The Effect of Resolution Level and Targeted Design in the Diagnostic Performance of Prenatal Chromosomal Microarray Analysis.

INTRODUCTION: This study was performed to assess the optimal resolution for prenatal testing by array comparative genomic hybridization (aCGH), aiming to balance between maximum diagnostic yield and minimal detection of variants of uncertain significance (VOUS). METHODS: This was a prospective study using data of 2,336 fetuses that underwent invasive prenatal diagnosis, and the samples were analyzed by aCGH. In total, six different aCGH platforms were studied; four different resolutions (0.18 Mb, 0.5 Mb, 1 Mb, and 2 Mb) and two platform designs (whole-genome [WG] and targeted). The results of these designs were compared based on their diagnostic yield and VOUS rate. The performance of the different designs was further analyzed according to indication for invasive testing. RESULTS: The diagnostic yield of copy number variants increased with increasing level of analysis. The detection rates of clinically significant chromosomal abnormalities were almost the same across our targeted array designs; 7.2% with 0.18 Mb backbone/0.05 Mb versus 7.1% with 0.5 Mb backbone/0.05 Mb (p >0.05). However, a significant difference in the rate of VOUS was observed; 9.4% with 0.18 Mb backbone/0.05 Mb versus 6% with 0.5 Mb backbone/0.05 Mb (p <0.001). After analyzing the results across different indications for testing, we found that the application of non-targeted platform designs and lower levels of resolution analysis (such as 1 Mb WG or 0.5 MbL/1 MbG WG) would offer similar diagnostic yield in most cases with major congenital anomalies, with lower VOUS rates. However, the sample size for many indication groups was too small to extract robust associations. CONCLUSION: It appears that the targeted array platform with 0.5 Mb backbone resolution and 0.05 Mb on targeted gene-rich regions is optimal for routine chromosomal microarray analysis use in prenatal diagnosis. It may be beneficial to individualize the minimum resolution in specific referral indications as the indications for invasive prenatal testing may be quite heterogeneous.

A novel familial mutation associated with Treacher Collins syndrome: A case report.

Treacher Collins syndrome (TCS) is a type of mandibulofacial dysostosis with incomplete penetrance and high intra- and interfamilial clinical heterogeneity, and it is associated with mutations of treacle ribosome biogenesis factor 1 (TCOF1), and RNA polymerase I and III subunit (POLR1)C and POLR1D genes. In the present case report, a patient with TCS with auricle dysplasia and hearing loss accompanied with intellectual disability is described. Sequence analysis was performed on blood samples from the patient and his father via oligonucleotide-based target capture, followed by next-generation sequencing. Alignment and variant calls were generated using the Burrows-Wheeler Aligner and Genome Analysis Toolkit, followed by bioinformatics analysis of the detected variants. A novel heterozygous mutation, c.911C>T (p.Ser304Leu), was detected in the TCOF1 gene, which was inherited from the father. The father of the patient only suffered from hearing loss. The present report is the first to identify an association between phenotypic variability and TCOF1 gene mutations and thus contributes to our understanding of the association between the genotype and phenotype in patients with TCS and offers clinically relevant information for diagnosis of the syndrome.

Non-invasive prenatal screening versus prenatal diagnosis by array comparative genomic hybridization: a comparative retrospective study.

OBJECTIVE: To calculate the proportion of array comparative genomic hybridization (aCGH) pathogenic results, that would not be detectable by non-invasive prenatal screening (NIPS). METHODS: This is a comparative study using data from 2779 fetuses, which underwent invasive prenatal diagnosis, and the samples were analyzed using aCGH. The simulated NIPS assay would test for trisomies 21, 18, 13, monosomy X, 47, XXX, 47, XYY, and 47, XXY. Indications for invasive testing were grouped into categories and the absolute, relative rates of pathogenic/likely pathogenic results of aCGH analysis that would not be detectable by NIPS were calculated. RESULTS: The expected rate of aCGH-detected abnormalities that would not be detectable by NIPS was 28.0% (95% CI 14.3-47.6) for nuchal translucency (NT) 95 to 99th centile; 14.3% (95% 5.0-34.6) for NT > 99th centile; 34.2% (95% CI 21.1-50.1) for high-risk first-trimester results (regardless of NT); 52.4% (95% CI 32.4-71.7) for second-trimester markers; and 50.0% (95% CI 26.8-73.2) for advanced maternal age. The overall rate of aCGH pathogenic/likely pathogenic results was 5.0% and 44.0% (95% CI 36.0-52.2) of them would not be detected by NIPS. CONCLUSIONS: Approximately half of the abnormal aCGH results would not be detectable by standard NIPS assays, highlighting the necessity of pre-test counseling, and illustrating the limitations of NIPS. © 2017 John Wiley & Sons, Ltd.

