Purpose:Multiplexed assays of variant effect (MAVEs) are transforming clinical variant interpretation. However, many genes are associated with more than one disease, making it unclear whether functional data generated in one disease context may be directly applicable to another. For example, germline BAP1 missense variants are associated with both BAP1 tumor predisposition syndrome ( BAP1 -TPDS) and Küry-Isidor syndrome (KURIS), a rare neurodevelopmental disorder. Here, we demonstrate how phenotype-specific calibration of BAP1 MAVE data enables disease-specific variant classification. Methods:Saturation genome editing (SGE) data for BAP1 were recalibrated using either BAP1 -TPDS- or KURIS-associated missense variants as pathogenic controls. Functional evidence strength was quantified using the Odds of Pathogenicity (OddsPath) framework and mapped to ACMG/AMP PS3/BS3 criteria. Recalibrated functional evidence was integrated with standard clinical criteria for variant classification. A workshop was developed to teach phenotype-specific MAVE recalibration to clinicians and variant curators and evaluated for educational impact. Results:Phenotype-specific recalibration using BAP1 -TPDS and KURIS controls yielded OddsPath values consistent with PS3_Strong evidence in both contexts. Application of KURIS-specific recalibration enabled the diagnosis of KURIS in an individual with a previously uncertain BAP1 missense variant. The educational workshop enabled quantitatively improved understanding in applying functional evidence. Conclusion:Phenotype-specific recalibration enables appropriately calibrated reuse of MAVE datasets across distinct disease contexts, increasing the clinical utility of MAVE datasets and the interpretability of variants in pleiotropic genes. This framework expands the diagnostic utility of existing functional datasets without requiring new experimental assays.

The diagnosis of a genetic etiology for fetal akinesia deformation sequence (FADS) in the prenatal setting is challenging. It is especially difficult in patients from isolated populations in which genetic testing has been limited and the background allelic frequencies are unknown. Lethal congenital contracture syndromes type 3 (LCCS3; OMIM 611369) is a rare autosomal recessive condition caused by biallelic pathogenic variants in the PIP5K1C gene. There are only 13 cases of LCCS3 in the medical literature. We describe three cases sharing a novel variant in PIP5K1C in an isolated Canadian population and provide the first detailed postnatal phenotyping of the condition in live born neonates. The repeatedly observed variant in the PIP5K1C gene and identification of three apparently unrelated cases suggest the possibility of a founder effect in this population. These cases add to our understanding of an ultra-rare genetic condition and provide personalized management in this underserviced population.

De novo heterozygous variants in CUGBP Elav-like family member 2 (CELF2) have recently been associated with a rare neurodevelopmental disorder, yet the mechanisms linking specific variants to distinct clinical phenotypes remain poorly understood. Here, we reported a cohort of 18 individuals and provided evidence that variants causing CELF2 mislocalization, but not protein-null variants, were associated with seizures. Using proband-derived human cortical neurons and transgenic mouse models, we demonstrated that CELF2 underwent activity-dependent nucleocytoplasmic shuttling in excitatory neurons and that its cytoplasmic retention caused neuronal hyperactivity, elevated seizure susceptibility, and learning and memory deficits. We further found that cytoplasmic CELF2 regulated mRNAs critical for synaptic function and neuronal excitability and implicated in epileptic seizures and intellectual disability. Drug screening further identified AKT signaling as a key regulator of CELF2 nucleocytoplasmic shuttling and a candidate target for reversing neuronal hyperactivity. Together, our findings expand the clinical and genetic spectrum of CELF2-related neurodevelopmental disorders and establish a variant-specific mechanism that links CELF2 mislocalization to neuronal hyperactivity, seizures, and cognitive impairment.

