Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study.

BACKGROUND: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). CONCLUSION: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.

Real World Data are Not Always Big Data: The Case for Primary Data Collection on Medication Use in Pregnancy in the Context of Birth Defects Research.

Many examples of the use of real-world data in the area of pharmacoepidemiology include "big data" such as insurance claims, medical records, or hospital discharge databases. However, "big" is not always better, particularly when studying outcomes with narrow windows of etiologic relevance. Birth defects are one such outcome, where specificity of exposure timing is critical. Studies with primary data collection can be designed to query details on the timing of medication use, as well as type, dose, frequency, duration, and indication, that can better characterize the "real world". Because birth defects are rare, etiologic studies are typically case-control in design, like the National Birth Defects Prevention Study, Birth Defects Study to Evaluate Pregnancy exposureS, and Slone Birth Defects Study. Recall bias can be a concern, but the ability to collect detailed information on both prescription and over-the-counter medication use and on other exposures such as diet, family history, and sociodemographic factors is a distinct advantage over claims and medical record data sources. Case-control studies with primary data collection are essential to advancing the pharmacoepidemiology of birth defects.

Insights From the Transition to Competency-Based Medical Education in Neurology Programs.

Canadian neurology residency programs recently transitioned to Competency-Based Medical Education (CBME). Iterative evaluation is required to optimize CBME implementation. This study aimed to examine the variability and challenges in uptake of CBME in neurology residency programs and identify its benefits and pitfalls. Neurology residents and faculty participated in respective anonymous surveys. Common barriers to uptake were identified from both perspectives. Orientation to CBME was adequate, but workload was increased and contributed to burnout for faculty and residents. It is premature to draw conclusions regarding benefits of CBME. Future research considerations include standardization of entrustment scales and reduction of stakeholder burden.

A milder form of molybdenum cofactor deficiency type A presenting as Leigh's syndrome-like phenotype highlighting the secondary mitochondrial dysfunction: a case report.

Background: Molybdenum cofactor deficiency (MoCD) (OMIM# 252150) is an autosomal-recessive disorder caused by mutations in four genes involved in the molybdenum cofactor (MOCO) biosynthesis pathway. Objectives: We report a milder phenotype in a patient with MOCS1 gene mutation who presented with a Leigh-like presentation. Case report: We present the case of a 10-year-old boy who was symptomatic at the age of 5 months with sudden onset of dyskinesia, nystagmus, and extrapyramidal signs following a febrile illness. Initial biochemical, radiological, and histopathological findings a Leigh syndrome-like phenotype; however, whole-exome sequencing detected compound heterozygous mutations in MOCS1 gene, c.1133 G>C and c.217C>T, confirming an underlying MoCD. This was biochemically supported by low uric acid level of 80 (110-282 mmol/L) and low cystine level of 0 (3-49), and a urine S-sulfocysteine at 116 (0-15) mmol/mol creatinine. The patient was administered methionine- and cystine-free formulas. The patient has remained stable, with residual intellectual, speech, and motor sequelae. Conclusion: This presentation expands the phenotypic variability of late-onset MoCD A and highlights the role of secondary mitochondrial dysfunction in its pathogenesis.

Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10-5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.

Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants.

The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.

Clinical milestones as triggers for palliative care intervention in progressive Supranuclear palsy and multiple system atrophy.

not required for reviews.

Predictive language comprehension in Parkinson's disease.