Prenatal diagnosis of 1p34.3 interstitial microdeletion by aCGH in a fetus with jaw bone abnormalities.

BACKGROUND: Interstitial microdeletions in 1p are extremely rare, as very few cases have been reported postnatally and only one prenatally, yet. There is a variability of phenotypic findings such as hypotonia, facial dysmorphisms, mild microcephaly, with being most common developmental delay. CASE PRESENTATION: The present case involved a female fetus with an interstitial deletion on 1p, presenting with micrognathia in the 2nd trimester routine ultrasound examination. Array-based comparative genomic hybridization (a-CGH) revealed a 2,7 Mb deletion located on 1p34.3 which could not be detected by standard karyotyping. CONCLUSIONS: This is the first prenatal case of an interstitial deletion in 1p34.3 with facial dysmorphism detected by a-CGH. Due to the use of a-CGH techniques submicroscopic imbalances could be detected, and a refined genotype-phenotype correlation could be achieved.

The experience of specialist inpatient treatment for anorexia nervosa: A qualitative study from adult patients' perspectives.

This qualitative study aimed to explore experiences of women currently undergoing specialist inpatient treatment for anorexia nervosa. Interviews were carried out with 21 women with a diagnosis of anorexia nervosa from a specialist adult inpatient eating disorder unit. Five master themes emerged using thematic analysis: (1) shifts in control, (2) experience of transition, (3) importance of supportive staff relationships, (4) sharing with peers and (5) process of recovery and self-discovery. Findings suggest that patients experience a process of change and adjustment in relation to levels of perceived personal control, attachment to the treatment environment and a sense of self-identity.

Driving with Glaucoma: Task Performance and Gaze Movements.

PURPOSE: The aim of this pilot study was to assess the driving performance and the visual search behavior, that is, eye and head movements, of patients with glaucoma in comparison to healthy-sighted subjects during a simulated driving test. METHODS: Driving performance and gaze behavior of six glaucoma patients and eight healthy-sighted age- and sex-matched control subjects were compared in an advanced driving simulator. All subjects underwent a 40-minute driving test including nine hazardous situations on city and rural roads. Fitness to drive was assessed by a masked driving instructor according to the requirements of the official German driving test. Several driving performance measures were investigated: lane position, time to line crossing, and speed. Additionally, eye and head movements were tracked and analyzed. RESULTS: Three out of six glaucoma patients passed the driving test and their driving performance was indistinguishable from that of the control group. Patients who passed the test showed an increased visual exploration in comparison to patients who failed; that is, they showed increased number of head and gaze movements toward eccentric regions. Furthermore, patients who failed the test showed a rightward bias in average lane position, probably in an attempt to maximize the safety margin to oncoming traffic. CONCLUSIONS: Our study suggests that a considerable subgroup of subjects with binocular glaucomatous visual field loss shows a safe driving behavior in a virtual reality environment, because they adapt their viewing behavior by increasing their visual scanning. Hence, binocular visual field loss does not necessarily influence driving safety. We recommend that more individualized driving assessments, which will take into account the patient's ability to compensate, are required.

Routine use of array comparative genomic hybridization (aCGH) as standard approach for prenatal diagnosis of chromosomal abnormalities. Clinical experience of 1763 prenatal cases.

OBJECTIVE: This study aims to evaluate the diagnostic yield of comparative genomic hybridization microarrays (aCGH) and compare it with conventional karyotype analysis of standard >5-Mb resolution. METHOD: A total of 1763 prenatal samples were analyzed by aCGH (CytoChip Focus Constitutional microarrays, BlueGnome, Cambridge). The diagnostic yield of chromosomal abnormalities detected by aCGH was assessed, compared with conventional karyotype analysis. RESULTS: The result was pathogenic/unknown penetrance in 125 cases (7.1%), and a variant of unknown significance (VOUS) was detected in 13 cases (0.7%). Out of the 125 cases with abnormal findings, 110 were also detected by conventional karyotype analysis. The aCGH increment in diagnostic yield was 0.9% (15/1763) and 1.6% when VOUS were included. Stratifying the sample according to indications for prenatal invasive testing, the highest values of diagnostic yield increment were observed for patients positive for second-trimester sonographic markers (1.5%) and for the presence of fetal structural anomalies (1.3%). In contrast, the incremental yield was marginal in patients with fetus with increased nuchal translucency (0.5%). CONCLUSION: The present study indicates that routine implementation of aCGH offers an incremental yield over conventional karyotype analysis, which is also present in cases with 'milder' indications, further supporting its use as a first-tier test.

