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This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access.European Journal of Human Genetics advance online publication, 18 March 2015; doi:10.1038/ejhg.2015.57. ispartof: European Journal of Human Genetics vol:23 issue:11 pages:1438-50 ispartof: location:England status: published

Given the cost constraints of the European health-care systems, criteria are needed to decide which genetic services to fund from the public budgets, if not all can be covered. To ensure that high-priority services are available equitably within and across the European countries, a shared set of prioritization criteria would be desirable. A decision process following the accountability for reasonableness framework was undertaken, including a multidisciplinary EuroGentest/PPPC-ESHG workshop to develop shared prioritization criteria. Resources are currently too limited to fund all the beneficial genetic testing services available in the next decade. Ethically and economically reflected prioritization criteria are needed. Prioritization should be based on considerations of medical benefit, health need and costs. Medical benefit includes evidence of benefit in terms of clinical benefit, benefit of information for important life decisions, benefit for other people apart from the person tested and the patient-specific likelihood of being affected by the condition tested for. It may be subject to a finite time window. Health need includes the severity of the condition tested for and its progression at the time of testing. Further discussion and better evidence is needed before clearly defined recommendations can be made or a prioritization algorithm proposed. To our knowledge, this is the first time a clinical society has initiated a decision process about health-care prioritization on a European level, following the principles of accountability for reasonableness. We provide points to consider to stimulate this debate across the EU and to serve as a reference for improving patient management.

We have studied DNA polymorphisms at loci in the pericentromeric region on the long arm of chromosome 21 in 200 families with trisomy 21, in order to determine the meiotic origin of nondisjunction. Maintenance of heterozygosity for parental markers in the individual with trisomy 21 was interpreted as resulting from a meiosis I error, while reduction to homozygosity was attributed to a meiosis II error. Nondisjunction was paternal in 9 cases and was maternal in 188 cases, as reported earlier. Among the 188 maternal cases, nondisjunction occurred in meiosis I in 128 cases and in meiosis II in 38 cases; in 22 cases the DNA markers used were uninformative. Therefore meiosis I was responsible for 77.1% and meiosis II for 22.9% of maternal nondisjunction. Among the 9 paternal nondisjunction cases the error occurred in meiosis I in 2 cases (22.2%) and in meiosis II in 7 (77.8%) cases. Since there was no significant difference in the distribution of maternal ages between maternal I error versus maternal II error, it is unlikely that an error at a particular meiotic stage contributes significantly to the increasing incidence of Down syndrome with advancing maternal age. Although the DNA polymorphisms used were at loci which map close to the centromere, it is likely that rare errors in meiotic-origin assignments may have occurred because of a small number of crossovers between the markers and the centromere. Analysis of these polymorphisms may provide a more accurate understanding of the meiotic stage of nondisjunction in trisomy 21 than that previously provided by chromosomal heteromorphisms.

BACKGROUND: Down syndrome (DS) is characterized by the presence of an extra full or partial human chromosome 21 (Hsa21). An invaluable model to define genotype-phenotype correlations in DS is the study of the extremely rare cases of partial (segmental) trisomy 21 (PT21), the duplication of only a delimited region of Hsa21 associated or not to DS. A systematic retrospective reanalysis of 125 PT21 cases described up to 2015 allowed the creation of the most comprehensive PT21 map and the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. We reanalyzed at higher resolution three cases previously published and we accurately searched for any new PT21 reports in order to verify whether HR-DSCR limits could prospectively be confirmed and possibly refined.METHODS: Hsa21 partial duplications of three PT21 subjects were refined by adding array-based comparative genomic hybridization data. Seven newly described PT21 cases fulfilling stringent cytogenetic and clinical criteria have been incorporated into the PT21 integrated map.RESULTS: The PT21 map now integrates fine structure of Hsa21 sequence intervals of 132 subjects onto a common framework fully consistent with the presence of a duplicated HR-DSCR, on distal 21q22.13 sub-band, only in DS subjects and not in non-DS individuals. No documented exception to the HR-DSCR model was found.CONCLUSIONS: The findings presented here further support the association of the HR-DSCR with the diagnosis of DS, representing an unbiased validation of the original model. Further studies are needed to identify and characterize genetic determinants presumably located in the HR-DSCR and functionally associated to the critical manifestations of DS.

This study investigated the contribution of interaural timing differences (ITDs) in different frequency regions to binaural unmasking (BU) of speech. Speech reception thresholds (SRTs) and binaural intelligibility level differences (BILDs) were measured in two-talker babble in 6 young normal-hearing (NH) and 9 elderly hearing-impaired (HI) listeners with normal or closeto- normal hearing at and below 1.5 kHz. Target sentences were presented diotically, embedded in a stream of diotic or dichotic maskers. Both target and masker sentences were split into frequency regions above and below 1.25 kHz. In the dichotic listening conditions, the maskers were lateralized to the left side by introducing 0.68-ms ITDs in either the low-frequency band, the high-frequency band, or both bands simultaneously. BILDs were found to be similar in both listener groups when the ITDs were imposed on the lowfrequency band only. ITDs in the high-frequency band alone did not produce any BILD in any of the groups. However, when ITDs were imposed in both frequency bands, the NH listeners yielded significantly greater BILDs than the HI listeners. The results suggest that, on a group level, HI listeners relied solely on ITDs in the low-frequency band while NH listeners were able to utilize envelope ITDs above 1.25 kHz to facilitate the BU of speech.