Verb and action knowledge deficits are reported in persons with Parkinson's disease (PD), even in the absence of dementia or mild cognitive impairment. However, the impact of these deficits on combinatorial semantic processing is less well understood. Following on previous verb and action knowledge findings, we tested the hypothesis that PD impairs the ability to integrate event-based thematic fit information during online sentence processing. Specifically, we anticipated persons with PD with age-typical cognitive abilities would perform more poorly than healthy controls during a visual world paradigm task requiring participants to predict a target object constrained by the thematic fit of the agent-verb combination. Twenty-four PD and 24 healthy age-matched participants completed comprehensive neuropsychological assessments. We recorded participants' eye movements as they heard predictive sentences (The fisherman rocks the boat) alongside target, agent-related, verb-related, and unrelated images. We tested effects of group (PD/control) on gaze using growth curve models. There were no significant differences between PD and control participants, suggesting that PD participants successfully and rapidly use combinatory thematic fit information to predict upcoming language. Baseline sentences with no predictive information (e.g., Look at the drum) confirmed that groups showed equivalent sentence processing and eye movement patterns. Additionally, we conducted an exploratory analysis contrasting PD and controls' performance on low-motion-content versus high-motion-content verbs. This analysis revealed fewer predictive fixations in high-motion sentences only for healthy older adults. PD participants may adapt to their disease by relying on spared, non-action-simulation-based language processing mechanisms, although this conclusion is speculative, as the analyses of high- vs. low-motion items was highly limited by the study design. These findings provide novel evidence that individuals with PD match healthy adults in their ability to use verb meaning to predict upcoming nouns despite previous findings of verb semantic impairment in PD across a variety of tasks.

Using Deep Learning for Task and Tremor Type Classification in People with Parkinson's Disease.

Hand tremor is one of the dominating symptoms of Parkinson's disease (PD), which significantly limits activities of daily living. Along with medications, wearable devices have been proposed to suppress tremor. However, suppressing tremor without interfering with voluntary motion remains challenging and improvements are needed. The main goal of this work was to design algorithms for the automatic identification of the tremor type and voluntary motions, using only surface electromyography (sEMG) data. Towards this goal, a bidirectional long short-term memory (BiLSTM) algorithm was implemented that uses sEMG data to identify the motion and tremor type of people living with PD when performing a task. Moreover, in order to automate the training process, hyperparamter selection was performed using a regularized evolutionary algorithm. The results show that the accuracy of task classification among 15 people living with PD was 84±8%, and the accuracy of tremor classification was 88±5%. Both models performed significantly above chance levels (20% and 33% for task and tremor classification, respectively). Thus, it was concluded that the trained models, based on using purely sEMG signals, could successfully identify the task and tremor types.

Real-Time Performance Assessment of High-Order Tremor Estimators Used in a Wearable Tremor Suppression Device.

The side effects and complications of traditional treatments for treating pathological tremor have led to a growing research interest in wearable tremor suppression devices (WTSDs) as an alternative approach. Similar to how the human brain coordinates the function of the human system, a tremor estimator determines how a WTSD functions. Although many tremor estimation algorithms have been developed and validated, whether they can be implemented on a cost-effective embedded system has not been studied; furthermore, their effectiveness on tremor signals with multiple harmonics has not been investigated. Therefore, in this study, four tremor estimators were implemented, evaluated, and compared: Weighted-frequency Fourier Linear Combiner (WFLC), WFLC-based Kalman Filter (WFLC-KF), Band-limited Multiple FLC, and enhanced High-order WFLC-KF (eHWFLC-KF). This study aimed to evaluate the performance of each algorithm on a bench-top tremor suppression system with 18 recorded tremor motion datasets; and compare the performance of each estimator. The experimental evaluation showed that the eHWFLC-KF-based WTSD achieved the best performance when suppressing tremor with an average of 89.3% reduction in tremor power, and an average error when tracking voluntary motion of 6.6°/s. Statistical analysis indicated that the eHWFLC-KF-based WTSD is able to reduce the power of tremor better than the WFLC and WFLC-KF, and the BMFLC-based WTSD is better than the WFLC. The performance when tracking voluntary motion is similar among all systems. This study has proven the feasibility of implementing various tremor estimators in a cost-effective embedded system, and provided a real-time performance assessment of four tremor estimators.

Preliminary Assessment of the Safety of a Fault-Tolerant Control-based Wearable Tremor Suppression Glove.