Deletion of 4.4 Mb at 2q33.2q33.3 May Cause Growth Deficiency in a Patient with Mental Retardation, Facial Dysmorphic Features and Speech Delay.

A patient with a rare interstitial deletion of chromosomal band 2q33.2q33.3 is described. The clinical features resembled the 2q33.1 microdeletion syndrome (Glass syndrome), including mental retardation, facial dysmorphism, high-arched narrow palate, growth deficiency, and speech delay. The chromosomal aberration was characterized by whole genome BAC aCGH. A comparison of the current patient and Glass syndrome features revealed that this case displayed a relatively mild phenotype. Overall, it is suggested that the deleted region of 2q33 causative for Glass syndrome may be larger than initially suggested.

Homonymous Visual Field Loss and Its Impact on Visual Exploration: A Supermarket Study.

PURPOSE: Homonymous visual field defects (HVFDs) may critically interfere with quality of life. The aim of this study was to assess the impact of HVFDs on a supermarket search task and to investigate the influence of visual search on task performance. METHODS: Ten patients with HVFDs (four with a right-sided [HR] and six with a left-sided defect [HL]), and 10 healthy-sighted, sex-, and age-matched control subjects were asked to collect 20 products placed on two supermarket shelves as quickly as possible. Task performance was rated as "passed" or "failed" with regard to the time per correctly collected item (TC -failed = 4.84 seconds based on the performance of healthy subjects). Eye movements were analyzed regarding the horizontal gaze activity, glance frequency, and glance proportion for different VF areas. RESULTS: Seven of 10 HVFD patients (three HR, four HL) passed the supermarket search task. Patients who passed needed significantly less time per correctly collected item and looked more frequently toward the VFD area than patients who failed. HL patients who passed the test showed a higher percentage of glances beyond the 60° VF (P < 0.05). CONCLUSION: A considerable number of HVFD patients performed successfully and could compensate for the HVFD by shifting the gaze toward the peripheral VF and the VFD area. TRANSLATIONAL RELEVANCE: These findings provide new insights on gaze adaptations in patients with HVFDs during activities of daily living and will enhance the design and development of realistic examination tools for use in the clinical setting to improve daily functioning. (http://www.clinicaltrials.gov, NCT01372319, NCT01372332).

Binocular glaucomatous visual field loss and its impact on visual exploration--a supermarket study.

Advanced glaucomatous visual field loss may critically interfere with quality of life. The purpose of this study was to (i) assess the impact of binocular glaucomatous visual field loss on a supermarket search task as an example of everyday living activities, (ii) to identify factors influencing the performance, and (iii) to investigate the related compensatory mechanisms. Ten patients with binocular glaucoma (GP), and ten healthy-sighted control subjects (GC) were asked to collect twenty different products chosen randomly in two supermarket racks as quickly as possible. The task performance was rated as "passed" or "failed" with regard to the time per correctly collected item. Based on the performance of control subjects, the threshold value for failing the task was defined as µ+3σ (in seconds per correctly collected item). Eye movements were recorded by means of a mobile eye tracker. Eight out of ten patients with glaucoma and all control subjects passed the task. Patients who failed the task needed significantly longer time (111.47 s ±12.12 s) to complete the task than patients who passed (64.45 s ±13.36 s, t-test, p < 0.001). Furthermore, patients who passed the task showed a significantly higher number of glances towards the visual field defect (VFD) area than patients who failed (t-test, p < 0.05). According to these results, glaucoma patients with defects in the binocular visual field display on average longer search times in a naturalistic supermarket task. However, a considerable number of patients, who compensate by frequent glancing towards the VFD, showed successful task performance. Therefore, systematic exploration of the VFD area seems to be a "time-effective" compensatory mechanism during the present supermarket task.

Driving with binocular visual field loss? A study on a supervised on-road parcours with simultaneous eye and head tracking.

