An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP.

Valosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), which manifests as myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who harbor heterozygous VCP variants (12 de novo and 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or a multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performed in vitro functional studies and in silico modeling to investigate the impact of these variants on protein function. In contrast to MSP variants, most missense variants had decreased ATPase activity, and one caused hyperactivation. Other variants were predicted to cause haploinsufficiency, suggesting a loss-of-function mechanism. This cohort expands the spectrum of VCP-related disease to include neurodevelopmental disease presenting in childhood.

Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder.

Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.

Genetic counseling clinic model expansion: Impact on access for general genetics clinic.

Cincinnati Children's Hospital Medical Center (CCHMC) implemented a Genetic Counseling Clinic (GCC), where the appointment for a general genetics indication is conducted solely by a genetic counselor (GC). We conducted a retrospective chart review of 211 patient encounters scheduled in the GCC between January 1, 2022 and June 30, 2022 and collected patient demographics, wait time, appointment characteristics, referral indication, and clinical recommendations. To study impact on patient access, we compared patient demographics and appointment characteristics with 912 patient encounters scheduled in the General Genetics Clinic with a geneticist during the same time period. We found that there were not significant differences in patient demographics scheduled in the GCC as compared with the General Genetics Clinic with the exception of insurance type, where patients scheduled in the GCC were more likely to have private insurance. Patients scheduled in the GCC had a significantly shorter wait time, were more likely to complete their appointment, were more often new to the genetics division, and were more likely to be seen via telehealth (audio plus video or audio-only) as compared with patients scheduled in the General Genetics Clinic. The most common indications for patients scheduled in the GCC were post-test counseling (36.0%) followed by pre-test counseling and coordination of testing (22.3%), and first-line testing for autism, intellectual disability, and developmental delay (13.7%). Completed appointments in the GCC often resulted in the GC ordering genetic testing (67.5%). After genetic testing results were received, most patients (72.7%) did not require subsequent follow-up with the genetics division, thereby reducing burden to the medical genetics team. Our GCC increased access to genetic services and allowed GCs and clinical geneticists to better work at the top of their scope of practice.

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment.

VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.

The gendered pay gap in genetic counseling.

A gendered pay gap in the genetic counseling profession has been identified in recent years, though reasons for its existence have not been explored in depth. The primary aim of this study was to determine what demographic characteristics and career experiences influence annual salary rates and which of those factors differ between male and female genetic counselors. The secondary aim of this study was to determine whether genetic counselors perceive a pay gap and to identify attitudes toward their salaries. Surveys were sent to the nearly 4,000 genetic counselors who are members of the National Society of Genetic Counselors (NSGC), and we report results from 355 respondents. A significant interaction was found between gender and position (direct vs. non-direct patient care). In the best-fitting multiple regression model, male genetic counselors earned $23,736 more than females in non-direct patient care roles (p < .001) and $1,552 more than females in direct patient care roles (p < .001). Years of experience, leadership experience score, negotiation attempts, licensure, and certification were all found to be predictors of annual salary. Most female genetic counselors perceived there to be a pay gap and most male genetic counselors did not (p = .01). Results from this study could contribute to changes in employment and compensation practices, as well as impact genetic counselors' strategies in role- and salary-based conversations.

Investigation of the Use of a Family Health History Application in Genetic Counseling.

The paper-based pedigree is the current standard for family health history (FHH) documentation in genetic counseling. Several tools for electronic capture of family health data have been developed to improve re-use and accessibility, data quality and standardization, ease of updating, and integration with electronic medical records. One such tool, the tablet-based Proband application, provides a flexible approach to data capture in dynamic and diverse clinical settings. This study compared Proband FHH collection to paper-based methods and investigated the usability of Proband in a clinical setting. After one use by 23 genetic counselors and students, Proband had 91% accuracy with a FHH audio scenario, which was significantly less (p < 0.001) than paper's 96% accuracy. These differences were attributed to incorrect or missing ages of grandparents (p < 0.001) and great-aunts/uncles (p = 0.012) and missing documentation of consanguinity (p < 0.001). Possible explanations for these differences include greater experience with paper FHH documentation and pre-populated prompts for consanguinity on the paper template used. Proband's perceived usability increased with use, with individual System Usability Scores increasing between first and last use (p = 0.033). We conclude that tools for dynamic, provider-driven FHH documentation such as Proband show promise for improving risk assessment accuracy and quality patient care.

Posterior fossa anomalies diagnosed with fetal MRI: associated anomalies and neurodevelopmental outcomes.

OBJECTIVE: The purpose of this study was to describe the relationship between intracranial and extracranial anomalies and neurodevelopmental outcome for fetuses diagnosed with a posterior fossa anomaly (PFA) on fetal MRI. METHODS: Cases of Dandy-Walker malformation, vermian hypogenesis/hypoplasia, and mega cisterna magna (MCM) were identified through the Fetal Care Center of Cincinnati between January 2004 and December 2010. Parental interview and retrospective chart review were used to assess neurodevelopmental outcome. RESULTS: Posterior fossa anomalies were identified in 59 fetuses; 9 with Dandy-Walker malformation, 36 with vermian hypogenesis/hypoplasia, and 14 with MCM. Cases with isolated PFAs (14/59) had better outcomes than those with additional anomalies (p = 0.00016), with isolated cases of MCM all being neurodevelopmentally normal. Cases with additional intracranial anomalies had a worse outcome than those without intracranial anomalies (p = 0.00017). The presence of extracranial anomalies increased the likelihood of having a poor outcome (p = 0.00014) as did the identification of an abnormal brainstem (p = 0.00018). CONCLUSION: Intracranial and extracranial anomalies were good predictors of neurodevelopmental outcome in this study. The prognosis was poor for individuals with an abnormal brainstem, whereas those with isolated MCM had normal neurodevelopmental outcome.