The advent of wearable tremor suppression de-vices (WTSDs) has provided a promising alternative approach for parkinsonian tremor management, especially for individuals whose tremors are not managed by conventional treatment options. Currently, research in WTSDs has shown successful results with a tremor suppression ratio of up to 99 %; however, the user safety of WTSDs has not been properly considered, especially in the occurrence of unexpected events, such as faults and disturbances. In this study, a fault-tolerant control system was developed and integrated into the control system of a WTSD for the first time. The safety and tremor suppression performance of the proposed system under the influence of a measurement loss fault were tested and evaluated on 18 tremor motion datasets, specifically by quantifying the tremor power suppression ratio and the error when tracking voluntary motion. The experimental evaluation showed that the proposed system could remain functional and safe to use in the existence of the fault, with an average user motion tracking error of 1.5º. It was also found that the proposed system achieved significantly improved performance in both metrics when compared to the system without a fault-tolerant controller. Clinical Relevance-This work improves the safety and robustness of WTSDs making them more suitable for use as an additional treatment for parkinsonian tremor.

The Case for Medicine-Pediatrics Training in the U.S. Military.

Residency programs in the combined specialty of Internal Medicine-Pediatrics (Med-Peds) are not offered in the military graduate medical education system despite existing in the civilian sector for over 50 years. This residency consists of 4 years of training and results in the development of board-certified internists and pediatricians who can care for patients from infancy to death. This versatility, combined with an emphasis on the transition from childhood to adulthood, would be valuable to the Military Health System. Med-Peds physicians could serve in a variety of settings depending on the needs of the military: in the outpatient clinic, in the hospital, or in an operational setting. Specifically, Med-Peds doctors could operate as critical care extenders in austere or operational environments to patients of all ages. This could improve outcomes of pediatric casualties in war because of specific training in both medical and pediatric intensive care units. Med-Peds physicians would integrate seamlessly into the Military Health System to work alongside family medicine doctors, internists, and pediatricians to provide high-quality primary care to service members; this may also allow for the increased flexibility of the medical corps. As there are already military residency programs in pediatrics and internal medicine, the required infrastructure for such a training program exists. The addition of this residency may also lead to more interest in military medicine from prospective applicants to medical school. This essay uses personal experience to explain how the addition of this specialty to the military would benefit the medical mission domestically and abroad.

Triggers for Referral to Specialized Palliative Care in Advanced Neurologic and Neurosurgical Conditions: A Systematic Review.

Background and Objectives: To systematically review the literature for the most suitable trigger criteria for referral to specialist palliative care services in life-limiting and life-threatening neurologic and neurosurgical conditions. Methods: Literature searches were conducted in Ovid MEDLINE and EMBASE (1990-December 2020). To be included, studies must have trigger/referral criteria clearly outlined, a ≥75% nononcology neurosciences population, and consensus or guidelines documents regarding palliative neurosciences or trigger/referral criteria. We excluded studies that had an oncologic or non-neurosciences population as the main focus of study, trigger and referral criteria not clearly outlined, and no primary or duplicative data. The protocol was registered with PROSPERO (CRD4202013579), and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The American Academy of Neurology Clinical Practice Guidelines Process Manual was used to assess for risk of bias. Results: Our search identified 1,748 publications, of which 22 articles met the eligibility criteria. Studies were considered in 2 main groups: (A) studies designed specifically to identify trigger criteria for referral to specialized neuropalliative care services (n = 9) and (B) studies that retrospectively reported the reason for referral to specialized palliative care or reflected a consensus statement among people with advanced neurologic illness (n = 13). Overall, the results suggest that several published referral triggers for specialized neuropalliative care are based on expert consensus. However, there is a growing body of literature providing evidence-based condition-specific triggers for multiple sclerosis, parkinsonism, amyotrophic lateral sclerosis, and dementia. Discussion: There is a growing body of research that outlines evidence-based referral triggers for neuropalliative care. The ambiguity of nomenclature surrounding referral triggers in the current literature and field of neuropalliative care was a limitation to this study. We suggest that condition-specific triggers are likely to be the most effective for identifying the appropriate patients and timing for referral to specialist palliative care. (PROSPERO registration number: CRD42020135791, crd.york.ac.uk/prospero).

