Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype.

Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.

Errors in Genome Sequencing Result Disclosures: A Randomized Controlled Trial Comparing Neonatology Non-Genetics Healthcare Professionals and Genetic Counselors.

PURPOSE: We compared the rate of errors in genome sequencing (GS) result disclosures by genetic counselors (GC) and trained non-genetics healthcare professionals (NGHP) in SouthSeq, a randomized trial utilizing GS in critically ill infants. METHODS: Over 400 recorded GS result disclosures were analyzed for major and minor errors. We used Fisher's exact test to compare error rates between GCs and NGHPs and performed a qualitative content analysis to characterize error themes. RESULTS: Major errors were identified in 7.5% of disclosures by NGHPs and in no disclosures by GCs. Minor errors were identified in 32.1% of disclosures by NGHPs and in 11.4% of disclosures by GCs. While most disclosures lacked errors, NGHPs were significantly more likely to make any error than GCs for all result types (positive, negative, or uncertain). Common major error themes include omission of critical information, overstating a negative result, and overinterpreting an uncertain result. The most common minor error was failing to disclose negative secondary findings. CONCLUSION: Trained NGHPs made clinically significant errors in GS result disclosures. Characterizing common errors in result disclosure can illuminate gaps in education to inform the development of future genomics training and alternative service delivery models.

Critical components of genomic medicine practice for non-genetics healthcare professionals: Genetic counselors' perspectives and implications for medical education.

Genetic services are increasingly provided by non-genetics healthcare professionals (NGHPs) with minimal formal training in genetics/genomics. Research demonstrates gaps in knowledge and clinical practices in genetics/genomics among NGHPs, but there is a lack of consensus on the specific knowledge needed by NGHPs to effectively provide genetic services. As clinical genetics professionals, genetic counselors (GCs) have insight into the critical components of genetics/genomics knowledge and practices needed by NGHPs. This study explored GCs' beliefs regarding whether NGHPs should provide genetic services and identified GCs' perceptions of the components of knowledge and clinical practice in genetics/genomics that are most critical for NGHPs providing genetic services. Two hundred and forty GCs completed an online quantitative survey with 17 participating in a follow-up qualitative interview. Descriptive statistics and cross-comparisons were generated for survey data. Interview data were analyzed using an inductive qualitative method for cross-case analysis. Most GCs disagreed with NGHPs providing genetic services, but beliefs varied widely, ranging from disagreement due to perceived gaps in knowledge or clinical skills to acceptance of NGHPs providing genetic services due to limited access to genetics professionals. Across survey and interview data, GCs endorsed the interpretation of genetic test results, understanding implications of results, collaboration with genetics professionals, knowledge of the risks and benefits to testing, and recognizing indications for genetic testing as critical components of knowledge and clinical practice for NGHPs. Several recommendations for improving the provision of genetic services were provided by respondents including educating NGHPs to provide genetic services through case-based continuing medical education and increasing collaboration between NGHPs and genetics professionals. As GCs are healthcare providers with experience and vested interests in educating NGHPs, their perspectives can help inform the creation of continuing medical education to ensure patients' access to high-quality genomic medicine care from providers of varying backgrounds.

Intra-abdominal pressure during Pilates: unlikely to cause pelvic floor harm.

INTRODUCTION AND HYPOTHESIS: The objective was to describe the intra-abdominal pressures (IAP) generated during Pilates Mat and Reformer activities, and determine whether these activities generate IAP above a sit-to-stand threshold. METHODS: Twenty healthy women with no symptomatic vaginal bulge, median age 43 (range 22-59 years), completed Pilates Mat and Reformer exercise routines each consisting of 11 exercises. IAP was collected by an intra-vaginal pressure transducer, transmitted wirelessly to a base station, and analyzed for maximal and area under the curve (AUC) IAP. RESULTS: There were no statistically significant differences in the mean maximal IAP between sit-to-stand and any of the Mat or Reformer exercises in the study population. Six to twenty-five percent of participants exceeded their individual mean maximal IAP sit-to-stand thresholds for 10 of the 22 exercises. When measuring AUC from 0 cm H2O, half the exercises exceeded the mean AUC of sit-to-stand, but only Pilates Reformer and Mat roll-ups exceeded the mean AUC of sit-to-stand when calculated from a threshold of 40 cm H2O (consistent with, for example, walking). CONCLUSION: Our results support recommending this series of introductory Pilates exercises, including five Mat exercises and six Reformer exercises to women desiring a low IAP exercise routine. More research is needed to determine the long-term effects of Pilates exercise on post-surgical exercise rehabilitation and pelvic floor health.