There is a narrative told among healthcare providers that the public stories of trisomy 18 do not reflect the experiences of the many families navigating this diagnosis. This is in the context of a recognised paradigm shift occurring in the treatment of children born with trisomy 18 from one focused solely on comfort to one that considers the potential of medical-surgical interventions to afford survival. This study aims to elicit and explore phenomenologically parents' narratives of trisomy 18. The focus is on the full spectrum of trisomy 18: whether it was diagnosed before or after birth, whether the child's life was of short or long duration and whether invasive or palliative care was sought. While trisomy 18 was not univocal of the children's stories, as a focus of this qualitative inquiry unified them. Healthcare providers may benefit from understanding how trisomy 18 may affect a particular diagnosis experience, whether made during pregnancy or the days after birth when parents are still getting to know their child. As parents live with this diagnosis, pregnancy and the life of their child may be shaped by an uncertainty of a life-limiting condition, whereby care is bounded by what is and is not possible. And, we may appreciate how trisomy 18 imparts meanings on ordinary and extraordinary moments for children and their families in a recognisable form. The understandings gained from this research may support healthcare professionals' reflective clinical practices as they care for children and their families affected by this diagnosis.

Background There have been an increasing number of publications related to trisomy 18 associated with a shift in the philosophy of care. The objective of this review is to understand the scope of contemporary literature informing the care of children born alive with trisomy 18. Methods Included was peer-reviewed, primary literature in MEDLINE, Embase, CINAHL, Scopus, Web of Science, and Cochrane Library from 2012 to 2023 reporting outcomes of children born alive with trisomy 18. Data extraction involved descriptive statistics of the types of studies, and an inductive thematic analysis of the questions addressed by the studies. Results Of 4628 records identified, 229 met inclusion criteria. Key themes were organized around the domains: What is trisomy 18? What are the chances of survival with trisomy 18? What can be done to improve the chances of survival with trisomy 18? How do children with trisomy 18 die? Do surgical interventions provide a benefit? Are there non-surgical options? What knowledge is informing medical management? How is life described for children with trisomy 18? What are children with trisomy 18 like as babies and as they get older? What is life like for families caring for children with trisomy 18? Conclusions A sizeable number of publications grouped trisomy 18 with other syndromes. Relatively few showed the longitudinal evolution of medical issues associated with trisomy 18, nor did they unfold the clinical heterogeneity of this population. This review shows the limited knowledge base guiding decision-making and care for children born alive with trisomy 18.

Background Historically, children born alive with trisomy 18 were considered to have a lethal genetic condition such that no medical interventions were provided. While survival is now recognized to be possible, these children's lives include aspects of technological dependency, medical complexity, and neurodevelopmental disabilities.Objectives The primary aim of this study was to describe the outcomes of a contemporary Canadian population-based cohort of children born alive with trisomy 18.Methods A retrospective study was conducted to review the records of children born alive with trisomy 18 from January 2012 to December 2023 in Central/Northern Alberta. Demographic and clinical information were abstracted, including features reported in the literature associated with morbidity and mortality. Outcomes were described, including technological dependency, time spent in the hospital, and survival.Results In total, 37 liveborn infants with complete trisomy 18 were identified. While most died in hospital following medical-surgical interventions and/or comfort-care palliation, nine were discharged home. All of these children had been born at term with a birthweight >= 1750 g. While they relied on medical technologies such as home oxygen and feeding tubes at the time of discharge, most were able to spend a considerable amount of time at home rather than being re-hospitalized. At the time of this review, four remain alive varying in age from 6 to 9 years.Conclusions Trisomy 18 is not a homogeneous clinical condition. Some children may have their lives extended to spend their lives at home with their families.

Cranial sutures are complex structures integrating mechanical forces with osteogenesis which are often affected in craniofacial syndromes. While premature fusion is frequently described, rare pathological widening of cranial sutures is a comparatively understudied phenomenon. This narrative review aims to bring to light the biologically variable underlying causes of widened sutures and persistent fontanelles leading to a common outcome. The authors herein present four syndromes, selected from a literature review, and their identified biological mechanisms in the context of altered suture physiology, exploring the roles of progenitor cell differentiation, extracellular matrix production, mineralization, and bone resorption. This article illustrates the gaps in understanding of complex craniofacial disorders, and the potential for further unification of genetics, cellular biology, and clinical pillars of health science research to improve treatment outcomes for patients.