Post-chiasmal visual pathway lesions and glaucomatous optic neuropathy cause binocular visual field defects (VFDs) that may critically interfere with quality of life and driving licensure. The aims of this study were (i) to assess the on-road driving performance of patients suffering from binocular visual field loss using a dual-brake vehicle, and (ii) to investigate the related compensatory mechanisms. A driving instructor, blinded to the participants' diagnosis, rated the driving performance (passed/failed) of ten patients with homonymous visual field defects (HP), including four patients with right (HR) and six patients with left homonymous visual field defects (HL), ten glaucoma patients (GP), and twenty age and gender-related ophthalmologically healthy control subjects (C) during a 40-minute driving task on a pre-specified public on-road parcours. In order to investigate the subjects' visual exploration ability, eye movements were recorded by means of a mobile eye tracker. Two additional cameras were used to monitor the driving scene and record head and shoulder movements. Thus this study is novel as a quantitative assessment of eye movements and an additional evaluation of head and shoulder was performed. Six out of ten HP and four out of ten GP were rated as fit to drive by the driving instructor, despite their binocular visual field loss. Three out of 20 control subjects failed the on-road assessment. The extent of the visual field defect was of minor importance with regard to the driving performance. The site of the homonymous visual field defect (HVFD) critically interfered with the driving ability: all failed HP subjects suffered from left homonymous visual field loss (HL) due to right hemispheric lesions. Patients who failed the driving assessment had mainly difficulties with lane keeping and gap judgment ability. Patients who passed the test displayed different exploration patterns than those who failed. Patients who passed focused longer on the central area of the visual field than patients who failed the test. In addition, patients who passed the test performed more glances towards the area of their visual field defect. In conclusion, our findings support the hypothesis that the extent of visual field per se cannot predict driving fitness, because some patients with HVFDs and advanced glaucoma can compensate for their deficit by effective visual scanning. Head movements appeared to be superior to eye and shoulder movements in predicting the outcome of the driving test under the present study scenario.

Prenatal diagnosis of two de novo 4q35-qter deletions characterized by array-CGH.

BACKGROUND: The 4q- syndrome is a well known genetic condition caused by a partial terminal or interstitial deletion in the long arm of chromosome 4. The great variability in the extent of these deletions and the possible contribution of additional genetic rearrangements, such as unbalanced translocations, lead to a wide spectrum of clinical manifestations. The majority of reports of 4q- cases are associated with large deletions identified by conventional chromosome analysis; however, the widespread clinical use of novel molecular techniques such as array comparative genomic hybridization (a-CGH) has increased the detection rate of submicroscopic chromosomal aberrations associated with 4q- phenotype. RESULTS: Herein we report two prenatal cases of 4qter deletions which presented the first with no sonographic findings and the second with brain ventriculomegaly combined with oligohydramnios. Standard karyotyping demonstrated a deletion at band q35.1 of chromosome 4 in both cases. The application of a-CGH confirmed the diagnosis and offered a precise characterization of the genetic defect. CONCLUSIONS: We provide a review of the currently available literature on the prenatal diagnostic approach of 4q- syndrome and we compare our results with other published cases. Our data suggest that the identification and the precise molecular characterization of new cases with 4q- syndrome will contribute in elucidating the genetic spectrum of this disorder.

Idiopathic acquired dacryocystocele treated with endonasal endoscopic dacryocystorhinostomy.

A 64-year-old woman presented with a medial canthal mass in her left eye, which was accompanied only by mild epiphora. There was no history of dacryocystitis, bloody tears, midfacial trauma or surgery. Physical examination showed a non-inflammatory, subcutaneous, immobile mass below the level of the medial canthal tendon. Lacrimal irrigation demonstrated blockage at the nasolacrimal duct. A CT revealed a non-enhancing, low density, cystic lesion in the inferomedial aspect of the left orbit without bony erosion, which was compatible with an idiopathic acquired dacryocystocele. The patient underwent endonasal endoscopic dacryocystorhinostomy (DCR) and silicone intubation. Epiphora resolved immediately after surgery. Two years after surgery, the patient has had no recurrence of either the epiphora or the orbital. Idiopathic acquired dacryocystocele associated only with epiphora without accompanying dacryocystitis although rare should be considered in the differential diagnosis of acquired non-inflammatory medial canthal masses. Endonasal endoscopic DCR represents a safe and effective treatment.

Macular hole formation after toxoplasmic retinochoroiditis.

A 56-year-old female patient presented with toxoplasmic retinochoroiditis (TR) in the right eye. Optical coherence tomography revealed a full-thickness macular hole (MH) in the affected eye. Fluorescence angiography and indocyanine green-angiography disclosed focal choroidal ischaemia in the area of inflammation. Heidelberg retinal flowmetry confirmed the significant hypoperfusion in this area. Proper medication was administered. Ophthalmological examination 4 weeks later revealed an improvement of the clinical findings without visual restoration. This case supports the clinical hypothesis that retinochoroidal ischaemia due to TR may induce the development of MH, indicating that patients with TR may have a certain risk for MH formation.