The influence of hearing aid (HA) signal processing on the perception of spatially dynamic sounds has not been systematically investigated so far. Previously, we observed that for elderly hearing-impaired (EHI) listeners concurrent distractor sounds impaired the detectability of left-right source movements, and reverberation that of near-far source movements (Lundbeck et al, Trends Hear 2017). Here, we explored potential ways of improving these deficits with HAs. To that end, we carried out detailed acoustic analyses on the stimuli used previously to examine the impact of two beamforming algorithms and a binaural coherence-based noise reduction scheme on the cues underlying movement perception. While the binaural cues remained mostly unchanged, the applied processing led to greater monaural spectral changes, as well as increases in signal-to-noise ratio and direct-to-reverberant sound ratio. Based on these findings, we conducted a listening test with 20 EHI listeners. That is, we performed aided measurements of movement detectability with three different processing conditions in two acoustic scenarios. Our results indicate that, for both movement dimensions, the applied processing could partly restore source movement detection in the presence of concurrent distractor sounds.

Hearing-impaired (HI) listeners, as well as elderly listeners, typically have a reduced ability to discriminate the fundamental frequency (F0) of complex tones compared to young normal-hearing (NH) listeners. Several studies have shown that musical training, on the other hand, leads to improved F0-discrimination performance for NH listeners. It is unclear whether a comparable effect of musical training occurs for listeners whose sensory encoding of F0 is degraded. To address this question, F0 discrimination was investigated for three groups of listeners (14 young NH, 9 older NH and 10 HI listeners), each including musicians and non-musicians, using complex tones that differed in harmonic content. Musical training significantly improved F0 discrimination for all groups of listeners, especially for complex tones containing low-numbered harmonics. In a second experiment, the sensitivity to temporal fine structure cues (TFS) was estimated in the same listeners. Although TFS cues were degraded for the two older groups of listeners, musicians showed better performance than non-musicians. Additionally, a significant correlation was obtained between F0-discrimination performance and sensitivity to TFS cues for complex tones with low and intermediate harmonic numbers. These findings suggest that musical training may enhance both sensory encoding of TFS cues and F0 discrimination in young and older listeners with or without hearing loss.

This study examined differences in benefit from bilateral directional processing. Groups of listeners with symmetric or asymmetric audiograms 2 dB profited more from low-frequency binaural cues than from greater SNR improvement, while for smaller BILDs the opposite was true. Audiometric asymmetry reduced the BILD influence. In spatially diffuse noise, the maximal SNR improvement was beneficial. Moreover, binaural tone-in-noise detection performance (N0Sπ threshold) at 500 Hz predicted the benefit from low-frequency binaural cues effectively. These results provide a basis for adapting bilateral directional processing to the user and the scenario.

For cochlear implant users, temporal and place cue are assumed to varyalong two orthogonal perceptual dimensions linked to pitch height and timbre.Here, the effect of electrode place, pulse rate, and amplitude modulationfrequency on those perceptual dimensions was investigated. Combinations ofdifferent electrode places with differing pulse rates or modulation frequencieswere presented to the participants while they were asked to rate pitch heightand sound quality using multiple verbal attributes. The results indicate thattemporal and place cues induce two perceptual dimensions that can be bothlinked to pitch and timbre.

Speech reception thresholds (SRTs) in noise improve when the speech and noise sources are spatially separated. This spatial release from masking (SRM) is usually investigated in fixed-head situations. We studied free-head situations in audio and audio-visual conditions. We compared normally- hearing and cochlear-implant (CI) users’ spontaneous and directed head- orientation strategies when attending to speech in noise with a progressively declining signal-to-noise ratio. SRM-model predictions suggested benefits of head orientation away from the target speech that we hypothesized would motivate head rotation. As signal-to-noise ratio declined, observed head tracks differed greatly between listeners. Audio-visual presentation reduced the amount of head rotation. When directed, listeners made more effective use of head rotation. Audio and audio-visual SRTs were acquired at fixed, 0, and 30 deg head orientations with respect to the target speech. At the most favourable 30-deg head orientation, SRM reached 8 and 6 dB for NH listeners and CI users respectively. Lip-reading yielded improvements of 3 and 5 dB on average across conditions. CI users confirmed that training in optimizing both their position and head orientation with respect to target speaker and noise source position in a social setting was both currently missing and likely valuable.