The introduction of next generation sequencing (NGS) technologies has revolutionized the practice of Medical Genetics, and despite initial reticence in its application to prenatal genetics (PG), it is becoming gradually routine, subject to availability. Guidance for the clinical implementation of NGS in PG, in particular whole exome sequencing (ES), has been provided by several professional societies with multiple clinical studies quoting a wide range of testing yields. ES was introduced in our tertiary care center in 2017; however, its use in relation to prenatally assessed cases has been limited to the postnatal period. In this study, we review our approach to prenatal testing including the use of microarray (CMA), and NGS technology (gene panels, ES) over a period of three years. The overall diagnostic yield was 30.4%, with 43.2% of those diagnoses being obtained through CMA, and the majority by using NGS technology (42% through gene panels and 16.6% by ES testing, respectively). Of these, 43.4% of the diagnoses were obtained during ongoing pregnancies. Seventy percent of the abnormal pregnancies tested went undiagnosed. We are providing a contemporary, one tertiary care center retrospective view of a real-life PG practice in the context of an evolving use of NGS within a Canadian public health care system that may apply to many similar jurisdictions around the world.

Clinical exome sequencing (ES) is the most comprehensive genomic test to identify underlying genetic diseases in Canada. We performed this retrospective cohort study to investigate the diagnostic yield of clinical ES in adulthood. Inclusion criteria were: (1) Adult patients ≥18 years old; (2) Patients underwent clinical ES between January 1 and December 31, 2021; (3) Patients were seen in the Department of Medical Genetics. We reviewed patient charts. We applied American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification guidelines for interpretation of variants. Non-parametric Fisher's exact statistical test was used. Seventy-seven patients underwent clinical ES. Fourteen different genetic diseases were confirmed in 15 patients: FBXO11, MYH7, MED13L, NSD2, ANKRD11 (n = 2), SHANK3, RHOBTB2, CDKL5, TRIO, TCF4, SCN1, SMAD3, POGZ, and EIF2B3 diseases. The diagnostic yield of clinical ES was 19.5%. Patients with a genetic diagnosis had a significantly higher frequency of neurodevelopmental disorders than those with no genetic diagnosis (p = 0.00339). The diagnostic yield of clinical ES was the highest in patients with seizures (35.7%), and with progressive neurodegenerative diseases (33.3%). Clinical ES is a helpful genomic test to provide genetic diagnoses to the patients who are referred to medical genetic clinics due to suspected genetic diseases in adulthood to end their diagnostic odyssey. Targeted next generation sequencing panels for specific phenotypes may decrease the cost of genomic test in adulthood.

Background: The lack of comfort with core genetic and genomic competencies among medical trainees and physicians is a barrier to the implementation of precision medicine. To address this, we developed short online modules to promote genetic competencies for use post-graduate medical education. Methods: The educational toolkit was delivered as short online podcasts accompanied by slides. Each core module is approximately 15-20 minutes, and covered basic genetics, genetic testing, counselling and consenting, and interpreting and delivering results. These were supplemented by case-based modules on cancer genetics, prenatal genetics and cardiogenetics. The modules had pre- and post-test multiple choice questions pertaining to genetic and genomic competencies, attitudes towards precision medicine, and perceived competence. Results: Based on the pre- and post-test data, residents reported a discordance between how often they cared for patients with genetic disorders and their level of confidence with core genetic competencies. Post-module evaluations demonstrated a significant increase in confidence in interpreting a microarray, and basic genetics knowledge.Conclusions: Our study demonstrates that podcast modules are an innovative method to promote genetic and genomic competencies to postgraduate medical trainees. Limitations to our study included a small sample size, and further work is needed identify and address barriers to implementation. We suggest that integration at the post-graduate medical education level will be crucial to further promoting the development of precision medicine competencies in medical trainees and physicians.