Effects of walking speeds and carrying techniques on intra-abdominal pressure in women.

INTRODUCTION AND HYPOTHESIS: Walking speed and carrying technique affect intra-abdominal pressure (IAP) in women. In this study, we tested the feasibility of monitoring IAP outside the laboratory environment and compared IAP while study participants were (1) carrying 13.6 kg (similar to a 3-month old in car seat) in six different ways while walking 100 m; and (2) while walking 400 m at self-selected slow, normal, and fast paces. METHODS: Forty-six healthy women between 19 and 54 years completed the walking and lifting activities; the order for each was randomized. IAP was monitored with an intravaginal pressure transducer that wirelessly transmitted pressure data to a portable base station. We analyzed maximal peak IAP and area under the curve (AUC) IAP. RESULTS: Monitoring IAP outside of the laboratory was feasible. Mean maximal IAP during walking increased as pace increased: 42.5 [standard deviation (SD) 10.2], 50.5 (10.9), and 62.0 (12.1) cmH2O for slow, medium, and fast speeds, respectively: p < 0.0001 by mixed-model analysis of variance (ANOVA). The corresponding AUC of IAP for walking decreased as pace increased. The awkward carry, side carry, and front carry activities each resulted in higher mean maximal IAP [65.8 (10.6), 67.7 (12.8), and 77.3 (13.1) cmH2O, respectively] than the carry-in-backpack activity [55.5 (11.4) cmH2O; p < 0.0001]. CONCLUSION: Subtle variations in walking speed or method of carrying a toddler-size load can produce significant changes in IAP. Whether these changes increase the risk of pelvic floor disorders is not yet clear. However, these data suggest that further inquiry into optimal methods and appliances to assist women in carrying may create a lower IAP profile.

Intra-abdominal pressures during activity in women using an intra-vaginal pressure transducer.

Strenuous physical activity has been linked to pelvic floor disorders in women. Using a novel wireless intra-vaginal pressure transducer, intra-abdominal pressure was measured during diverse activities in a laboratory. Fifty-seven women performed a prescribed protocol using the intra-vaginal pressure transducer. We calculated maximal, area under the curve and first moment of the area intra-abdominal pressure for each activity. Planned comparisons of pressure were made between levels of walking and cycling and between activities with reported high pressure in the literature. Findings indicate variability in intra-abdominal pressure amongst individuals doing the same activity, especially in activities that required regulation of effort. There were statistically significant differences in maximal pressure between levels of walking, cycling and high pressure activities. Results for area under the curve and first moment of the area were not always consistent with maximal pressure. Coughing had the highest maximal pressure, but had lower area under the curve and first moment of the area compared to most activities. Our data reflect novel findings of maximal, area under the curve and first moment of the area measures of intra-abdominal pressure, which may have clinical relevance for how physical activity relates to pelvic floor dysfunction.

More complicated than it looks: the vagaries of calculating intra-abdominal pressure.

Activities thought to induce high intra-abdominal pressure (IAP), such as lifting weights, are restricted in women with pelvic floor disorders. Standardized procedures to assess IAP during activity are lacking and typically only focus on maximal IAP variably defined. Our intent in this methods article is to establish the best strategies for calculating maximal IAP and to add area under the curve and first moment of the area as potentially useful measures in understanding biologic effects of IAP. Thirteen women completed a range of activities while wearing an intravaginal pressure transducer. We first analyzed various strategies heuristically using data from 3 women. The measure that seemed to best represent maximal IAP was an average of the 3, 5, or 10 highest values, depending on activity, determined using a top-down approach, with peaks at least 1 second apart using algorithms written for Matlab computer software, we then compared this strategy with others commonly reported in the literature quantitatively using data from 10 additional volunteers. Maximal IAP calculated using the top-down approach differed for some, but not all, activities compared with the single highest peak or to averaging all peaks. We also calculated area under the curve, which allows for a time component, and first moment of the area, which maintains the time component while weighing pressure amplitude. We validated methods of assessing IAP using computer-generated sine waves. We offer standardized methods for assessing maximal area under the curve and first moment of the area for IAP to improve future reporting and application of this clinically relevant measure in exercise science.