Exome sequencing identifies genetic variants in anophthalmia and microphthalmia.

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

Survey-based identification of design requirements and constraints for a wearable tremor suppression device.

Introduction: Parkinsonian tremor has severely impacted the lives of 65% of individuals with Parkinson's disease, and nearly 25% do not respond to traditional treatments. Although wearable tremor suppression devices (WTSDs) have become a promising alternative approach, this technology is still in the early stages of development, and no studies have reported the stakeholders' opinions on this technology and their desired design requirements. Methods: An online survey was distributed to affected Canadians and Canadian movement disorder specialists (MDS) to acquire information on demographics, the current state of treatments, opinions on the WTSDs, and the desired design requirements of future WTSDs. Results: A total of 101 affected individuals and 24 MDS completed the survey. It was found that both groups are generally open to using WTSDs to manage tremor. The most important design requirement to end users is the adaptability to lifestyle, followed by weight and size, accurate motion, comfort, safety, quick response, and cost. Lastly, most of the participants (65%) think that the device should cost under $500. Conclusions: The findings from this study can be used as guidelines for the development of future WTSDs, such that the future generations could be evaluated and accepted by the end users.

A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study.

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (Ndiscovery  = 3978; Nreplication  = 2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (Ndiscovery_TDT  = 440; Nreplication_TDT  = 275) and case-control analyses separately in infants (Ndiscovery_CCI  = 1635; Nreplication_CCI  = 990) and mothers (case status defined by infant; Ndiscovery_CCM  = 1703; Nreplication_CCM  = 1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (pdiscovery  = 4.08 × 10-9 ; preplication  = 2.44 × 10-4 ). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (pdiscovery  = 1.61 × 10-7 ; preplication  = 0.0016). Two other SNPs were suggestively associated (p < 1 × 10-6 ) with OHD in only the discovery sample. In the case-control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds ( × discovery < 1 × 10-5 and preplication < 0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (pdiscovery  = 1.42 × 10-6 ; preplication  = 0.04). Additional SNPs with pdiscovery < 1 × 10-5 were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings.

Exome sequencing identifies variants in infants with sacral agenesis.

BACKGROUND: Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA. METHODS: Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child-parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child-father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced. RESULTS: Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N = 1) and SPTBN5 (Spectrin Beta, Non-erythrocytic 5; N = 2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X-linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children. CONCLUSIONS: To our knowledge, this is the first study reporting a possible association between ID1 and non-syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non-syndromic SA and provide data for future studies.

Exome sequencing of child-parent trios with bladder exstrophy: Findings in 26 children.

Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency ≤ 0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect.

Real-Time Voluntary Motion Prediction and Parkinson's Tremor Reduction Using Deep Neural Networks.

Wearable tremor suppression devices (WTSD) have been considered as a viable solution to manage parkinsonian tremor. WTSDs showed their ability to improve the quality of life of individuals suffering from parkinsonian tremor, by helping them to perform activities of daily living (ADL). Since parkinsonian tremor has been shown to be nonstationary, nonlinear, and stochastic in nature, the performance of the tremor models used by WTSDs is affected by their inability to adapt to the nonlinear behaviour of tremor. Another drawback that the models have is their limitation to estimate or predict one step ahead, which introduces delay when used in real time with WTSDs, which compromises performance. To address these issues, this work proposes a deep neural network model that learns the correlations and nonlinearities of tremor and voluntary motion, and is capable of multi-step prediction with minimal delay. A generalized model that is task and user-independent is presented. The model achieved an average estimation percentage accuracy of 99.2%. The average future voluntary motion prediction percentage accuracy with 10, 20, 50, and 100 steps ahead was 97.0%, 94.0%, 91.6%, and 89.9%, respectively, with prediction time as low as 1.5 ms for 100 steps ahead. The proposed model also achieved an average of 93.8% ± 1.5% in tremor reduction when it was tested in an experimental setup in real time. The tremor reduction showed an improvement of 25% over the Weighted Fourier Linear Combiner (WFLC), an estimator commonly used with WTSDs.