Slit-lamp examination revealed bilateral iris flocculi (Fig A, right eye; Fig B, left eye), and pigment epithelial excrescences at the pupillary border in a 35-year-old patient. Computed tomography angiography with axial (Fig C) and sagittal (Fig D) views diagnosed a type B aortic aneurysm (right aberrant subclavian artery to infrarenal artery). The patient carried a heterozygous, pathogenic variant in the ACTA2 gene (c.445C>T, p.Arg149Cys) that causes familial thoracic aortic aneurysms and dissections (TAAD). No other family members had TAAD. She did not have livedo reticularis, which is often observed in this condition. Similar iris findings may occur in familial amyloidotic polyneuropathy and with chronic topical treatment using acetylcholinesterase inhibitors (Magnified version of Fig A-D is available online at www.aaojournal.org).

The development of the cerebral cortex requires balanced expansion and differentiation of neural stem/progenitor cells (NPCs), which rely on precise regulation of gene expression. Because NPCs often exhibit transcriptional priming of cell-fate-determination genes, the ultimate output of these genes for fate decisions must be carefully controlled in a timely fashion at the post-transcriptional level, but how that is achieved is poorly understood. Here, we report that de novo missense variants in an RNA-binding protein CELF2 cause human cortical malformations and perturb NPC fate decisions in mice by disrupting CELF2 nucleocytoplasmic transport. In self-renewing NPCs, CELF2 resides in the cytoplasm, where it represses mRNAs encoding cell fate regulators and neurodevelopmental disorder-related factors. The translocation of CELF2 into the nucleus releases mRNA for translation and thereby triggers NPC differentiation. Our results reveal that CELF2 translocation between subcellular compartments orchestrates mRNA at the translational level to instruct cell fates in cortical development.

We report a case of a de novo ring 21 complex chromosomal rearrangement in a fetus presenting with hydrops. Noninvasive prenatal testing (NIPT) failed to detect the imbalance. This case highlights the need to understand the various limitations and strengths of NIPT technology when counseling patients.

Due to the high mortality rate of CRC, screening programmes have been designed to screen the population for CRC prior to the onset of symptoms. The high burden of disease CRC causes has also made the field of CRC screening, diagnosis and treatment a prime area for the development of novel medical technology. Historically, these technologies have been limited to the fields of biochemical testing of stool and fiber optic visualization of the colon using the colonoscope. A new and exciting field for technology development is the application of molecular genetics in the profiling of colorectal tumours. Genetic profiling will allow clinicians to develop a personalized treatment plan for the administration of chemotherapeutic agents and biologics in the treatment of CRC. Personalized medicine has the potential to improve outcomes by selecting the chemotherapeutic agent that has the best likelihood of effectiveness for a given patient’s specific tumour. In order for this practice to become the standard of care, links between genetic profiles and chemotherapeutic effectiveness must be known and technolo gies for analysing the relevant gene profiles must be developed. The application of this technology to stage II CRC in particular is an active field of research. Currently, the five year survival rate for stage I CRC is approximate ly 93%. This survival rate falls to approximately 80% for patients with stage II disease. 3 The effectiveness of adjuvant chemotherapy for stage II CRC disease is currently an area of debate in the field of oncology. 4

