is characterised by neonatal hypotonia and feeding difficulties, intrauterine or later growth retardation, truncal obesity and precocious puberty. During the neonatal period its clinical phenotype shows great similarities with that of Prader-Willi syndrome. CASE DESCRIPTION: We describe two patients with dysmaturity, neonatal hypotonia and feeding difficulties who initially showed clinical signs of Prader-Willi syndrome. However, molecular testing for this disorder was normal. Some years later, additional molecular testing confirmed the diagnosis of maternal uniparental disomy 14. CONCLUSION: Maternal uniparental disomy 14 shows many phenotypic similarities with Prader-Willi syndrome. In a hypotonic neonate, molecular testing for maternal uniparental disomy 14 should therefore be considered if Prader-Willi syndrome has been excluded.