Persistent falcine sinus in the newborn: 3 case reports of associated anomalies.

The falcine sinus is a normal embryonic structure that is situated between the 2 layers of the falx cerebri and drains the deep cerebral venous system into the superior sagittal sinus. It normally involutes after birth and is uncommon in adults. Although it is often an isolated and incidental finding, it can also be associated with a number of other conditions including but not limited to vein of Galen arterial malformations (VGAM), atretic parietal cephaloceles, acrocephalosyndactyly (Apert syndrome), absence of the corpus callosum, absence of the tentorium, osteogenesis imperfecta, or Chiari II malformations. We present a case series of 3 pediatric patients born with a persistent falcine sinus and an associated condition, including a VGAM, an APC, and a sinus thrombosis. The purpose of this article is to highlight the importance of understanding anatomic variations in the cerebral venous system to help aid in the proper diagnosis and treatment of associated pathologies.

Development of a wireless intra-vaginal transducer for monitoring intra-abdominal pressure in women.

Pelvic floor disorders (PFD) affect one of every four women in the United States. Elevated intra-abdominal pressure (IAP) during daily activity or strenuous physical activity has been identified as a risk factor in the prevalence of PFD. However, the relationship between IAP and physical activity is poorly understood and oftentimes activity restrictions are prescribed by physicians without clinical evidence linking various activities to elevated IAP. There are currently no pressure transducers capable of monitoring IAP non-invasively out of a clinical environment. To overcome this shortcoming, a novel intra-vaginal pressure transducer (IVT) was developed to continuously monitor IAP. Improvements were made to the first generation IVT by incorporating wireless capability to enhance the device's mobility while creating a more robust IAP monitoring system. To ensure the changes maintained the functionality of the original device design, comparison testing with standard clinical pressure transducers in both bench top and clinical settings was conducted. The wireless device was found to have high linearity, robust signal transmission, and dynamic response that outperforms the clinical standard rectal transducer and is similar to the original first generation non-wireless design. The wireless IVT presented here is a mobile wireless device capable of measuring, storing and transmitting IAP data during various physical activities.

Clinical evaluation of a wireless intra-vaginal pressure transducer.

OBJECTIVE: To describe the development, feasibility and validity of a wireless intra-vaginal pressure transducer (IVT) which can be used to measure intra-abdominal pressure in real-world settings. STUDY DESIGN: A feasibility study was conducted in sixteen physically active women to determine retention and comfort of various IVT prototype designs during activity. A criterion validity study was conducted among women undergoing urodynamic testing to determine the accuracy of the IVT prototypes when compared to accepted clinical standards. RESULTS: A final prototype wireless IVT was developed after four design revisions of the second generation model. The feasibility study found that women reported the final prototype comfortable to wear and easily retained during physical activity. Intra-abdominal pressure measurements from the final prototype IVT compared favorably to standard urodynamic transducers, thus confirming evidence of its utility. CONCLUSION: We have successfully advanced the design of a wireless, intra-vaginal pressure transducer which provides accurate measures of intra-abdominal pressure. The final wireless IVT is better tolerated by patients and overcomes limitations of traditional urodynamic testing while laying the foundations for intra-abdominal pressure monitoring outside of the clinic environment.

Education and Training of Non-Genetics Providers on the Return of Genome Sequencing Results in a NICU Setting.

To meet current and expected future demand for genome sequencing in the neonatal intensive care unit (NICU), adjustments to traditional service delivery models are necessary. Effective programs for the training of non-genetics providers (NGPs) may address the known barriers to providing genetic services including limited genetics knowledge and lack of confidence. The SouthSeq project aims to use genome sequencing to make genomic diagnoses in the neonatal period and evaluate a scalable approach to delivering genome sequencing results to populations with limited access to genetics professionals. Thirty-three SouthSeq NGPs participated in a live, interactive training intervention and completed surveys before and after participation. Here, we describe the protocol for the provider training intervention utilized in the SouthSeq study and the associated impact on NGP knowledge and confidence in reviewing, interpreting, and using genome sequencing results. Participation in the live training intervention led to an increased level of confidence in critical skills needed for real-world implementation of genome sequencing. Providers reported a significant increase in confidence level in their ability to review, understand, and use genome sequencing result reports to guide patient care. Reported barriers to implementation of genome sequencing in a NICU setting included test cost, lack of insurance coverage, and turn around time. As implementation of genome sequencing in this setting progresses, effective education of NGPs is critical to provide access to high-quality and timely genomic medicine care.