The paradigm of medical resident duty hours is currently undergoing vast changes, as research has demonstrated the negative effects of sleep deprivation on the wellbeing of both patients and residents alike. These changes began in the United States, where reduced work hour schedules for residents have been implemented within the past decade. However, the effectiveness of these changes has been debated in the literature. In Canada, this issue has only recently come into spotlight. Under the guidance of the Royal College of Physicians and Surgeons of Canada, a task force was assembled in 2012 with two main objectives: gather all evidence related to resident duty hours, fatigue, and patient safety, and to create a national Canadian consensus on resident duty hours. In 1984, New York City was the setting of a new wave of thinking about residency training programs within the medical profession. That year, the death of Libby Zion, a lawyer’s daughter, initiated the Zion vs. New York Hospital case, which would have an indirect impact on international rules for resident work hours. Traditionally, it was not uncommon for residents to work up to 36 consecutive hours with minimal sleep, accumulating well over 100 hours of work in a week. Some considered this a rite of passage into the medical profession, while others saw it as a valuable learning tool. When the death of teenager Libby Zion was traced down to a medical error, more attention was drawn to the effect of sleep deprivation on residents’ performance on the wards. What effect does sleep deprivation have on residents? One review found that with acute sleep deprivation, residents showed decreased performance on tasks that required prolonged, vigilant concentration, but were resilient in performing brief, psychomotor tasks requiring manual dexterity and short-term recall.1 Furthermore, resident mood was affected, with increased anger, hostility, and symptoms of depression being noted – all factors that hinder the physician-patient relationship. In addition, one study found that extended shifts put residents’ safety at risk, by increasing the likelihood of reporting a motor vehicle accident after a call shift.2 A landmark study published in the New England Journal of Medicine compared two different work schedules head-to-head.3 The first schedule, considered “traditional,” had an average of 77-81 work hours per week with up to 34 hours of continuous work and 1 in 3 overnight call. The second, or “interventional” schedule, had 60-63 work hours per week maximum, 16 hours of continuous work maximum, and a day-call versus night-call designation, rather than a whole day of call. These schedules were randomized among internal medicine residents, and patient safety measures were prospectively followed. When researchers compared the traditional schedule and interventional schedule respectively, they found that residents made 35.9% more serious medical errors (136.0 vs. 100.1 per 1000 patient-days), 22.0% more total medical errors (193.2 vs. 158.4 per 1000 patient-days), 20.8% more serious medication errors (99.7 vs. 82.5 per 1000 patient-days), and 96.5% more serious diagnostic errors (21.6 vs. 11.0 per 1000 patient-days), while on the traditional schedule.3 In light of these findings, in 2003 the Accreditation Council for Graduate Medical Education (ACGME) in the United States instituted limits on resident work hours: 16 hours maximum for continuous shifts for PGY-1 (more hours allowed for seniors), 80 hours maximum per week, and 1 day off per week averaged over a 4-week period.4 Any residency program’s accreditation is endangered if their work protocols are not congruent with the ACGME. Unfortunately, data collected after these changes have shown mixed results as to the effectiveness of reduced hours. A systematic review of 7 studies (one of which was conducted after the 2003 ACGME changes) comparing reduced hour schedules with traditional schedules looked at mortality, adverse events, and medication errors as outcomes.5 The results showed that some outcomes improved, others declined, and still others showed no change. For example, mortality was largely unaffected by reduced hours, but medication errors were reduced.5 The authors emphasized a distinction between mortality outcomes, and task-based outcomes, the latter of which may be more susceptible to sleep deprivation. Although there were limitations within the studies in this review, such as the failure to measure baseline characteristics, the point is raised that reduced-hour schedules may not have the effects that were once anticipated. There may be negative consequences with reduced hour work schedules. Proponents of the traditional, long hour work schedules raise the argument that by reducing hours and increasing patient hand-over, an element of discontinuity is introduced which in itself may increase medical errors. In addition, fewer predictable hours may not prepare residents for independent practice, where hours are not limited and may be unpredictable. This may be reflected by an increase in the length of residency programs to allow for adequate clinical exposure. A survey of surgical residents in the United States found that many are unsatisfied with the reduced work-hour changes: 55.1% believed their education declined, and 68.4% felt they were not being prepared for senior roles.6 Although 61.9% of junior surgical residents had an increase in their quality of life, 54.4% of senior residents found a decline in their quality of life, likely due to seniors adopting the work that the juniors could not complete on their reduced hour schedules. Shockingly, 67.6% of surgical residents reported non-compliance with the work-hour limits, and 62.1% reported falsifying duty hours.6 In Canada, the resident association of each province has the daunting task of negotiating collective agreements for medical resTides of change The future of Canadian medical resident work hours Jouseph Barkho (Meds 2015) Faculty Reviewer: Dr. Catherine Yanchula, MD, CCFP, FCFP (Department of Family Medicine)

Animal bites, especially bites to the head, neck and face, are common injuries in children.1 It is estimated that in the pediatric population dog bites account for 0.3% to 1.5% of all presentations for medical care.1 Children are most likely to be bitten by a familiar dog at home and are frequently bitten due to a provoked attack.1-3 Appropriate adult supervision could prevent many of these bites from occurring.