Severe cervical scoliosis in the fetus.

OBJECTIVE: This study provides prenatal characteristics and postnatal outcomes of patients with severe cervical scoliosis. METHODS: A retrospective analysis of clinical information from cases prenatally diagnosed with severe cervical scoliosis (>90° angulation) in the Fetal Care Center at Cincinnati Children's Hospital Medical Center between 2007 and 2010 was performed. We excluded iniencephaly and tumors of the head or neck. RESULTS: We identified five patients with severe cervical scoliosis. The fetal spine abnormality was diagnosed between 18 and 27 weeks of gestation. Classical cesarean section was recommended in all patients. There were no immediate airway or neurological complications in the delivery room. Extravertebral anomalies were present in four of the five patients. These patients had a more complicated clinical course and three separate syndromes including a complex collagenopathy, heterotaxy, and Klippel-Feil syndrome were identified. One patient had an isolated cervical deformation secondary to a large uterine fibroid with a benign clinical course. None of the infants have required spinal surgery. CONCLUSION: Our patients suggest that connective tissue diseases or heterotaxy may be important risk factors for the development of severe cervical scoliosis. There were no significant long-term complications directly related to cervical scoliosis.

Pediatric Epilepsy Surgery: The Prognostic Value of Central Nervous System Comorbidities in Patients and their Families

Central nervous system comorbidities have been identified in patients with epilepsy. Several of these comorbidities have been correlated with poor surgery outcomes in patient cohorts. The authors sought to determine if prevalence of comorbidities in pediatric epilepsy surgery patients and their families correlate with long-term seizure outcome in a cross-sectional analysis. Three-generation pedigrees were elicited to compare family history of epilepsy, ADHD, anxiety, autism, bipolar disorder, cognitive disability, depression, migraine, and motor disability to surgery outcomes in 52 patients. Proportions of affected patients and relatives were compared to general population comorbidity rates and the patients' most recent seizure outcome classification. Patients and families had significantly higher rates of comorbidities than the general population. Poorer long-term seizure outcomes following resective surgery were associated with autism or cognitive disability in patients. Together these data support evidence for a common pathophysiological mechanism between epilepsy and central nervous system comorbidities.

Epilepsy prevalence and severity predictors in MRI-identified focal cortical dysplasia.

OBJECTIVES: To determine the prevalence of epilepsy and drug-resistant epilepsy in pediatric patients with focal cortical dysplasia (FCD) identified by magnetic resonance imaging (MRI). To determine clinical and imaging differences between those with drug-resistant epilepsy, drug-responsive epilepsy, and no epilepsy among children with MRI-identified FCD. METHODS: A keyword search of a hospital radiology database identified 97 study participants for inclusion in this retrospective study. Participants were included if they were under 18 years of age at time of database query and had an MRI between 2004 and 2013 showing FCD. Exclusion was based on imaging and clinical characteristics. Data was gathered using a chart review and supplemental questionnaire. RESULTS: In this cohort of patients with imaging findings compatible with FCD, 29% had not developed epilepsy. The prevalence of epilepsy and drug-resistant epilepsy was 71.13% (95% C.I.=61.05-79.89%) and 32.99% (95% C.I.=23.78-43.27%), respectively. Patients with epilepsy were more likely to have temporal (p=0.029) or frontal (p=0.044) lobe lesions and a family history of seizures (p=0.003) than those without epilepsy. Age of seizure onset was later in those with drug-responsive epilepsy than those with drug-resistant epilepsy (p=0.0002). A later age of seizure onset (OR=1.22, p=0.0441, 95% C.I.=1.00-1.486) and absence of developmental delay (OR=3.624, p=0.0497, 95% C.I.=1.002-13.110) predicted a less severe epilepsy phenotype. CONCLUSIONS: Previous studies have only assessed patient cohorts with FCD and epilepsy, limiting the data on "asymptomatic" or "atypically presenting" FCD. Identifying a surprisingly large, novel cohort of children with FCD that had not developed epilepsy helps define prognosis and inform clinical management of children with FCD on imaging.

The Clinical Utility of a Single-Nucleotide Polymorphism Microarray in Patients With Epilepsy at a Tertiary Medical Center.

Microarray testing has revolutionized clinical cytogenetics, as it provides a significantly higher resolution and greater clinical yield than karyotype analysis. This study assessed the clinical utility of single-nucleotide polymorphism microarray in patients with epilepsy. Study subjects were patients between the ages of birth to 23 years who were diagnosed with epilepsy and had a microarray performed at Cincinnati Children's Hospital Medical Center. Statistical analysis explored the association of microarray results and brain magnetic resonance imaging (MRI), seizure type, and structural malformations. Approximately 17.7% (26/147) of participants had an abnormal microarray as defined by laboratory guidelines. There were no differences in frequency of abnormal brain MRI or seizure type between the abnormal and normal microarray groups. There was a higher prevalence of musculoskeletal malformations (P < .0035) and cardiovascular malformations (P < .0081) in subjects with abnormal microarrays. Clinicians should consider microarray analysis in individuals who have epilepsy, especially in combination with musculoskeletal malformation or cardiovascular malformation.