Regulation of Pituitary Progenitor Differentiation by ß-Catenin.

The pituitary gland is a critical organ that is necessary for many physiological processes, including growth, reproduction, and stress response. The secretion of pituitary hormones from specific cell types regulates these essential processes. Pituitary hormone cell types arise from a common pool of pituitary progenitors, and mutations that disrupt the formation and differentiation of pituitary progenitors result in hypopituitarism. Canonical WNT signaling through CTNNB1 (ß-catenin) is known to regulate the formation of the POU1F1 lineage of pituitary cell types. When ß-catenin is deleted during the initial formation of the pituitary progenitors, Pou1f1 is not transcribed, which leads to the loss of the POU1F1 lineage. However, when ß-catenin is deleted after lineage specification, there is no observable effect. Similarly, the generation of a ß-catenin gain-of-function allele in early pituitary progenitors or stem cells results in the formation of craniopharyngiomas, whereas stimulating ß-catenin in differentiated cell types has no effect. PROP1 is a pituitary-specific transcription factor, and the peak of PROP1 expression coincides with a critical time point in pituitary organogenesis-that is, after pituitary progenitor formation but before lineage specification. We used a Prop1-cre to conduct both loss- and gain-of-function studies on ß-catenin during this critical time point. Our results demonstrate that pituitary progenitors remain sensitive to both loss and gain of ß-catenin at this time point, and that either manipulation results in hypopituitarism.

Reproducibility of intra-abdominal pressure measured during physical activities via a wireless vaginal transducer.

AIMS: In the urodynamics laboratory setting, a wireless pressure transducer, developed to facilitate research exploring intra-abdominal pressure (IAP) and pelvic floor disorders, was highly accurate. We aimed to study reproducibility of IAP measured using this transducer in women during activities performed in an exercise science laboratory. METHODS: Fifty-seven women (mean ± SD, age 30.4 ±9.3 years; body mass index, 22.4 ± 2.68 kg/m) completed 2 standardized activity sessions using the same transducer at least 3 days apart. Pressure data for 31 activities were transmitted wirelessly to a base station and analyzed for mean net maximal IAP, area under the curve, and first moment of the area. Activities included typical exercises, lifting 13.6 to 18.2 kg, and simulated household tasks. Analysis for test-retest reliability included Bland-Altman plots with absolute limits of agreement, Wilcoxon signed rank tests to assess significant differences between sessions, intraclass correlations, and κ statistics to assess intersession agreement in highest versus other quintiles of maximal IAP. RESULTS: Few activities exhibited significant differences between sessions in maximal IAP, or in area under the curve and first moment of the area values. For 13 activities, the agreement between repeat measures of maximal IAP was better than ±10 cm H20; for 20 activities, better than ±15 cm H20. The absolute limits of agreement increased with mean IAP. The highest quintile of IAP demonstrated fair/substantial agreement between sessions in 25 of 30 activities. CONCLUSIONS: Reproducibility of IAP depends on the activity undertaken. Interventions geared toward lowering IAP should account for this, maximize efforts to improve IAP reproducibility.

A Gel filled intravaginal transducer for extended measurements of intra-abdominal pressure.

Limitations of the standard urogynecological pressure transducers have not adequately provided reliable measurements of intra-abdominal pressure (IAP) during physical activities. A previous novel intravaginal pressure transducer (IVT) was developed in order to overcome the shortcomings in existing technology. The design of the IVT was validated though comparisons with existing pressure transducers in both the clinical and bench top settings. However, a number of improvements were needed to overcome limitations in the previous design. A larger elastomeric capsule with transducer was developed and filled with silicone gel to replace the existing saline filled capsule and to better integrate proposed wireless technology. Impulse response and frequency testing were compared between the saline filled IVT and the new gel filled sensor and were found to be equivalent. Additional testing was performed on the gel filled device including drift and temperature measurements of sensitivity and offset. Results show the temperature coefficient of offset and sensitivity within correctible limitations with our proposed signal conditioner circuits.